1. Please check and comment entries here.
Table of Contents

    Topic review

    Phytochemicals in Prostate Cancer

    View times: 34
    Submitted by: Natália Cruz-Martins

    Definition

    Prostate cancer is a heterogeneous disease, the second deadliest malignancy in men and the most commonly diagnosed cancer among men. Traditional plants have been applied to handle various diseases and to develop new drugs. Medicinal plants are potential sources of natural bioactive compounds that include alkaloids, phenolic compounds, terpenes, and steroids. 

    1. Introduction

    1.1. A Brief Overview on Prostate Cancer

    The rapid growth of chronic diseases over the past century, including cancers, has emerged as among the most difficult situations for public health systems in underdeveloped and developing countries [1]. Cancer is one of the most prominent health issues in all countries due to its growing prevalence, mortality rate and high treatment cost in both genders and in all ages. In general, cancer remains not only a cause of tremendous damage to health but also the second leading cause of morbidity worldwide [2][3].
    Cancer is caused by uncontrolled cell proliferation that can take place in different tissues and spread into surrounding and distant tissues [4]. Despite the main progress made in cancer biology, cancer remains one of the principal causes of mortality, and those who survive can experience permanent complications (e.g., physical, cognitive, psychosocial struggles, and treatment side effects) [5][6]. It is of great concern to note that cancer is a widespread disease and diagnoses are sharply increasing globally. Many risk factors are mentioned for this rise and lifestyle changing play the most important role [7].
    Oncology studies have shown several types of cancer that are commonly diagnosed, including prostate, lung/bronchus, colorectal, breast, stomach, and liver cancer [8]. Although there is some variation in cancer prevalence, prostate cancer was the most commonly diagnosed cancer in the United States of America (USA), Europe and Oceania in 2012 [9]. In the past decade, much attention has been focused on prostate cancer [10] due to the alarming number of patients and the high mortality rate [11][12]. In fact, prostate cancer is the second most deadly malignancy in men after skin cancer [13]. Also, it is the most frequently diagnosed cancer among men, with a high mortality rate. About 1.6 million new cases of prostate cancer were diagnosed in 2015, and 366,000 deaths were reported [14]. In comparison to 2012, there was an increase of about 45% in incidence and 19% in mortality rate [15][16][17][18]. According to the American Cancer Society, the risk of cancer diagnosis in men in their lifetime is 1 in 9, and about 1 man in 41 will die due to prostate cancer [19].
    The prostate is a glandular organ found under the bladder composed of epithelial cells arranged in a fibromuscular stromal network [20]. Although it has been difficult to establish the definitive etiological clues linking prostate cancer development to incidence, several studies have consistently linked the disease with common risk factors, namely age, race, dietary and physical activity [8][21]. Prostate cancer incidence is, in essence, influenced by age since the risks of being diagnosed with it increases with age [22]. Apart from age and race, Attard et al. [10] have reported that family history, for example a first-degree relative (e.g., father, son, or brother) with prostate cancer has surfaced as the greatest risk factor. According to Pandey, et al. [23], either genetic or somatic mutations contribute 10% or less to the causes of prostate cancer, whilst the remaining 90% has been attributed to epigenetic changes such as lifestyle. However, it is evident that a process that associates risk factors with cancer is inflammation [24]. In order to understand the significant role of inflammation in cancer, it is important to unpack the physiological and pathological processes attributed to inflammation.
    Early detection of prostate cancer, like other malignancies, is important for better management and to prevent mortality and reduce morbidity rates, so many studies have been conducted to evaluate the risk of prostate cancer based on signs and symptoms [25]. Some of them have concentrated on lower urinary tract symptoms (LUTS) like hesitancy, nycturia, urinary retention and frequency, but almost all of them concluded that there are no signs and symptoms that are highly predictive of prostate cancer [26] and because it is vital for primary care providers and family physicians to suspect prostate cancer in patients who developed LUTS, it recommended that prostate-specific antigen (PSA) screening, but also digital rectal examination (DRE) should be performed for all of these patients and if any abnormalities detected, patients should be referred to urologists for complementary work-up and distinguishing between prostate cancer and benign prostatic hyperplasia [27][28].
    PSA measurement was introduced in 1987 to verify the response to prostate cancer treatment, but was soon adopted for prostate cancer screening too [29][30] and after widespread use of PSA as a screening test, a dramatic rise in incidence was reported from 1989 to 1992 and from 1995 this rise continued with a slight slope until 2001 and after that has fluctuated year to year revealing changes in screening practices [31]. After prostate cancer screening with PSA started in 1991 mortalities have declined and this may be due to early detection and proper management of patients [32]. The cut-off point of 4.0 ng/mL was considered for PSA screening and studies have shown that with this threshold the negative predictive value of PSA for detecting prostate cancer is 89% in men with a median age of 69 years [33], so patients with PSA levels >4 ng/mL in two tests should undergo other work-up like prostate biopsy, multiparametric MRI [34] and whole body bone scans [35]. On the other hand, PSA is not entirely specific for prostate cancer, and other conditions, such as prostatitis, urinary tract infection (UTI), older age, benign prostate hyperplasia (BPH) and bicycle riding can cause elevations in PSA levels, and some medications, like 5α-reductase inhibitors, aspirin, thiazide and statins cause decreases in PSA levels [13][36]. Furthermore, most prostate cancers are not harmful if not diagnosed and treated, and using PSA for diagnosis for prostate cancer results in over-diagnosis and over- treatment, so nowadays there is a vigorous debate about the usefulness of PSA screening for early detection of prostate cancer [37][38]. As a result, researchers have introduced other biomarkers for prostate cancer, such as free PSA, human kallikerin 2, prostate cancer antigen 3, prostate-specific membrane antigen, etc. [39] to better diagnose prostate cancer and avoid over-diagnosis and over- treatment, but there is a public consensus that with evaluation of patient risk factors, physicians can separate high-risk patients and focus on them to not miss any significant cancer, in addition, to decline over-treatment and diagnosis [14][40].
    Prostate cancer is a heterogeneous disease, so to anticipate the behavior of cancer, evaluating risk factors is very important [41]. Epidemiological studies have consistently emphasized the notion that naturally-occurring dietary agents possess chemopreventive properties and could easily suppress several malignancies, including that of the prostate [15]. However, there has been an inconsistency regarding a recommended plant-based diet, related nutrients, phytochemicals and prostate health [42].

    1.2. Prostate Cancer: Main Risk Factors

    The main risk factors can be stratified into two groups: non-modified and modified factors. Non-modified factors are age, family history, ethnicity, and genetic factors [40].

    1.2.1. Non-Modified Risk Factors

    Age: Before 40 years of age, mens’ risk of developing prostate cancer is low. On the other hand, men older than 55 years of age have 17 times more risk of developing prostate cancer than men <55 years old [43]. The mean age when prostate cancer is detected in the United States is 66 years old [44].
    Ethnicity: Incidence (60%) and mortality rate (2.4 times) of prostate cancer in African-American men is higher than for other races, and Hispanic men, Asian/Pacific Islanders, American Indian/Alaskan Natives are in lower risk of developing prostate cancer [44] and it has been shown that prostate cancer incidence in men who immigrate to regions with higher prevalence rate, is higher than men in their country of origin and this increase depends on the length of stay in that area [45][46].
    Family and genetic factors: Patients with a positive prostate cancer family history have a higher risk of having this disorder than others, especially a positive history among first degree relatives and in multiple relatives and under 65 years old [47]. Until now more than 105 loci show that increased risk of prostate cancer have been identified, suggesting about 30% of heritability [48][49]. Table 1 showed the relative risk of a family history of prostate cancer [47][50].
    Table 1. Relative risk of prostate cancer in patients with a positive family history.

    Risk Group

    Relative Risk of Prostate Cancer

    Father and brother had prostate cancer

    9

    ≥2 first degree relatives having prostate cancer

    4.39

    Brothers having prostate cancer

    3.14

    First degree relative with prostate cancer at the age of<65

    2.87

    Second degree relative with prostate cancer

    2.52

    One first degree relative with prostate cancer

    2.48

    Father having prostate cancer

    2.35

    First degree relative with prostate cancer at the age of ≥65

    1.92

    Height: Another factor that increases prostate cancer risk is height. Taller men are in greater risk of progressive prostate cancer, not total prostate cancer [51] and an overall relative risk of 1.19 has been estimated for prostate cancer per 10 cm increase in height [52].

    1.2.2. Modified Risk Factors

    Obesity: There is no clear relationship between obesity (body mass index (BMI) >25 kg/m2 [53]) and increased risk of prostate cancer, but it is proven that obese men are at higher risk of advanced prostate cancer and biochemical recurrence [54][55], and also recent studies showed that risk of recurrence in patients who have weight gain after radical prostatectomy (RP) is higher [56]. Risk of advanced prostate cancer is six times higher than for non-obese men [43] and the risk of mortality increases by 20% for every 5 kg/m2 increase in BMI [54]. The importance of this issue is highlighted by the fact that we know that the world’s obese population has at least doubled since 1980 [57] and this can be due to lifestyle changes of patients that have resulted in lower physical activity and higher fat and red meat intake. Physical activity, especially vigorous activity, decreases prostate cancer risk, advance prostate cancer, mortality and recurrence of prostate cancer, and increases survival and it has been shown that physical activity for at least 3 h/week, even jugging and brisk walking, decreases cancer-specific mortality rate [58][59][60]. On the other hand, an inactive lifestyle has been related to higher PSA [60]. Many studies have revealed that higher intakes of fat, red meat, and dairy foods increase the risk of prostate cancer, but it is not proven yet. Dairy products contain a lot of fat and calcium, and high consumption of calcium increases the risk of prostate cancer, and this is probably due to disturbance of the metabolism of vitamin D [61], but non-dairy calcium intake does not change prostate cancer risk [62]. A 2012 study showed that high amounts of red meat and dairy foods elevate the prostate cancer risk 12-fold [63], and there is no specific amount for daily calcium intake, but some studies revealed that consumption of calcium >2000 mg/day raises the risk of prostate cancer [64].
    Infectious disease: Infections and chronic inflammation leading to cellular damage and hyperproliferation cause 16% of worldwide malignancies [65] and some studies have revealed that UTI, sexually transmitted diseases and prostatitis could cause the development of prostate cancer via this mechanism, but it is uncertain [40][66]. At present, no specific infectious agent has been proven to cause prostate cancer. However, some evidence for the role of Trichomonas vaginalis in prostate cancer has been shown [67].
    Occupational and external exposure: some jobs have a higher risk of prostate cancer due to exposure to specific materials, for example farmers who are exposed to pesticides and other chemical materials have a two times higher risk of prostate cancer [18][68] and also higher exposure to sunlight due to UV and ionizing radiation is related to an increased risk of prostate cancer [69][70].
    Smoking: Cigarette smokers have a higher probability of developing prostate cancer, including advanced and hormone resistant forms, spreading metastasis and higher mortality rates and it depends on the amount (pack/year) and duration of smoking and it showed that the risk of mortality and recurrence of prostate cancer in former smoker patients, who quit smoking 10 years before diagnosing prostate cancer is similar to that of non-smoking patients [58]. Some researchers are interested in the association among prostate cancer and alcohol intake, and many studies on this topic have been done, but mixed results were obtained, although one case-control study revealed that heavy drinkers have lower PSA levels and are in higher risk of advanced disease at detection [71][72].
    Endogenous hormones: Androgens cause the proliferation and differentiation of the luminal epithelium of the prostate and play a key role in prostate carcinogenesis and establishing cancer, and because of these facts many patients respond to androgen deprivation treatment. For a long time, researchers believed that high serum androgen level was a risk factor of prostate cancer, but the last pooled analysis could not find any link between prostate cancer and serum androgen levels, but it found a connection among sex-hormone-binding globulin serum concentration and cancer risk [73]. Previously estrogens were a choice of treatment in castration-resistant prostate cancer and have been considered as a protective agent for cancer, but recently more studies have presented evidence for a pro-carcinogenic effect of estrogen on prostate cancer and shown that early exposure to estrogens increases the risk of later prostate cancer [74][75]. A pooled analysis in 2008 showed a strong connection between insulin-like growth factor-I and the risk of prostate cancer [76], but epidemiologic studies reviewed in 2011 revealed mixed findings, although they suggested that the insulin-like growth factor axis affects cancer progression rather than initiation [77]. The core genetic changes that cause activation of oncogenes and inactivation of tumor suppressors are responsible for the start and progression of prostate cancer, and epigenetic and structural genomic changes like deletion, chromosomal rearrangement, and amplification that result in gene fusion with new biologic functions are responsible for these changes. Chromatin remodeling, hypomethylation and promotor methylation that cause epigenetic regulation of gene expression play a significant part in the development and evolution of prostate cancer. Androgen receptors (AR) play a key role in prostate cancer, and changes in ARs like amplification, mutations, and ligand promiscuity are determining factors in progressive castrate-resistant prostate malignancies because these changes sensitize the ARs to low levels of intra-tumoral androgen [78]. The basic drivers for the initiation of prostate cancer are based on gene fusions of TMPRSS2 and the ETS family oncogenic transcription factors [79].

    2. Therapeutic Strategies: A Brief Summary

    To properly treat prostate cancer, patients should undergo full evaluation, including DRE, checking PSA and LFT, life expectancy and comorbidity evaluation, abdominal-pelvic CT, MRI and radionuclide bone scans if needed, and based on these data and characterizations of tumor (Table 2), including clinical stage, Gleason score, tumor volume, invasion and metastasis, patients are stratified into low, intermediate, high and very high risk groups and the cancer divided to localized, locally advance and metastatic prostate cancer [80][81][82].
    Table 2. Classification of the risk groups of prostate cancer [83].

    Risk Group

    Clinical Stage

    PSA (ng/mL)

    Gleason Score

    Biopsy Criteria

    Low

    T1a or T1c

    <10

    2–6

    Unilateral or <50% of core involved

    Intermediate

    T1b, T1c, or T2a

    <10

    3 + 4 = 7

    Bilateral

    High

    T1b, T1c, T2b, or T3

    10–20

    4 + 3 = 7

    >50% of core involved or perineural invasion or ductal differentiation

    Very high

    T4

    >20

    8–10

    Lymphovascular invasion or neuroendocrine differentiation

    There are some established options for treating prostate cancer, like watchful waiting (WW), active surveillance (AS), radiation therapy (RT), hormone therapy (HT), and radical prostatectomy (RP) [80]. The goal of conservative management (AS, WW) is to reduce over-treatment [81]. In WW, patients are followed until new symptoms appear or get worse [80], so WW is suitable for poor prognosis patients with low life expectancy [81]. AS is suitable for low-risk prostate cancer or patients with <5 years life expectancy and in AS, physicians monitor patients closely and some periodic work- ups like DRE, PSA checking, prostate biopsy, and MRI are done, and every time the evidence is in favor of cancer progression, patients then become candidates for other definite treatments [80][84]. RP is the first option introduced for treating prostate cancer [85], and it remains a typical form of management because it is the only method that cures the prostate cancer and the goal of RP is to eradicate cancer while conserving urinary continence and if possible potency [81]. Patients with intermediate and high-risk prostate cancer and life expectancy > 5 years are good candidates for RP, and RT is an option for managing almost all prostate cancer groups alone or with another modality, except got low and intermediate risk prostate cancer patients with low life expectancy (<5 years) [84]. RT and RP are the most common methods for managing prostate cancer, and so far, no study has establish the superiority of one of these two methods over the other and complications in both methods are common, and also there are no significant differences between the survival rates of these two methods [80]. There are different approaches for RP, including perineal, retropubic, laparoscopic and robotic, but until now there is no clear evidence that any one of this methods is better than the others in cancer control, cancer-related urinary continence and erectile function conservation, although some poorly designed studies have revealed that robot-assisted RP is better than laparoscopic methods in reducing positive surgical margins [86]. The most popular methods for RT that could be accompanied with HT are external beam radiotherapy and brachytherapy that have side effects like rectal and bladder toxicity and these side effects are more common in external beam radiotherapy. Other treatments like cryoablation and high-intensity focused ultrasound ablation have been introduced, but there is no proof to support their superiority [83][87]. Finally, physicians should choose the proper treatment based on tumor characterization and the patient’s condition after the acceptance of the patient [88].
    Many prostate cancer patients have more progressive disease, and management of these patients is different. In patients with symptomatic non-metastatic prostate cancer who are not candidates for curative treatment and patients with symptomatic metastatic prostate cancer, androgen deprivation therapy (ADT) is an option for palliative therapy, but we should not use ADT on patients with asymptomatic locally advanced prostate cancer or biochemical recurrence after curative therapy [82][89]. There are several methods for ADT. The gold standard is bilateral orchiectomy that diminishes the testosterone level below 15 ng/dL on average [90] but this has some disadvantages like irreversibility, physical and psychological pressure on the patients, so HT was introduced [91]. Luteinizing hormone-releasing hormone (LH-RH) agonists (leuprolide, goserelin, triptorelin) and antagonists (degarelix, abiraterone), non-steroidal antiandrogens (bicalutamide, flutamide, nilutamide) are three major drug categories used for ADT with LH-RH agonists being more prevalent, but the risk of flare phenomena is lower when using a LH-RH antagonist [91][92]. Intermittent or continuous ADT are two separate methods for managing systemic prostate cancer, but there is no difference between overall survival and cancer-specific survival of these two methods [82].
    It is likely that after any curative management patients eventually relapse, that includes rising PSA or nodal involvement. If patients develop rising PSA after RP, the European Association of Urology guidelines advise early salvage radiotherapy (SRT) [82] and some retrospective studies have revealed that adding ADT to early SRT had some benefits in biochemical progression-free survival after 5 years [93]. In patients with PSA relapsing after RT, salvage RP is the first choice for local control of cancer. Salvage RP increases the risk of anastomotic stricture, urinary incontinence, erectile dysfunction, and rectal injury, so other alternative methods are available, like salvage cryoablation, high and low dose rates brachytherapy [82][94]. For management of nodal relapse, surgical and salvage lymph node dissection (LND) is the only choice. There are no specific criteria for candidate patients for salvage LND, but this should be considered and this method should be used for highly selected patients [82][95].
    As we said, patients with the progressive disease can be managed with ADT, but some of these patients develop castration resistance, that is, castrated serum testosterone is less than 50 ng/dL, and the patient has biochemical or radiologic progression [96]. First-line treatment for this situation is abiraterone, enzalutamide or docetaxel (DX)-based chemotherapy and second-line treatment options depend on the chosen first-line treatment. If the patient was treated with abiraterone or enzalutamide as first-line treatment, DX-based chemotherapy is the next option and vice versa. If DX-based chemotherapy was used first and the patient responded, we can repeat this chemotherapy regimen again, but there is usually no improvement in the survival of patients [82][97]. Most of these patients developed with painful bone metastasis, but external-beam radiotherapy is very effective in relieving pain [98]. Finally, it is important to say that managing these patients needs teamwork, and the urologist, oncologist, psychologist, nurse, and even social workers should work together to manage patients properly [99].
    Prostate cancer, like the other cancers, is an expensive disease and imposes a great burden on both the health system and patients, and these expenditures are increasing year by year which may due to over-treatment, over work-up or over-diagnosis and increased survival [100]. In 2010, the budget expended for prostate cancer care in the United States was 11.8 billion dollars, and in 2013 and 2017 this budget was $13.0 and $14.8 billion, respectively [101]. In Iran, direct medical costs for prostate cancer were estimated at about 12.5 million USD in 2016 for about 500 patients [102] and the cost for metastatic castration-resistant prostate cancer in Italy in 2016 ranged from €196.5–228.0 million [103]. These cost variations may be due to differences in incidence and management protocols between countries [100], and most of these monies were expended for treatment [103], so having preventive strategies and using natural products for managing prostate cancer patients it is possible to markedly decrease the economic burden of this disease.

    3. Plant Extracts and Plant-Derived Bioactives in Prostate Cancer

    Traditional plants have been used to treat and cure various diseases [104], and this has led to increased use of medicinal plants in the search for new drugs from nature [105]. The discovery of new drugs is often established based on the knowledge that plant extracts can be used to treat diseases in humans. The plants are potential sources of natural bioactive compounds that are, but not limited to, secondary metabolites [106]. Cragg and Newman [107] have stated that any part of a plant such as leaves, bark, flowers, and seeds may contain these secondary metabolites. Although little is known of the primary processes of the secondary metabolites in plants, Bodeker [108] reported that secondary metabolites are essential and important in plant use by people. In this regard, herbal medicines, which have been increasingly used in cancer treatment, represent a rich pool of new and bioactive chemical entities for the development of chemotherapeutic agents with many exhibiting favorable side effect and toxicity profiles compared to conventional chemotherapeutic agents [6][109]. In this sense, in the following section the plant extracts and corresponding bioactive constituents with anti-prostate cancer potential are carefully described. Lastly, a special emphasis on clinical studies confirming the plant-derived phytochemicals anti-prostate cancer potential is also given.

    3.1. Plant Extracts with Anti-Prostate Cancer Potential

    Among the plant extracts with anti-prostate cancer potential (Table 3), the most remarkable ones belong to the Annonaceae, Apocynaceae, Asteraceae, Combretaceae, Euphorbiaceae, Fabaceae, Lamiaceae, Malvaceae, Phyllantheraceae, Poaceae, Rutaceae, Solanaceae and Zingiberaceae families (Figure 1).
    Figure 1. Plant species with anti-prostate cancer potential and its respective modes of action.
    Table 3. Medicinal plants with anti-prostate cancer effects.

    Plant Species

    Family

    In Vitro

    In Vivo

    References

    Acacia catechu

    Fabaceae

    +

    -

    [110]

    Achillea santolinoides

    Asteraceae

    +

    -

    [111]

    Achillea teretifolia

    Asteraceae

    +

    -

    [112]

    Allium wallichii

    Amaryllidaceae

    +

    -

    [113]

    Aloe perryi

    Xanthorrhoeaceae

    +

    -

    [114]

    Anaxagorea brevipes

    Annonaceae

    +

    -

    [115]

    Angelica gigas

    Apiaceae

    -

    +

    [116][117]

    Annona muricata

    Annonaceae

    +

    -

    [118]

    Anogeissus latifolia

    Combretaceae

    +

    -

    [110]

    Apocynum venetum

    Apocynaceae

    +

    -

    [119]

    Arachis hypogaea

    Fabaceae

    +

    -

    [120]

    Baliospermum montanum

    Euphorbiaceae

    +

    +

    [121]

    Berberis libanotica

    Berberidaceae

    +

    -

    [122]

    Byrsonima crassifolia

    Malpighiaceae

    +

    -

    [123]

    Calliandra portoricensis

    Fabaceae

    +

    -

    [124]

    Capsicum chinense

    Solanaceae

    +

    -

    [123]

    Carica papaya

    Caricaceae

    +

    -

    [125]

    Cascabela peruviana

    Apocynaceae

    +

    -

    [126]

    Chenopodium hybridum

    Amaranthaceae

    +

    -

    [127]

    Cnidoscolus chayamansa

    Euphorbiaceae

    +

    -

    [123]

    Cornus mas

    Cornaceae

    +

    -

    [128]

    Costus pulverulentus

    Costaceae

    +

    -

    [129]

    Crataegus Pinnatifida

    Rosaceae

    +

    -

    [130]

    Crocus sativus

    Iridaceae

    +

    +

    [131][132][133]

    Curcuma longa

    Zingiberaceae

    +

    -

    [131][134]

    Cymbopogon citratus

    Poaceae

    +

    -

    [135]

    Cymbopogon giganteus

    Poaceae

    +

    -

    [135]

    Euphorbia microsciadia

    Euphorbiaceae

    +

    -

    [111]

    Euphorbia szovitsii

    Euphorbiaceae

    +

    -

    [111]

    Eurycoma longifolia

    Simaroubaceae

    +

    +

    [136]

    Fagara zanthoxyloides

    Rutaceae

    +

    -

    [137]

    Fagopyrum esculentum

    Polygonaceae

    +

    -

    [138]

    Fagopyrum tataricum

    Polygonaceae

    +

    -

    [138]

    Ficus deltoidea var. angustifolia

    Moraceae

    +

    -

    [139]

    Ficus deltoidea var. deltoidea

    Moraceae

    +

    -

    [139]

    Formosa lambsquarters

    Amaranthaceae

    +

    -

    [138]

    Glycine max

    Fabaceae

    +

    -

    [140]

    Glycyrrhiza uralensis

    Fabaceae

    +

    -

    [141]

    Haplophyllum perforatum

    Rutaceae

    +

    -

    [111]

    Helicteres hirsuta

    Malvaceae

    +

    -

    [142]

    Hertia angustifolia

    Asteraceae

    +

    -

    [111]

    Hibiscus sabdariffa

    Malvaceae

    +

    +

    [143]

    Leucaena leucocephala

    Fabaceae

    +

    -

    [123]

    Lysimachia ciliata

    Primulaceae

    +

    -

    [144]

    Malmea depressa

    Annonaceae

    +

    -

    [123]

    Maytenus royleana

    Celastraceae

    +

    +

    [145]

    Medicago sativa

    Fabaceae

    +

    -

    [111]

    Melissa officinalis

    Lamiaceae

    +

    -

    [146][147]

    Mentha arvensis

    Lamiaceae

    +

    -

    [148]

    Mentha spicata

    Lamiaceae

    +

    -

    [148]

    Mentha viridis

    Lamiaceae

    +

    -

    [148]

    Moringa oleifera

    Moringaceae

    +

    -

    [110]

    Nepeta cataria

    Lamiaceae

    +

    -

    [149]

    Nigella sativa

    Ranunculaceae

    +

    -

    [131][150]

    Oryza sativa

    Poaceae

    +

    -

    [151]

    Paeonia lactiflora

    Paeoniaceae

    +

    -

    [152].

    Paramignya trimera

    Rutaceae

    +

    -

    [153]

    Phyllanthus amarus

    Phyllanthaceae

    +

    -

    [154]

    Phyllanthus niruri

    Phyllanthaceae

    +

    -

    [154]

    Phyllanthus urinaria

    Phyllanthaceae

    +

    -

    [154]

    Phyllanthus watsonii

    Phyllanthaceae

    +

    -

    [154]

    Plumbago zeylanica

    Plumbaginaceae

    +

    -

    [155]

    Polygonatum sp

    Asparagaceae

    +

    -

    [156]

    Pseudocedrela kotchyi

    Meliaceae

    +

    -

    [137]

    Psidium guajava

    Myrtaceae

    +

    +

    [138][157][158]

    Punica granatum

    Lythraceae

    +

    +

    [5][159][160][161]

    Quisqualis indica

    Combretaceae

    +

    +

    [162]

    Remotiflori radix

    Campanulaceae

    +

    +

    [163]

    Salvia multicaulis Vahl

    Lamiaceae

    +

    -

    [111]

    Salvia trilobal

    Lamiaceae

    +

    -

    [164]

    Sigesbeckia orientalis

    Asteraceae

    +

    -

    [165]

    Sophora alopecuroides

    Fabaceae

    +

    -

    [111]

    Sutherlandia frutescens

    Fabaceae

    +

    +

    [166]

    Terminalia bellerica

    Combretaceae

    +

    -

    [110]

    Terminalia catappa

    Combretaceae

    +

    -

    [123]

    Urtica dioica

    Urticaceae

    +

    -

    [111][167]

    Vitis rotundifolia

    Vitaceae

    +

    -

    [168]

    Wedelia chinensis

    Asteraceae

    -

    +

    [169][170]

    Withania coagulans

    Solanaceae

    -

    +

    [171]

    Xylopia aethiopica

    Annonaceae

    +

    -

    [172]

    Zanthoxyli fructus

    Rutaceae

    +

    +

    [173]

    Zingiber officinale

    Zingiberaceae

    +

    +

    [131][174][175]

    +: Showed in vitro or in vivo antiproliferative effect; -: Not found.

    3.2. Plant-Derived Bioactives with Anti-Prostate Cancer Potential

    Many classes of metabolites isolated from medicinal plants have been reported for their activity against prostate cancer, namely alkaloids, phenolic compounds, and terpenoids (Table 4).
    Table 4. Plant derived-compounds with anti-prostate cancer effects.

    Bioactive Compounds

    In Vitro

    In Vivo

    References

    Alkaloids

         

    (−)-Anonaine

    +

    -

    [176]

    (−)-Caaverine

    +

    -

    [176]

    (−)-Nuciferine

    +

    -

    [176]

    6-Hydroxycrinamine

    +

    -

    [177]

    7-Hydroxydehydronuciferine

    +

    -

    [176]

    Capsaicin

    +

    -

    [178]

    Crinamine

    +

    -

    [177]

    Emetine

    +

    +

    [179][180]

    Liriodenine

    +

    -

    [176]

    Lycorine

    +

    +

    [177][181]

    Matrine

    +

    -

    [182]

    Oxymatrine

    +

    -

    [182]

    Oxysophocarpine

    +

    -

    [182]

    Schisanspheninal A

    +

    -

    [183]

    Sophocarpine

    +

    -

    [182]

    Tetrandrine

    +

    -

    [184]

    Carotenoids

         

    Crocetin

    +

    -

    [133]

    Crocin

    +

    -

    [132]

    Fatty acid

         

    (E)-ethyl 8-methylnon-6-enoate

    +

    -

    [123]

    Phenolic compounds

         

    α-Mangostin

    +

    +

    [185].

    γ-Tocopherol

    +

    -

    [186]

    δ-Tocotrienol

    +

    -

    [186]

    (-)-5,7-Difluoroepicatechin-3-O-gallate

    +

    -

    [187]

    (-)-Epicatechin-3-O-gallate

    +

    -

    [187]

    10-Gingerol

    +

    -

    [175]

    6-Gingerol

    +

    -

    [175]

    6-Prenylnaringenin

    +

    -

    [188]

    6-Shogoal

    +

    -

    [175]

    7-o-Galloyl catechin

    +

    -

    [189]

    8-Gingerol

    +

    -

    [175]

    8-Prenylnaringenin

    +

    -

    [188]

    Afzelin

    +

    -

    [190]

    Altholactone

    +

    -

    [191]

    Apigenin

     

    +

    [192]

    Camptothin B

    +

    -

    [141]

    Catechin

    +

    -

    [189]

    Catechin-3-o-gallate

    +

    -

    [189]

    Chlorogenic acid

    +

    -

    [130]

    Chrysin

    +

    -

    [193]

    Cinnamaldehyde

    +

    -

    [194]

    Cornusiin A

    +

    -

    [141]

    Cornusiin H

    +

    -

    [141]

    Curcumin

    +

    +

    [195][196][197][198]

    Decursin

    +

    -

    [117]

    Decursinol angelate

    +

    -

    [117]

    Dehydrozingerone

    +

    -

    [199]

    Delphinidin

    +

    +

    [200][201]

    Ellagic acid

    +

    +

    [202][203]

    Eugenol

    +

    -

    [194]

    Fisetin

    +

    +

    [204]

    Flavokawain A

    +

    +

    [205]

    Flavopiridol

    +

    +

    [206]

    Garcinol

    +

    +

    [207][208]

    Ginkgetin

    +

    +

    [209]

    Hesperetin

    +

    -

    [210]

    Hirsutenone

    +

    -

    [211]

    HLBT-100 or HLBT-001 (5,3′-dihydroxy- 6,7,8,4′-tetramethoxyflavanone)

    +

    -

    [212]

    Honokiol

    +

    -

    [213]

    Icarisid II

    +

    -

    [214]

    Isoangustone A

    +

    -

    [215][216]

    Isovitexin

    +

    -

    [139]

    Juglone

    +

    -

    [217]

    Licoricidin

    +

    -

    [215][216]

    Magnolol

    +

    -

    [218]

    Mangiferin

    +

    +

    [219][220]

    Maysin

    +

    -

    [221]

    Methyl gallate

    +

    -

    [189]

    Osthol

    +

    -

    [4][222]

    Oxyfadichalcones A

    +

    -

    [223]

    Oxyfadichalcones B

    +

    -

    [223]

    Oxyfadichalcones C

    +

    -

    [223]

    Oxyfadichalcones D

    +

    -

    [223]

    Oxyfadichalcones E

    +

    -

    [223]

    Oxyfadichalcones F

    +

    -

    [223]

    Oxyfadichalcones G

    +

    -

    [223]

    Paeonol

    +

    +

    [224]

    Peperotetraphin

    +

    -

    [225]

    Physangulatins I

    +

    -

    [226]

    Plumbagin

    +

    +

    [155][227]

    Punicalagin

    +

    -

    [228]

    Quercetin

    +

    +

    [229][230][231]

    Resveratrol

    +

    +

    [232][233][234]

    Rutin

    +

    -

    [235]

    Tannic acid

    +

    -

    [236]

    Tricin

    +

    -

    [237]

    Xanthohumol

    +

    -

    [182][238]

    Protein

         

    Agglutinin

    +

    +

    [239]

    Diffusa cyclotide 1

    +

    -

    [240]

    Diffusa cyclotide 2

    +

    -

    [240]

    Diffusa cyclotide 3

    +

    +

    [240]

    Lectin ConBr

    +

    -

    [241]

    Lectin ConM

    +

    -

    [241]

    Lectin DLasiL

    +

    -

    [241]

    Lectin DSclerL

    +

    -

    [241]

    Terpenoids

         

    α-Santalol

    +

    +

    [242]

    4S,5R,9S,10R-Labdatrien-6,19-olide

    +

    -

    [243]

    (20R)-Dammarane-3β,12β,20,25-tetrol (25-OH-PPD)

    +

    +

    [244]

    Andrographolide

    +

    +

    [245]

    Celastrol

    +

    +

    [246]

    Citral

    +

    -

    [135]

    Diosgenin

    +

    -

    [247].

    Euphol

    +

    -

    [248]

    Isocuparenal

    +

    -

    [183]

    Jungermannenone A

    +

    -

    [249]

    Jungermannenone B

    +

    -

    [249]

    Muricins M

    +

    -

    [250]

    Muricins N

    +

    -

    [250]

    Nummularic acid

    +

    -

    [251]

    Oenotheralanosterol B

    +

    -

    [252]

    Plectranthoic acid

    +

    -

    [253]

    Sutherlandioside D

    +

    -

    [166].

    Widdaranal A

     

    -

    [183]

    Widdaranal B

    +

    -

    [183]

    Widdarol peroxide

    +

    -

    [183]

    Withaferin A

    +

    -

    [254]

    -, no effect observed; +, positive effect.

    4. Evidence from Clinical Studies

    Prostate cancer patients are progressively using complementary and alternative medicines in order to support the immune system in addition to conventional treatments (Table 5). This minimizes morbidity related to conventional treatments, enhances the quality of life, eventually, in the hope of finding a cure when conventional treatment fails [255].
    Table 5. Clinical trials showing the anti-prostate cancer potential of plant-derived phytochemicals.

    Phytochemicals/Formulae

    Bioactive Effect

    Reference

    Danshen (Salvia miltiorrhiza)

    Protective effects; Improved survival (5–10%)

    [256]

    TCM formulae (Chai-Hu-Jia-Long-Gu-Mu-Li-Tang)

    Improved survival

    [257]

    Pomegranate juice

    Extension of PSA doubling time, with no adverse effects

    [258][259][260]

    Pomegranate, green tea, broccoli, turmeric

    Decreased PSA levels

    [261]

    Resveratrol

    Decreased the circulating levels of androgen precursors

    [262]

     

    Extension of PSA doubling time, with no adverse effects

    [263]

    PC-SPEC

    Decreased PSA levels

    [264]

    The entry is from 10.3390/nu11071483

    References

    1. Etemadi, A.; Sadjadi, A.; Semnani, S.; Nouraie, S.M.; Khademi, H.; Bahadori, M. Cancer registry in Iran: A brief overview. Arch. Iran. Med. 2008, 11, 577–580.
    2. Casey, S.C.; Amedei, A.; Aquilano, K.; Azmi, A.S.; Benencia, F.; Bhakta, D.; Bilsland, A.E.; Boosani, C.S.; Chen, S.; Ciriolo, M.R.; et al. Cancer prevention and therapy through the modulation of the tumor microenvironment. Semin. Cancer Biol. 2015, 35, S199–S223.
    3. Siegel, R.L.; Fedewa, S.A.; Miller, K.D.; Goding-Sauer, A.; Pinheiro, P.S.; Martinez-Tyson, D.; Jemal, A. Cancer statistics for hispanics/latinos, 2015. CA Cancer J. Clin. 2015, 65, 457–480.
    4. Shokoohinia, Y.; Jafari, F.; Mohammadi, Z.; Bazvandi, L.; Hosseinzadeh, L.; Chow, N.; Bhattacharyya, P.; Farzaei, M.H.; Farooqi, A.A.; Nabavi, S.M.; et al. Potential anticancer properties of osthol: A comprehensive mechanistic review. Nutrients 2018, 10, 36.
    5. Sharma, P.; McClees, S.F.; Afaq, F. Pomegranate for prevention and treatment of cancer: An update. Molecules 2017, 22, 177.
    6. Novio, S.; Cartea, M.E.; Soengas, P.; Freire-Garabal, M.; Nunez-Iglesias, M.J. Effects of Brassicaceae isothiocyanates on prostate cancer. Molecules 2016, 21, 626.
    7. Torre, L.A.; Siegel, R.L.; Ward, E.M.; Jemal, A. Global cancer incidence and mortality rates and trends—An update. Cancer Epidemiol. Prev. Biomark. 2015, 25, 16–27.
    8. Giovannucci, E.; Harlan, D.M.; Archer, M.C.; Bergenstal, R.M.; Gapstur, S.M.; Habel, L.A.; Pollak, M.; Regensteiner, J.G.; Yee, D. Diabetes and cancer: A consensus report. CA Cancer J. Clin. 2010, 60, 207–221.
    9. Ferlay, J.; Soerjomataram, I.; Ervik, M.; Dikshit, R.; Eser, S.; Mathers, C.; Rebelo, M.; Parkin, D.; Forman, D.; Bray, F. Globocan 2012 v1.0, Cancer Incidence and Mortality Worldwide: Iarc Cancerbase No. 11; International Agency for Research on Cancer: Lyon, France, 2015.
    10. Attard, G.; Parker, C.; Eeles, R.A.; Schroder, F.; Tomlins, S.A.; Tannock, I.; Drake, C.G.; de Bono, J.S. Prostate cancer. Lancet 2016, 387, 70–82.
    11. Klotz, L.; Vesprini, D.; Sethukavalan, P.; Jethava, V.; Zhang, L.; Jain, S.; Yamamoto, T.; Mamedov, A.; Loblaw, A. Long-term follow-up of a large active surveillance cohort of patients with prostate cancer. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2015, 33, 272–277.
    12. Abedi, A.-R.; Fallah-Karkan, M.; Allameh, F.; Ranjbar, A.; Shadmehr, A. Incidental prostate cancer: A 10-year review of a tertiary center, Tehran, Iran. Res. Rep. Urol. 2018, 10, 1–6.
    13. Daniyal, M.; Siddiqui, Z.A.; Akram, M.; Asif, H.; Sultana, S.; Khan, A. Epidemiology, etiology, diagnosis and treatment of prostate cancer. Asian Pac. J. Cancer Prev. 2014, 15, 9575–9578.
    14. Pernar, C.H.; Ebot, E.M.; Wilson, K.M.; Mucci, L.A. The epidemiology of prostate cancer. Cold Spring Harb. Perspect. Med. 2018, 3, a030361.
    15. Barve, A.; Khor, T.O.; Hao, X.; Keum, Y.S.; Yang, C.S.; Reddy, B.; Kong, A.N. Murine prostate cancer inhibition by dietary phytochemicals—Curcumin and phenyethylisothiocyanate. Pharm. Res. 2008, 25, 2181–2189.
    16. Dunn, M.W.; Kazer, M.W. Prostate cancer overview. Semin. Oncol. Nurs. 2011, 27, 241–250.
    17. Ferlay, J.; Soerjomataram, I.; Dikshit, R.; Eser, S.; Mathers, C.; Rebelo, M.; Parkin, D.M.; Forman, D.; Bray, F. Cancer incidence and mortality worldwide: Sources, methods and major patterns in globocan 2012. Int. J. Cancer 2015, 136, E359–E386.
    18. Bashir, M.N. Epidemiology of prostate cancer. Asian Pac. J. Cancer Prev. 2015, 16, 5137–5141.
    19. American Cancer Society. Key Statistics for Prostate Cancer; American Cancer Society: Atlanta, GA, USA, 2018.
    20. Packer, J.R.; Maitland, N.J. The molecular and cellular origin of human prostate cancer. Biochim. Biophys. Acta 2016, 1863, 1238–1260.
    21. Mills, P.K.; Beeson, W.L.; Phillips, R.L.; Fraser, G.E. Cohort study of diet, lifestyle, and prostate cancer in adventist men. Cancer 1989, 64, 598–604.
    22. Chan, J.M.; Stampfer, M.J.; Giovannucci, E.L. What causes prostate cancer? A brief summary of the epidemiology. Semin. Cancer Biol. 1998, 8, 263–273.
    23. Pandey, M.K.; Gupta, S.C.; Nabavizadeh, A.; Aggarwal, B.B. Regulation of cell signaling pathways by dietary agents for cancer prevention and treatment. Semin. Cancer Biol. 2017, 46, 158–181.
    24. Mantovani, A.; Allavena, P.; Sica, A.; Balkwill, F. Cancer-related inflammation. Nature 2008, 454, 436–444.
    25. Hamilton, W.; Sharp, D. Symptomatic diagnosis of prostate cancer in primary care: A structured review. Br. J. Gen. Pr. 2004, 54, 617–621.
    26. Young, S.-M.; Bansal, P.; Vella, E.T.; Finelli, A.; Levitt, C.; Loblaw, A. Systematic review of clinical features of suspected prostate cancer in primary care. Can. Fam. Physician 2015, 61, e26–e35.
    27. Quinlan, M.; O’Daly, B.; O’Brien, M.; Gardner, S.; Lennon, G.; Mulvin, D.; Quinlan, D. The value of appropriate assessment prior to specialist referral in men with prostatic symptoms. Ir. J. Med Sci. 2009, 178, 281–285.
    28. Nam, R.K.; Kattan, M.W.; Chin, J.L.; Trachtenberg, J.; Singal, R.; Rendon, R.; Klotz, L.H.; Sugar, L.; Sherman, C.; Izawa, J. Prospective multi-institutional study evaluating the performance of prostate cancer risk calculators. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2011, 29, 2959–2964.
    29. Brown, M.L.; Potosky, A.L.; Thompson, G.B.; Kessler, L.K. The knowledge and use of screening tests for colorectal and prostate cancer: Data from the 1987 national health interview survey. Prev. Med. 1990, 19, 562–574.
    30. Barry, M.J. Screening for Prostate Cancer—The Controversy That Refuses to Die; Massachusetts Medical Society: Waltham, MA, USA, 2009.
    31. Siegel, R.; Ma, J.; Zou, Z.; Jemal, A. Cancer statistics, 2014. CA Cancer J. Clin. 2014, 64, 9–29.
    32. Center, M.M.; Jemal, A.; Lortet-Tieulent, J.; Ward, E.; Ferlay, J.; Brawley, O.; Bray, F. International variation in prostate cancer incidence and mortality rates. Eur. Urol. 2012, 61, 1079–1092.
    33. Thompson, I.M.; Pauler, D.K.; Goodman, P.J.; Tangen, C.M.; Lucia, M.S.; Parnes, H.L.; Minasian, L.M.; Ford, L.G.; Lippman, S.M.; Crawford, E.D. Prevalence of prostate cancer among men with a prostate-specific antigen level ≤ 4.0 ng per milliliter. N. Engl. J. Med. 2004, 350, 2239–2246.
    34. Ghai, S.; Haider, M.A. Multiparametric-mri in diagnosis of prostate cancer. Indian J. Urol. Iju J. Urol. Soc. India 2015, 31, 194.
    35. Cook, G.J.; Azad, G.; Padhani, A.R. Bone imaging in prostate cancer: The evolving roles of nuclear medicine and radiology. Clin. Transl. Imaging 2016, 4, 439–447.
    36. Zheng, X.-Y.; Zhang, P.; Xie, L.-P.; You, Q.-H.; Cai, B.-S.; Qin, J. Prostate-specific antigen velocity (PSAV) and PSAV per initial volume (PSAVD) for early detection of prostate cancer in Chinese men. Asian Pac. J. Cancer Prev. 2012, 13, 5529–5533.
    37. Hayes, J.H.; Barry, M.J. Screening for prostate cancer with the prostate-specific antigen test: A review of current evidence. JAMA 2014, 311, 1143–1149.
    38. Eggener, S.E.; Cifu, A.S.; Nabhan, C. Prostate cancer screening. JAMA 2015, 314, 825–826.
    39. Prensner, J.R.; Rubin, M.A.; Wei, J.T.; Chinnaiyan, A.M. Beyond psa: The next generation of prostate cancer biomarkers. Sci. Transl. Med. 2012, 4, rv123–rv127.
    40. Cuzick, J.; Thorat, M.A.; Andriole, G.; Brawley, O.W.; Brown, P.H.; Culig, Z.; Eeles, R.A.; Ford, L.G.; Hamdy, F.C.; Holmberg, L. Prevention and early detection of prostate cancer. Lancet Oncol. 2014, 15, e484–e492.
    41. Jahn, J.L.; Giovannucci, E.L.; Stampfer, M.J. The high prevalence of undiagnosed prostate cancer at autopsy: Implications for epidemiology and treatment of prostate cancer in the prostate-specific antigen-era. Int. J. Cancer 2015, 137, 2795–2802.
    42. Chan, J.M.; Giovannucci, E.L. Vegetables, fruits, associated micronutrients, and risk of prostate cancer. Epidemiol. Rev. 2001, 23, 82–86.
    43. Bashir, M.N.; Ahmad, M.R.; Malik, A. Risk factors of prostate cancer: A case-control study in Faisalabad, Pakistan. Asian Pac. J. Cancer Prev. 2014, 15, 10237–10240.
    44. Howlader, N.; Noone, A.; Krapcho, M.; Miller, D.; Bishop, K.; Altekruse, S.; Kosary, C.; Yu, M.; Ruhl, J.; Tatalovich, Z. Seer Cancer Statistics Review. 1975–2013. National Cancer Institute: Bethesda, MD, USA. Available online: https://seer.cancer.gov/archive/csr/1975_2013/ (accessed on 10 September 2018).
    45. Goggins, W.B.; Wong, G. Cancer among asian indians/pakistanis living in the united states: Low incidence and generally above average survival. Cancer Causes Control. 2009, 20, 635–643.
    46. Hemminki, K.; Ankerst, D.P.; Sundquist, J.; Mousavi, S.M. Prostate cancer incidence and survival in immigrants to Sweden. World J. Urol. 2013, 31, 1483–1488.
    47. Kiciński, M.; Vangronsveld, J.; Nawrot, T.S. An epidemiological reappraisal of the familial aggregation of prostate cancer: A meta-analysis. PLoS ONE 2011, 6, e27130.
    48. Eeles, R.A.; Al Olama, A.A.; Benlloch, S.; Saunders, E.J.; Leongamornlert, D.A.; Tymrakiewicz, M.; Ghoussaini, M.; Luccarini, C.; Dennis, J.; Jugurnauth-Little, S. Identification of 23 new prostate cancer susceptibility loci using the icogs custom genotyping array. Nat. Genet. 2013, 45, 385.
    49. Hoffmann, T.J.; Van Den Eeden, S.K.; Sakoda, L.C.; Jorgenson, E.; Habel, L.A.; Graff, R.E.; Passarelli, M.N.; Cario, C.L.; Emami, N.C.; Chao, C.R. A large multi-ethnic genome-wide association study of prostate cancer identifies novel risk variants and substantial ethnic differences. Cancer Discov. 2015, 5, 878–891.
    50. Hemminki, K.; Czene, K. Attributable risks of familial cancer from the family-cancer database. Cancer Epidemiol. Prev. Biomark. 2002, 11, 1638–1644.
    51. Möller, E.; Wilson, K.M.; Batista, J.L.; Mucci, L.A.; Bälter, K.; Giovannucci, E. Body size across the life course and prostate cancer in the health professionals follow-up study. Int. J. Cancer 2016, 138, 853–865.
    52. Zuccolo, L.; Harris, R.; Gunnell, D.; Oliver, S.; Lane, J.A.; Davis, M.; Donovan, J.; Neal, D.; Hamdy, F.; Beynon, R. Height and prostate cancer risk: A large nested case-control study (protect) and meta-analysis. Cancer Epidemiol. Prev. Biomark. 2008, 17, 2325–2336.
    53. Anuurad, E.; Shiwaku, K.; Nogi, A.; Kitajima, K.; Enkhmaa, B.; Shimono, K.; Yamane, Y. The new bmi criteria for asians by the regional office for the western pacific region of who are suitable for screening of overweight to prevent metabolic syndrome in elder Japanese workers. J. Occup. Health 2003, 45, 335–343.
    54. Cao, Y.; Ma, J. Body-mass index, prostate cancer-specific mortality and biochemical recurrence: A systematic review and meta-analysis. Cancer Prev. Res. 2011, 4, 486–501.
    55. Ma, J.; Li, H.; Giovannucci, E.; Mucci, L.; Qiu, W.; Nguyen, P.L.; Gaziano, J.M.; Pollak, M.; Stampfer, M.J. Prediagnostic body-mass index, plasma c-peptide concentration, and prostate cancer-specific mortality in men with prostate cancer: A long-term survival analysis. Lancet Oncol. 2008, 9, 1039–1047.
    56. Joshu, C.E.; Mondul, A.M.; Menke, A.; Meinhold, C.L.; Han, M.; Humphreys, E.; Freedland, S.J.; Walsh, P.C.; Platz, E.A. Weight gain is associated with an increased risk of prostate cancer recurrence after prostatectomy in the PSA era. Cancer Prev. Res. 2011, 4, 544–551.
    57. World Health Organization. Global Status Report on Alcohol and Health; World Health Organization: Geneva, Switzerland, 2014.
    58. Kenfield, S.A.; Stampfer, M.J.; Chan, J.M.; Giovannucci, E. Smoking and prostate cancer survival and recurrence. JAMA 2011, 305, 2548–2555.
    59. Richman, E.L.; Kenfield, S.A.; Stampfer, M.J.; Paciorek, A.; Carroll, P.R.; Chan, J.M. Physical activity after diagnosis and risk of prostate cancer progression: Data from the cancer of the prostate strategic urologic research endeavor. Cancer Res. 2011, 71, 3889–3895.
    60. Loprinzi, P.D.; Kohli, M. Effect of Physical Activity and Sedentary Behavior on Serum Prostate-Specific Antigen Concentrations: Results from the National Health and Nutrition Examination Survey (NHANES), 2003–2006, Mayo Clinic Proceedings; Elsevier: Amsterdam, The Netherlands, 2013; pp. 11–21.
    61. Holt, S.K.; Kwon, E.M.; Koopmeiners, J.S.; Lin, D.W.; Feng, Z.; Ostrander, E.A.; Peters, U.; Stanford, J.L. Vitamin d pathway gene variants and prostate cancer prognosis. Prostate 2010, 70, 1448–1460.
    62. Kristal, A.R.; Arnold, K.B.; Neuhouser, M.L.; Goodman, P.; Platz, E.A.; Albanes, D.; Thompson, I.M. Diet, supplement use, and prostate cancer risk: Results from the prostate cancer prevention trial. Am. J. Epidemiol. 2010, 172, 566–577.
    63. Mahmood, S.; Qasmi, G.; Ahmed, A.; Kokab, F.; Zahid, M.F.; Afridi, M.I.; Razzaq, A. Lifestyle factors associated with the risk of prostate cancer among Pakistani men. J. Ayub Med. Coll. Abbottabad 2012, 24, 122–126.
    64. Butler, L.M.; Wong, A.S.; Koh, W.-P.; Wang, R.; Yuan, J.-M.; Mimi, C.Y. Calcium intake increases risk of prostate cancer among Singapore Chinese. Cancer Res. 2010, 70, 4941–4948.
    65. De Martel, C.; Ferlay, J.; Franceschi, S.; Vignat, J.; Bray, F.; Forman, D.; Plummer, M. Global burden of cancers attributable to infections in 2008: A review and synthetic analysis. Lancet Oncol. 2012, 13, 607–615.
    66. Sutcliffe, S.; Platz, E.A. Inflammation and prostate cancer: A focus on infections. Curr. Urol. Rep. 2008, 9, 243.
    67. Sutcliffe, S.; Neace, C.; Magnuson, N.S.; Reeves, R.; Alderete, J. Trichomonosis, a common curable sti, and prostate carcinogenesis—a proposed molecular mechanism. PLoS Pathog. 2012, 8, e1002801.
    68. Meyer, T.E.; Coker, A.L.; Sanderson, M.; Symanski, E. A case–control study of farming and prostate cancer in African-American and Caucasian men. Occup. Environ. Med. 2007, 64, 155–160.
    69. Nair-Shalliker, V.; Smith, D.P.; Egger, S.; Hughes, A.M.; Kaldor, J.M.; Clements, M.; Kricker, A.; Armstrong, B.K. Sun exposure may increase risk of prostate cancer in the high UV environment of new south wales, Australia: A case–control study. Int. J. Cancer 2012, 131, E726–E732.
    70. Myles, P.; Evans, S.; Lophatananon, A.; Dimitropoulou, P.; Easton, D.; Key, T.; Pocock, R.; Dearnaley, D.; Guy, M.; Edwards, S. Diagnostic radiation procedures and risk of prostate cancer. Br. J. Cancer 2008, 98, 1852.
    71. Zuccolo, L.; Lewis, S.J.; Donovan, J.L.; Hamdy, F.C.; Neal, D.E.; Smith, G.D. Alcohol consumption and PSA-detected prostate cancer risk—A case-control nested in the protect study. Int. J. Cancer 2013, 132, 2176–2185.
    72. McGregor, S.E.; Courneya, K.S.; Kopciuk, K.A.; Tosevski, C.; Friedenreich, C.M. Case–control study of lifetime alcohol intake and prostate cancer risk. Cancer Causes Control 2013, 24, 451–461.
    73. Endogenous Hormones and Prostate Cancer Collaborative Group; Roddam, A.W.; Allen, N.E.; Appleby, P.; Key, T.J. Endogenous sex hormones and prostate cancer: A collaborative analysis of 18 prospective studies. J. Natl. Cancer Inst. 2008, 100, 170–183.
    74. Nelles, J.L.; Hu, W.-Y.; Prins, G.S. Estrogen action and prostate cancer. Expert Rev. Endocrinol. Metab. 2011, 6, 437–451.
    75. Nelson, A.W.; Tilley, W.D.; Neal, D.E.; Carroll, J.S. Estrogen receptor beta in prostate cancer: Friend or foe? Endocr. Relat. Cancer 2014, 21, T219–T234.
    76. Roddam, A.W.; Allen, N.E.; Appleby, P.; Key, T.J.; Ferrucci, L.; Carter, H.B.; Metter, E.J.; Chen, C.; Weiss, N.S.; Fitzpatrick, A. Insulin-like growth factors, their binding proteins, and prostate cancer risk: Analysis of individual patient data from 12 prospective studies. Ann. Intern. Med. 2008, 149, 461–471.
    77. Uzoh, C.; Holly, J.; Biernacka, K.; Persad, R.; Bahl, A.; Gillatt, D.; Perks, C. Insulin-like growth factor-binding protein-2 promotes prostate cancer cell growth via igf-dependent or-independent mechanisms and reduces the efficacy of docetaxel. Br. J. Cancer 2011, 104, 1587.
    78. Robinson, D.; Van Allen, E.M.; Wu, Y.-M.; Schultz, N.; Lonigro, R.J.; Mosquera, J.-M.; Montgomery, B.; Taplin, M.-E.; Pritchard, C.C.; Attard, G. Integrative clinical genomics of advanced prostate cancer. Cell 2015, 161, 1215–1228.
    79. Klein, A.J.S.E.A. Epidemiology, etiology, and prevention of prostate cancer. In Campbell-Walsh Urology, 11th ed.; Wein, A.J., Ed.; Elsevier: Philadelphia, PA, USA, 2016; Volume 3, pp. 2543–2564.
    80. Sun, F.; Oyesanmi, O.; Fontanarosa, J.; Reston, J.; Guzzo, T.; Schoelles, K. Therapies for Clinically Localized Prostate Cancer: Update of a 2008 Systematic Review; Agency for Healthcare Research and Quality: Rockville, MD, USA, 2014.
    81. Mottet, N.; Bellmunt, J.; Bolla, M.; Briers, E.; Cumberbatch, M.G.; De Santis, M.; Fossati, N.; Gross, T.; Henry, A.M.; Joniau, S. EAU-ESTRO-SIOG guidelines on prostate cancer. Part 1: Screening, diagnosis, and local treatment with curative intent. Eur. Urol. 2017, 71, 618–629.
    82. Cornford, P.; Bellmunt, J.; Bolla, M.; Briers, E.; De Santis, M.; Gross, T.; Henry, A.M.; Joniau, S.; Lam, T.B.; Mason, M.D. EAU-ESTRO-SIOG guidelines on prostate cancer. Part II: Treatment of relapsing, metastatic, and castration-resistant prostate cancer. Eur. Urol. 2017, 71, 630–642.
    83. Wang, G.; Hu, F.B.; Mistry, K.B.; Zhang, C.; Ren, F.; Huo, Y.; Paige, D.; Bartell, T.; Hong, X.; Caruso, D.; et al. Association between maternal prepregnancy body mass index and plasma folate concentrations with child metabolic health. JAMA Pediatrics 2016, 170, e160845.
    84. Peeling, P.; Binnie, M.J.; Goods, P.S.R.; Sim, M.; Burke, L.M. Evidence-based supplements for the enhancement of athletic performance. Int. J. Sport Nutr. Exerc. Metab. 2018, 28, 178–187.
    85. Young, H.H. The early diagnosis and radical cure of carcinoma of the prostate: Being a study of 40 cases and presentation of a radical operation which was carried out in four cases. Johns Hopkins Hosp. Bull. 1905, 16, 315–321.
    86. Ramsay, C.; Pickard, R.; Robertson, C.; Close, A.; Vale, L.; Armstrong, N.; Barocas, D.; Eden, C.; Fraser, C.; Gurung, T. Systematic review and economic modelling of the relative clinical benefit and cost-effectiveness of laparoscopic surgery and robotic surgery for removal of the prostate in men with localised prostate cancer. Health Technol. Assess. 2012, 16, 1.
    87. Keyes, M.; Crook, J.; Morton, G.; Vigneault, E.; Usmani, N.; Morris, W.J. Treatment options for localized prostate cancer. Can. Fam. Physician 2013, 59, 1269–1274.
    88. Litwin, M.S.; Tan, H.-J. The diagnosis and treatment of prostate cancer: A review. JAMA 2017, 317, 2532–2542.
    89. Bayoumi, A.M.; Brown, A.D.; Garber, A.M. Cost-effectiveness of androgen suppression therapies in advanced prostate cancer. J. Natl. Cancer Inst. 2000, 92, 1731–1739.
    90. Oefelein, M.G.; Feng, A.; Scolieri, M.J.; Ricchiutti, D.; Resnick, M.I. Reassessment of the definition of castrate levels of testosterone: Implications for clinical decision making. Urology 2000, 56, 1021–1024.
    91. Seidenfeld, J.; Samson, D.J.; Hasselblad, V.; Aronson, N.; Albertsen, P.C.; Bennett, C.L.; Wilt, T.J. Single-therapy androgen suppression in men with advanced prostate cancer: A systematic review and meta-analysis. Ann. Intern. Med. 2000, 132, 566–577.
    92. Crawford, E.D.; Shore, N.D.; Moul, J.W.; Tombal, B.; Schröder, F.H.; Miller, K.; Boccon-Gibod, L.; Malmberg, A.; Olesen, T.K.; Persson, B.-E. Long-term tolerability and efficacy of degarelix: 5-year results from a phase iii extension trial with a 1-arm crossover from leuprolide to degarelix. Urology 2014, 83, 1122–1128.
    93. Goenka, A.; Magsanoc, J.M.; Pei, X.; Schechter, M.; Kollmeier, M.; Cox, B.; Scardino, P.T.; Eastham, J.A.; Zelefsky, M.J. Long-term outcomes after high-dose postprostatectomy salvage radiation treatment. Int. J. Radiat. Oncol. Biol. Phys. 2012, 84, 112–118.
    94. Chen, C.P.; Weinberg, V.; Shinohara, K.; Roach, M., III; Nash, M.; Gottschalk, A.; Chang, A.J.; Hsu, I.-C. Salvage HDR brachytherapy for recurrent prostate cancer after previous definitive radiation therapy: 5-year outcomes. Int. J. Radiat. Oncol. Biol. Phys. 2013, 86, 324–329.
    95. Karnes, R.J.; Murphy, C.R.; Bergstralh, E.J.; DiMonte, G.; Cheville, J.C.; Lowe, V.J.; Mynderse, L.A.; Kwon, E.D. Salvage lymph node dissection for prostate cancer nodal recurrence detected by 11c-choline positron emission tomography/computerized tomography. J. Urol. 2015, 193, 111–116.
    96. Allameh, F.; Rahavian, A.H.; Ghiasy, S. Prevalence of castration success rate in Iranian metastatic prostate cancer patients: A referral center statistics. Int. J. Cancer Manag. 2018, 11, e83613.
    97. Beer, T.; Garzotto, M.; Henner, W.; Eilers, K.; Wersinger, E. Multiple cycles of intermittent chemotherapy in metastatic androgen-independent prostate cancer. Br. J. Cancer 2004, 91, 1425.
    98. Dy, S.M.; Asch, S.M.; Naeim, A.; Sanati, H.; Walling, A.; Lorenz, K.A. Evidence-based standards for cancer pain management. J. Clin. Oncol. 2008, 26, 3879–3885.
    99. Esper, P.; Pienta, K. Supportive Care in the Patient with Hormone Refractory Prostate Cancer. Semin. Urol. Oncol. 1997, 15, 56–64.
    100. Roehrborn, C.G.; Black, L.K. The economic burden of prostate cancer. BJU Int. 2011, 108, 806–813.
    101. National Cancer Institute. Online Summary of Trends in Us Cancer Control Measures. Available online: https://progressreport.cancer.gov/after/economic_burden (accessed on 12 September 2018).
    102. Moghadam, M.F.; Rangchian, M.; Ayati, M.; Pourmand, G.; Zeinali, L.; Rasekh, H. Economic burden of prostate cancer in Iran. Value Health 2016, 19, A147.
    103. Restelli, U.; Ceresoli, G.L.; Croce, D.; Evangelista, L.; Maffioli, L.S.; Gianoncelli, L.; Bombardieri, E. Economic burden of the management of metastatic castrate-resistant prostate cancer in Italy: A cost of illness study. Cancer Manag. Res. 2017, 9, 789.
    104. Savithramma, N.; Rao, M.L.; Suhrulatha, D. Screening of medicinal plants for secondary metabolites. Middle-East. J. Sci. Res. 2011, 8, 579–584.
    105. Petrovska, B.B. Historical review of medicinal plants’ usage. Pharmacogn. Rev. 2012, 6, 1–5.
    106. Ghasemzadeh, A.; Ghasemzadeh, N. Flavonoids and phenolic acids: Role and biochemical activity in plants and human. J. Med. Plants Res. 2011, 5, 6697–6703.
    107. Cragg, G.M.; Newman, D.J. Natural product drug discovery in the next millennium. Pharm. Biol. 2001, 39 (Suppl. 1), 8–17.
    108. Bodeker, G. Traditional health system: Valuing biodiversity for human health and wellbeing. In Cultural and Spiritual Values in Biodiversity; Posey, D.A., Ed.; Intermediate Technology Publications: London, UK, 2000; pp. 261–284.
    109. Choi, Y.J.; Choi, Y.K.; Lee, K.M.; Cho, S.G.; Kang, S.Y.; Ko, S.G. Sh003 induces apoptosis of du145 prostate cancer cells by inhibiting ERK-involved pathway. BMC Complement. Altern. Med. 2016, 16, 507.
    110. Diab, K.A.; Guru, S.K.; Bhushan, S.; Saxena, A.K. In vitro anticancer activities of Anogeissus latifolia, Terminalia bellerica, Acacia catechu and Moringa oleiferna Indian plants. Asian Pac. J. Cancer Prev. 2015, 16, 6423–6428.
    111. Asadi-Samani, M.; Rafieian-Kopaei, M.; Lorigooini, Z.; Shirzad, H. A screening of growth inhibitory activity of iranian medicinal plants on prostate cancer cell lines. BioMedicine 2018, 8, 8.
    112. Bali, E.B.; Acik, L.; Elci, P.; Sarper, M.; Avcu, F.; Vural, M. In vitro anti-oxidant, cytotoxic and pro-apoptotic effects of Achillea teretifolia willd extracts on human prostate cancer cell lines. Pharmacogn. Mag. 2015, 11, S308–S315.
    113. Bhandari, J.; Muhammad, B.; Thapa, P.; Shrestha, B.G. Study of phytochemical, anti-microbial, anti-oxidant, and anti-cancer properties of Allium wallichii. BMC Complement. Altern. Med. 2017, 17, 102.
    114. Al-Oqail, M.M.; El-Shaibany, A.; Al-Jassas, E.; Al-Sheddi, E.S.; Al-Massarani, S.M.; Farshori, N.N. In vitro anti-proliferative activities of aloe perryi flowers extract on human liver, colon, breast, lung, prostate and epithelial cancer cell lines. Pak. J. Pharm. Sci. 2016, 29, 723–729.
    115. de Alencar, D.C.; Pinheiro, M.L.; Pereira, J.L.; de Carvalho, J.E.; Campos, F.R.; Serain, A.F.; Tirico, R.B.; Hernandez-Tasco, A.J.; Costa, E.V.; Salvador, M.J. Chemical composition of the essential oil from the leaves of Anaxagorea brevipes (Annonaceae) and evaluation of its bioactivity. Nat. Prod. Res. 2016, 30, 1088–1092.
    116. Zhang, J.; Wang, L.; Zhang, Y.; Li, L.; Tang, S.; Xing, C.; Kim, S.H.; Jiang, C.; Lu, J. Chemopreventive effect of Korean angelica root extract on tramp carcinogenesis and integrative “omic” profiling of affected neuroendocrine carcinomas. Mol. Carcinog. 2015, 54, 1567–1583.
    117. Tang, S.-N.; Zhang, J.; Wu, W.; Jiang, P.; Puppala, M.; Zhang, Y.; Xing, C.; Kim, S.-H.; Jiang, C.; Lü, J. Chemopreventive effects of Korean angelica vs. Its major pyranocoumarins on two lineages of transgenic adenocarcinoma of mouse prostate carcinogenesis. Cancer Prev. Res. 2015, 8, 835–844.
    118. Deep, G.; Kumar, R.; Jain, A.K.; Dhar, D.; Panigrahi, G.K.; Hussain, A.; Agarwal, C.; El-Elimat, T.; Sica, V.P.; Oberlies, N.H.; et al. Graviola inhibits hypoxia-induced NADPH oxidase activity in prostate cancer cells reducing their proliferation and clonogenicity. Sci. Rep. 2016, 6, 23135.
    119. Huang, S.P.; Ho, T.M.; Yang, C.W.; Chang, Y.J.; Chen, J.F.; Shaw, N.S.; Horng, J.C.; Hsu, S.L.; Liao, M.Y.; Wu, L.C.; et al. Chemopreventive potential of ethanolic extracts of luobuma leaves (Apocynum venetum L.) in androgen insensitive prostate cancer. Nutrients 2017, 9, 948.
    120. Chen, L.; Yan, F.; Chen, W.; Zhao, L.; Zhang, J.; Lu, Q.; Liu, R. Procyanidin from peanut skin induces antiproliferative effect in human prostate carcinoma cells du145. Chem. Biol. Interact. 2018, 288, 12–23.
    121. Cherian, A.M.; Snima, K.S.; Kamath, C.R.; Nair, S.V.; Lakshmanan, V.K. Effect of Baliospermum montanum nanomedicine apoptosis induction and anti-migration of prostate cancer cells. Biomed. Pharmacother. Biomed. Pharmacother. 2015, 71, 201–209.
    122. El-Merahbi, R.; Liu, Y.N.; Eid, A.; Daoud, G.; Hosry, L.; Monzer, A.; Mouhieddine, T.H.; Hamade, A.; Najjar, F.; Abou-Kheir, W. Berberis libanotica ehrenb extract shows anti-neoplastic effects on prostate cancer stem/progenitor cells. PLoS ONE 2014, 9, e112453.
    123. Fort, R.; Trinidad Barnech, J.; Dourron, J.; Colazzo, M.; Aguirre-Crespo, F.; Duhagon, M.; Álvarez, G. Isolation and structural characterization of bioactive molecules on prostate cancer from Mayan traditional medicinal plants. Pharmaceuticals 2018, 11, 78.
    124. Adaramoye, O.; Erguen, B.; Oyebode, O.; Nitzsche, B.; Hopfner, M.; Jung, K.; Rabien, A. Antioxidant, antiangiogenic and antiproliferative activities of root methanol extract of Calliandra portoricensis in human prostate cancer cells. J. Integr. Med. 2015, 13, 185–193.
    125. Pandey, S.; Walpole, C.; Cabot, P.J.; Shaw, P.N.; Batra, J.; Hewavitharana, A.K. Selective anti-proliferative activities of carica papaya leaf juice extracts against prostate cancer. Biomed. Pharmacother. Biomed. Pharmacother. 2017, 89, 515–523.
    126. Ramos-Silva, A.; Tavares-Carreon, F.; Figueroa, M.; De la Torre-Zavala, S.; Gastelum-Arellanez, A.; Rodriguez-Garcia, A.; Galan-Wong, L.J.; Aviles-Arnaut, H. Anticancer potential of Thevetia peruviana fruit methanolic extract. BMC Complement. Altern. Med. 2017, 17, 241.
    127. Podolak, I.; Olech, M.; Galanty, A.; Zaluski, D.; Grabowska, K.; Sobolewska, D.; Michalik, M.; Nowak, R. Flavonoid and phenolic acid profile by lc-ms/ms and biological activity of crude extracts from Chenopodium hybridum aerial parts. Nat. Prod. Res. 2016, 30, 1766–1770.
    128. Yousefi, B.; Abasi, M.; Abbasi, M.M.; Jahanban-Esfahlan, R. Anti-proliferative properties of cornus mass fruit in different human cancer cells. Asian Pac. J. Cancer Prev. 2015, 16, 5727–5731.
    129. Alonso-Castro, A.J.; Zapata-Morales, J.R.; Gonzalez-Chavez, M.M.; Carranza-Alvarez, C.; Hernandez-Benavides, D.M.; Hernandez-Morales, A. Pharmacological effects and toxicity of Costus pulverulentus c. Presl (Costaceae). J. Ethnopharmacol. 2016, 180, 124–130.
    130. Lee, M.S.; Lee, S.O.; Kim, K.R.; Lee, H.J. Sphingosine kinase-1 involves the inhibitory action of hif-1alpha by Chlorogenic acid in hypoxic du145 cells. Int. J. Mol. Sci. 2017, 18, 325.
    131. Zheng, J.; Zhou, Y.; Li, Y.; Xu, D.P.; Li, S.; Li, H.B. Spices for prevention and treatment of cancers. Nutrients 2016, 8, 495.
    132. D’Alessandro, A.M.; Mancini, A.; Lizzi, A.R.; De Simone, A.; Marroccella, C.E.; Gravina, G.L.; Tatone, C.; Festuccia, C. Crocus sativus stigma extract and its major constituent crocin possess significant antiproliferative properties against human prostate cancer. Nutr. Cancer 2013, 65, 930–942.
    133. Festuccia, C.; Mancini, A.; Gravina, G.L.; Scarsella, L.; Llorens, S.; Alonso, G.L.; Tatone, C.; Di Cesare, E.; Jannini, E.A.; Lenzi, A.; et al. Antitumor effects of saffron-derived carotenoids in prostate cancer cell models. Biomed Res. Int. 2014, 2014, 135048.
    134. Irshad, S.; Ashfaq, A.; Muazzam, A.; Yasmeen, A. Antimicrobial and anti-prostate cancer activity of turmeric (Curcuma longa L.) and black pepper (Piper nigrum L.) used in typical pakistani cuisine. Pak. J. Zool. 2017, 49, 1665–1669.
    135. Bayala, B.; Bassole, I.H.N.; Maqdasy, S.; Baron, S.; Simpore, J.; Lobaccaro, J.A. Cymbopogon citratus and Cymbopogon giganteus essential oils have cytotoxic effects on tumor cell cultures. Identification of citral as a new putative anti-proliferative molecule. Biochimie 2018, 153, 162–170.
    136. Tong, K.L.; Chan, K.L.; AbuBakar, S.; Low, B.S.; Ma, H.Q.; Wong, P.F. The in vitro and in vivo anti-cancer activities of a standardized quassinoids composition from Eurycoma longifolia on lncap human prostate cancer cells. PLoS ONE 2015, 10, e0121752.
    137. Kassim, O.O.; Copeland, R.L.; Kenguele, H.M.; Nekhai, S.; Ako-Nai, K.A.; Kanaan, Y.M. Antiproliferative activities of Fagara xanthoxyloides and Pseudocedrela kotschyi against prostate cancer cell lines. Anticancer Res. 2015, 35, 1453–1458.
    138. Lin, H.C.; Lin, J.Y. Immune cell-conditioned media suppress prostate cancer pc-3 cell growth correlating with decreased proinflammatory/anti-inflammatory cytokine ratios in the media using 5 selected crude polysaccharides. Integr. Cancer Ther. 2016, 15, Np13–Np25.
    139. Hanafi, M.M.M.; Afzan, A.; Yaakob, H.; Aziz, R.; Sarmidi, M.R.; Wolfender, J.L.; Prieto, J.M. In vitro pro-apoptotic and anti-migratory effects of Ficus deltoidea L. Plant extracts on the human prostate cancer cell lines pc3. Front. Pharmacol. 2017, 8, 895.
    140. Rayaprolu, S.J.; Hettiarachchy, N.S.; Horax, R.; Phillips, G.K.; Mahendran, M.; Chen, P. Soybean peptide fractions inhibit human blood, breast and prostate cancer cell proliferation. J. Food Sci. Technol. 2017, 54, 38–44.
    141. Park, S.Y.; Kwon, S.J.; Lim, S.S.; Kim, J.K.; Lee, K.W.; Park, J.H. Licoricidin, an active compound in the hexane/ethanol extract of Glycyrrhiza uralensis, inhibits lung metastasis of 4t1 murine mammary carcinoma cells. Int. J. Mol. Sci. 2016, 17, 934.
    142. Pham, H.N.T.; Sakoff, J.A.; Bond, D.R.; Vuong, Q.V.; Bowyer, M.C.; Scarlett, C.J. In vitro antibacterial and anticancer properties of Helicteres hirsuta lour. Leaf and stem extracts and their fractions. Mol. Biol. Rep. 2018, 45, 2125–2133.
    143. Chiu, C.T.; Chen, J.H.; Chou, F.P.; Lin, H.H. Hibiscus sabdariffa leaf extract inhibits human prostate cancer cell invasion via down-regulation of akt/nf-kb/mmp-9 pathway. Nutrients 2015, 7, 5065–5087.
    144. Koczurkiewicz, P.; Kowolik, E.; Podolak, I.; Wnuk, D.; Piska, K.; Labedz-Maslowska, A.; Wojcik-Pszczola, K.; Pekala, E.; Czyz, J.; Michalik, M. Synergistic cytotoxic and anti-invasive effects of mitoxantrone and triterpene saponins from Lysimachia ciliata on human prostate cancer cells. Planta Med. 2016, 82, 1546–1552.
    145. Shabbir, M.; Syed, D.N.; Lall, R.K.; Khan, M.R.; Mukhtar, H. Potent anti-proliferative, pro-apoptotic activity of the maytenus royleanus extract against prostate cancer cells: Evidence in in-vitro and in-vivo models. PLoS ONE 2015, 10, e0119859.
    146. Jahanban-Esfahlan, R.; Seidi, K.; Monfaredan, A.; Shafie-Irannejad, V.; Abbasi, M.M.; Karimian, A.; Yousefi, B. The herbal medicine melissa officinalis extract effects on gene expression of p53, bcl-2, her2, vegf-a and htert in human lung, breast and prostate cancer cell lines. Gene 2017, 613, 14–19.
    147. Jahanban-Esfahlan, A.; Modaeinama, S.; Abasi, M.; Abbasi, M.M.; Jahanban-Esfahlan, R. Anti proliferative properties of Melissa officinalis in different human cancer cells. Asian Pac. J. Cancer Prev. 2015, 16, 5703–5707.
    148. Sharma, V.; Hussain, S.; Gupta, M.; Saxena, A.K. In vitro anticancer activity of extracts of Mentha spp. Against human cancer cells. Indian J. Biochem. Biophys. 2014, 51, 416–419.
    149. Emami, S.A.; Asili, J.; Hossein Nia, S.; Yazdian-Robati, R.; Sahranavard, M.; Tayarani-Najaran, Z. Growth inhibition and apoptosis induction of essential oils and extracts of Nepeta cataria L. On human prostatic and breast cancer cell lines. Asian Pac. J. Cancer Prev. 2016, 17, 125–130.
    150. Mollazadeh, H.; Afshari, A.R.; Hosseinzadeh, H. Review on the potential therapeutic roles of nigella sativa in the treatment of patients with cancer: Involvement of apoptosis: Black cumin and cancer. J. Pharmacopunct. 2017, 20, 158–172.
    151. Uttama, S.; Itharat, A.; Rattarom, R.; Makchuchit, S.; Panthong, S.; Sakpakdeejaroen, I. Biological activities and chemical content of sung yod rice bran oil extracted by expression and soxhlet extraction methods. J. Med Assoc. Thail. Chotmaihet Thangphaet 2014, 97 (Suppl. 8), S125–S132.
    152. Zhang, Z.H.; Xie, D.D.; Xu, S.; Xia, M.Z.; Zhang, Z.Q.; Geng, H.; Chen, L.; Wang, D.M.; Wei, W.; Yu, D.X.; et al. Total glucosides of paeony inhibits lipopolysaccharide-induced proliferation, migration and invasion in androgen insensitive prostate cancer cells. PLoS ONE 2017, 12, e0182584.
    153. Nguyen, V.T.; Sakoff, J.A.; Scarlett, C.J. Physicochemical properties, antioxidant and anti-proliferative capacities of dried leaf and its extract from xao tam phan (Paramignya trimera). Chem. Biodivers. 2017, 14, e1600498.
    154. Tang, Y.Q.; Jaganath, I.B.; Manikam, R.; Sekaran, S.D. Phyllanthus spp. Exerts anti-angiogenic and anti-metastatic effects through inhibition on matrix metalloproteinase enzymes. Nutr. Cancer 2015, 67, 783–795.
    155. Nair, H.A.; Snima, K.S.; Kamath, R.C.; Nair, S.V.; Lakshmanan, V.K. Plumbagin nanoparticles induce dose and PH dependent toxicity on prostate cancer cells. Curr. Drug Deliv. 2015, 12, 709–716.
    156. Han, S.Y.; Hu, M.H.; Qi, G.Y.; Ma, C.X.; Wang, Y.Y.; Ma, F.L.; Tao, N.; Qin, Z.H. Polysaccharides from polygonatum inhibit the proliferation of prostate cancer-associated fibroblasts. Asian Pac. J. Cancer Prev. 2016, 17, 3829–3833.
    157. Peng, C.-C.; Peng, C.-H.; Chen, K.-C.; Hsieh, C.-L.; Peng, R.Y. The aqueous soluble polyphenolic fraction of Psidium guajava leaves exhibits potent anti-angiogenesis and anti-migration actions on du145 cells. Evid. Based Complement. Altern. Med. 2011, 2011, 219069.
    158. Chen, K.C.; Peng, C.C.; Chiu, W.T.; Cheng, Y.T.; Huang, G.T.; Hsieh, C.L.; Peng, R.Y. Action mechanism and signal pathways of Psidium guajava L. Aqueous extract in killing prostate cancer lncap cells. Nutr. Cancer 2010, 62, 260–270.
    159. Albrecht, M.; Jiang, W.; Kumi-Diaka, J.; Lansky, E.P.; Gommersall, L.M.; Patel, A.; Mansel, R.E.; Neeman, I.; Geldof, A.A.; Campbell, M.J. Pomegranate extracts potently suppress proliferation, xenograft growth, and invasion of human prostate cancer cells. J. Med. Food 2004, 7, 274–283.
    160. Pantuck, A.J.; Pettaway, C.A.; Dreicer, R.; Corman, J.; Katz, A.; Ho, A.; Aronson, W.; Clark, W.; Simmons, G.; Heber, D. A randomized, double-blind, placebo-controlled study of the effects of pomegranate extract on rising psa levels in men following primary therapy for prostate cancer. Prostate Cancer Prostatic Dis. 2015, 18, 242–248.
    161. Seidi, K.; Jahanban-Esfahlan, R.; Abasi, M.; Abbasi, M.M. Anti tumoral properties of Punica granatum (Pomegranate) seed extract in different human cancer cells. Asian Pac. J. Cancer Prev. 2016, 17, 1119–1122.
    162. Ub Wijerathne, C.; Park, H.S.; Jeong, H.Y.; Song, J.W.; Moon, O.S.; Seo, Y.W.; Won, Y.S.; Son, H.Y.; Lim, J.H.; Yeon, S.H.; et al. Quisqualis indica improves benign prostatic hyperplasia by regulating prostate cell proliferation and apoptosis. Biol. Pharm. Bull. 2017, 40, 2125–2133.
    163. Kim, A.; Im, M.; Ma, J.Y. Ethanol extract of remotiflori radix induces endoplasmic reticulum stress-mediated cell death through ampk/mtor signaling in human prostate cancer cells. Sci. Rep. 2015, 5, 8394.
    164. Atmaca, H.; Bozkurt, E. Apoptotic and anti-angiogenic effects of Salvia triloba extract in prostate cancer cell lines. Tumour Biol. J. Int. Soc. Oncodev. Biol. Med. 2016, 37, 3639–3646.
    165. Chang, C.C.; Hsu, H.F.; Huang, K.H.; Wu, J.M.; Kuo, S.M.; Ling, X.H.; Houng, J.Y. Anti-proliferative effects of Siegesbeckia orientalis ethanol extract on human endometrial rl-95 cancer cells. Molecules 2014, 19, 19980–19994.
    166. Lin, H.; Jackson, G.A.; Lu, Y.; Drenkhahn, S.K.; Brownstein, K.J.; Starkey, N.J.; Lamberson, W.R.; Fritsche, K.L.; Mossine, V.V.; Besch-Williford, C.L.; et al. Inhibition of gli/hedgehog signaling in prostate cancer cells by “cancer bush” Sutherlandia frutescens extract. Cell Biol. Int. 2016, 40, 131–142.
    167. Mohammadi, A.; Mansoori, B.; Aghapour, M.; Baradaran, B. Urtica dioica dichloromethane extract induce apoptosis from intrinsic pathway on human prostate cancer cells (pc3). Cell. Mol. Biol. 2016, 62, 78–83.
    168. Burton, L.J.; Rivera, M.; Hawsawi, O.; Zou, J.; Hudson, T.; Wang, G.; Zhang, Q.; Cubano, L.; Boukli, N.; Odero-Marah, V. Muscadine grape skin extract induces an unfolded protein response-mediated autophagy in prostate cancer cells: A tmt-based quantitative proteomic analysis. PLoS ONE 2016, 11, e0164115.
    169. Tsai, C.H.; Tzeng, S.F.; Hsieh, S.C.; Tsai, C.J.; Yang, Y.C.; Tsai, M.H.; Hsiao, P.W. A standardized Wedelia chinensis extract overcomes the feedback activation of her2/3 signaling upon androgen-ablation in prostate cancer. Front. Pharmacol. 2017, 8, 721.
    170. Tsai, C.H.; Tzeng, S.F.; Hsieh, S.C.; Lin, C.Y.; Tsai, C.J.; Chen, Y.R.; Yang, Y.C.; Chou, Y.W.; Lee, M.T.; Hsiao, P.W. Development of a standardized and effect-optimized herbal extract of Wedelia chinensis for prostate cancer. Phytomed. Int. J. Phytother. Phytopharm. 2015, 22, 406–414.
    171. Sarbishegi, M.; Khani, M.; Salimi, S.; Valizadeh, M.; Sargolzaei Aval, F. Antiproliferative and antioxidant effects of Withania coagulans extract on benign prostatic hyperplasia in rats. Nephro-Urol. Mon. 2016, 8, e33180.
    172. Adaramoye, O.; Erguen, B.; Nitzsche, B.; Hopfner, M.; Jung, K.; Rabien, A. Antioxidant and antiproliferative potentials of methanol extract of Xylopia aethiopica (dunal) a. Rich in pc-3 and lncap cells. J. Basic Clin. Physiol. Pharmacol. 2017, 28, 403–412.
    173. Yang, Y.; Ikezoe, T.; Takeuchi, T.; Adachi, Y.; Ohtsuki, Y.; Koeffler, H.P.; Taguchi, H. Zanthoxyli fructus induces growth arrest and apoptosis of lncap human prostate cancer cells in vitro and in vivo in association with blockade of the akt and ar signal pathways. Oncol. Rep. 2006, 15, 1581–1590.
    174. Karna, P.; Chagani, S.; Gundala, S.R.; Rida, P.C.G.; Asif, G.; Sharma, V.; Gupta, M.V.; Aneja, R. Benefits of whole ginger extract in prostate cancer. Br. J. Nutr. 2012, 107, 473–484.
    175. Brahmbhatt, M.; Gundala, S.R.; Asif, G.; Shamsi, S.A.; Aneja, R. Ginger phytochemicals exhibit synergy to inhibit prostate cancer cell proliferation. Nutr. Cancer 2013, 65, 263–272.
    176. Liu, C.M.; Kao, C.L.; Wu, H.M.; Li, W.J.; Huang, C.T.; Li, H.T.; Chen, C.Y. Antioxidant and anticancer aporphine alkaloids from the leaves of Nelumbo nucifera gaertn. Cv. Rosa-plena. Molecules 2014, 19, 17829–17838.
    177. Arai, M.A.; Akamine, R.; Sadhu, S.K.; Ahmed, F.; Ishibashi, M. Hedgehog/gli-mediated transcriptional activity inhibitors from Crinum asiaticum. J. Nat. Med. 2015, 69, 538–542.
    178. Ramos-Torres, A.; Bort, A.; Morell, C.; Rodriguez-Henche, N.; Diaz-Laviada, I. The pepper’s natural ingredient capsaicin induces autophagy blockage in prostate cancer cells. Oncotarget 2016, 7, 1569–1583.
    179. Bamji, Z.D.; Washington, K.N.; Akinboye, E.; Bakare, O.; Kanaan, Y.M.; Copeland, R.L., Jr. Apoptotic effects of novel dithiocarbamate analogs of emetine in prostate cancer cell lines. Anticancer Res. 2015, 35, 4723–4732.
    180. Akinboye, E.S.; Rosen, M.D.; Bakare, O.; Denmeade, S.R. Anticancer activities of emetine prodrugs that are proteolytically activated by the prostate specific antigen (PSA) and evaluation of in vivo toxicity of emetine derivatives. Bioorg. Med. Chem. 2017, 25, 6707–6717.
    181. Hu, M.; Peng, S.; He, Y.; Qin, M.; Cong, X.; Xing, Y.; Liu, M.; Yi, Z. Lycorine is a novel inhibitor of the growth and metastasis of hormone-refractory prostate cancer. Oncotarget 2015, 6, 15348–15361.
    182. Wang, Q.; Xu, J.; Li, X.; Zhang, D.; Han, Y.; Zhang, X. Comprehensive two-dimensional pc-3 prostate cancer cell membrane chromatography for screening anti-tumor components from radix Sophorae flavescentis. J. Sep. Sci. 2017, 40, 2688–2693.
    183. Poornima, B.; Siva, B.; Shankaraiah, G.; Venkanna, A.; Nayak, V.L.; Ramakrishna, S.; Venkat Rao, C.; Babu, K.S. Novel sesquiterpenes from Schisandra grandiflora: Isolation, cytotoxic activity and synthesis of their triazole derivatives using “click” reaction. Eur. J. Med. Chem. 2015, 92, 449–458.
    184. Lan, J.; Huang, L.; Lou, H.; Chen, C.; Liu, T.; Hu, S.; Yao, Y.; Song, J.; Luo, J.; Liu, Y.; et al. Design and synthesis of novel c14-urea-tetrandrine derivatives with potent anti-cancer activity. Eur. J. Med. Chem. 2018, 143, 1968–1980.
    185. Li, G.; Petiwala, S.M.; Nonn, L.; Johnson, J.J. Inhibition of chop accentuates the apoptotic effect of alpha-mangostin from the Mangosteen fruit (Garcinia mangostana) in 22rv1 prostate cancer cells. Biochem. Biophys. Res. Commun. 2014, 453, 75–80.
    186. Sato, C.; Kaneko, S.; Sato, A.; Virgona, N.; Namiki, K.; Yano, T. Combination effect of delta-tocotrienol and gamma-tocopherol on prostate cancer cell growth. J. Nutr. Sci. Vitaminol. 2017, 63, 349–354.
    187. Stadlbauer, S.; Steinborn, C.; Klemd, A.; Hattori, F.; Ohmori, K.; Suzuki, K.; Huber, R.; Wolf, P.; Grundemann, C. Impact of green tea catechin ecg and its synthesized fluorinated analogue on prostate cancer cells and stimulated immunocompetent cells. Planta Med. 2018, 84, 813–819.
    188. Busch, C.; Noor, S.; Leischner, C.; Burkard, M.; Lauer, U.M.; Venturelli, S. Anti-proliferative activity of hop-derived prenylflavonoids against human cancer cell lines. Wien. Med. Wochenschr. 2015, 165, 258–261.
    189. Afsar, T.; Trembley, J.H.; Salomon, C.E.; Razak, S.; Khan, M.R.; Ahmed, K. Growth inhibition and apoptosis in cancer cells induced by polyphenolic compounds of Acacia hydaspica: Involvement of multiple signal transduction pathways. Sci. Rep. 2016, 6, 23077.
    190. Zhu, K.C.; Sun, J.M.; Shen, J.G.; Jin, J.Z.; Liu, F.; Xu, X.L.; Chen, L.; Liu, L.T.; Lv, J.J. Afzelin exhibits anti-cancer activity against androgen-sensitive lncap and androgen-independent pc-3 prostate cancer cells through the inhibition of lim domain kinase 1. Oncol. Lett. 2015, 10, 2359–2365.
    191. Jiang, C.; Masood, M.; Rasul, A.; Wei, W.; Wang, Y.; Ali, M.; Mustaqeem, M.; Li, J.; Li, X. Altholactone inhibits nf-kappab and stat3 activation and induces reactive oxygen species-mediated apoptosis in prostate cancer du145 cells. Molecules 2017, 22, 240.
    192. Shukla, S.; Shankar, E.; Fu, P.; MacLennan, G.T.; Gupta, S. Suppression of nf-kappab and nf-kappab-regulated gene expression by apigenin through ikappabalpha and ikk pathway in tramp mice. PLoS ONE 2015, 10, e0138710.
    193. Ryu, S.; Lim, W.; Bazer, F.W.; Song, G. Chrysin induces death of prostate cancer cells by inducing ros and er stress. J. Cell. Physiol. 2017, 232, 3786–3797.
    194. Sharma, U.K.; Sharma, A.K.; Gupta, A.; Kumar, R.; Pandey, A.; Pandey, A.K. Pharmacological activities of cinnamaldehyde and eugenol: Antioxidant, cytotoxic and anti-leishmanial studies. Cell. Mol. Biol. 2017, 63, 73–78.
    195. Adahoun, M.A.; Al-Akhras, M.H.; Jaafar, M.S.; Bououdina, M. Enhanced anti-cancer and antimicrobial activities of curcumin nanoparticles. Artif. CellsNanomed. Biotechnol. 2017, 45, 98–107.
    196. Chen, Q.H. Curcumin-based anti-prostate cancer agents. Anti-Cancer Agents Med. Chem. 2015, 15, 138–156.
    197. Dorai, T.; Cao, Y.C.; Dorai, B.; Buttyan, R.; Katz, A.E. Therapeutic potential of curcumin in human prostate cancer. III. Curcumin inhibits proliferation, induces apoptosis, and inhibits angiogenesis of lncap prostate cancer cells in vivo. Prostate 2001, 47, 293–303.
    198. Perrone, D.; Ardito, F.; Giannatempo, G.; Dioguardi, M.; Troiano, G.; Lo Russo, L.; A, D.E.L.; Laino, L.; Lo Muzio, L. Biological and therapeutic activities, and anticancer properties of curcumin. Exp. Ther. Med. 2015, 10, 1615–1623.
    199. Kumar, C.; Rasool, R.U.; Iqra, Z.; Nalli, Y.; Dutt, P.; Satti, N.K.; Sharma, N.; Gandhi, S.G.; Goswami, A.; Ali, A. Alkyne-azide cycloaddition analogues of dehydrozingerone as potential anti-prostate cancer inhibitors via the pi3k/akt/nf-kb pathway. MedChemComm 2017, 8, 2115–2124.
    200. Jeong, M.H.; Ko, H.; Jeon, H.; Sung, G.J.; Park, S.Y.; Jun, W.J.; Lee, Y.H.; Lee, J.; Lee, S.W.; Yoon, H.G.; et al. Delphinidin induces apoptosis via cleaved hdac3-mediated p53 acetylation and oligomerization in prostate cancer cells. Oncotarget 2016, 7, 56767–56780.
    201. Hafeez, B.B.; Siddiqui, I.A.; Asim, M.; Malik, A.; Afaq, F.; Adhami, V.M.; Saleem, M.; Din, M.; Mukhtar, H. A dietary anthocyanidin delphinidin induces apoptosis of human prostate cancer pc3 cells in vitro and in vivo: Involvement of nuclear factor-κb signaling. Cancer Res. 2008, 68, 8564–8572.
    202. Naiki-Ito, A.; Chewonarin, T.; Tang, M.; Pitchakarn, P.; Kuno, T.; Ogawa, K.; Asamoto, M.; Shirai, T.; Takahashi, S. Ellagic acid, a component of pomegranate fruit juice, suppresses androgen-dependent prostate carcinogenesis via induction of apoptosis. Prostate 2015, 75, 151–160.
    203. Eskandari, E.; Heidarian, E.; Amini, S.A.; Saffari-Chaleshtori, J. Evaluating the effects of ellagic acid on pstat3, pakt, and perk1/2 signaling pathways in prostate cancer pc3 cells. J. Cancer Res. Ther. 2016, 12, 1266–1271.
    204. Lall, R.K.; Syed, D.N.; Khan, M.I.; Adhami, V.M.; Gong, Y.; Lucey, J.A.; Mukhtar, H. Dietary flavonoid fisetin increases abundance of high-molecular-mass hyaluronan conferring resistance to prostate oncogenesis. Carcinogenesis 2016, 37, 918–928.
    205. Li, X.; Yokoyama, N.N.; Zhang, S.; Ding, L.; Liu, H.M.; Lilly, M.B.; Mercola, D.; Zi, X. Flavokawain a induces deneddylation and skp2 degradation leading to inhibition of tumorigenesis and cancer progression in the tramp transgenic mouse model. Oncotarget 2015, 6, 41809–41824.
    206. Drees, M.; Dengler, W.A.; Roth, T.; Labonte, H.; Mayo, J.; Malspeis, L.; Grever, M.; Sausville, E.A.; Fiebig, H.H. Flavopiridol (l86–8275): Selective antitumor activity in vitro and activity in vivo for prostate carcinoma cells. Clin. Cancer Res. 1997, 3, 273.
    207. Wang, Y.; Tsai, M.-L.; Chiou, L.-Y.; Ho, C.-T.; Pan, M.-H. Antitumor activity of garcinol in human prostate cancer cells and xenograft mice. J. Agric. Food Chem. 2015, 63, 9047–9052.
    208. Behera, A.K.; Swamy, M.M.; Natesh, N.; Kundu, T.K. Garcinol and its role in chronic diseases. Adv. Exp. Med. Biol. 2016, 928, 435–452.
    209. Jeon, Y.J.; Jung, S.N.; Yun, J.; Lee, C.W.; Choi, J.; Lee, Y.J.; Han, D.C.; Kwon, B.M. Ginkgetin inhibits the growth of du-145 prostate cancer cells through inhibition of signal transducer and activator of transcription 3 activity. Cancer Sci. 2015, 106, 413–420.
    210. Shirzad, M.; Heidarian, E.; Beshkar, P.; Gholami-Arjenaki, M. Biological effects of hesperetin on interleukin-6/phosphorylated signal transducer and activator of transcription 3 pathway signaling in prostate cancer pc3 cells. Pharmacogn. Res. 2017, 9, 188–194.
    211. Kang, S.; Kim, J.E.; Li, Y.; Jung, S.K.; Song, N.R.; Thimmegowda, N.R.; Kim, B.Y.; Lee, H.J.; Bode, A.M.; Dong, Z.; et al. Hirsutenone in alnus extract inhibits akt activity and suppresses prostate cancer cell proliferation. Mol. Carcinog. 2015, 54, 1354–1362.
    212. Lowe, H.I.C.; Toyang, N.J.; Watson, C.T.; Ayeah, K.N.; Bryant, J. Hlbt-100: A highly potent anti-cancer flavanone from Tillandsia recurvata (L.). Cancer Cell Int. 2017, 17, 38.
    213. Hahm, E.-R.; Karlsson, A.I.; Bonner, M.Y.; Arbiser, J.L.; Singh, S.V. Honokiol inhibits androgen receptor activity in prostate cancer cells. Prostate 2014, 74, 408–420.
    214. Miura, Y.; Oyama, M.; Iguchi, K.; Ito, T.; Baba, M.; Shikama, Y.; Usui, S.; Hirano, K.; Iinuma, M.; Mikamo, H. Anti-androgenic activity of icarisid II from Epimedium herb in prostate cancer lncap cells. J. Nutr. Sci. Vitaminol. 2015, 61, 201–204.
    215. Park, S.Y.; Lim, S.S.; Kim, J.K.; Kang, I.J.; Kim, J.S.; Lee, C.; Kim, J.; Park, J.H. Hexane-ethanol extract of glycyrrhiza uralensis containing licoricidin inhibits the metastatic capacity of du145 human prostate cancer cells. Br. J. Nutr. 2010, 104, 1272–1282.
    216. Seon, M.R.; Park, S.Y.; Kwon, S.J.; Lim, S.S.; Choi, H.J.; Park, H.; Lim, D.Y.; Kim, J.S.; Lee, C.H.; Kim, J.; et al. Hexane/ethanol extract of glycyrrhiza uralensis and its active compound isoangustone a induce g1 cycle arrest in du145 human prostate and 4t1 murine mammary cancer cells. J. Nutr. Biochem. 2012, 23, 85–92.
    217. Fang, F.; Chen, S.; Ma, J.; Cui, J.; Li, Q.; Meng, G.; Wang, L. Juglone suppresses epithelial-mesenchymal transition in prostate cancer cells via the protein kinase b/glycogen synthase kinase-3beta/snail signaling pathway. Oncol. Lett. 2018, 16, 2579–2584.
    218. McKeown, B.T.; McDougall, L.; Catalli, A.; Hurta, R.A. Magnolol causes alterations in the cell cycle in androgen insensitive human prostate cancer cells in vitro by affecting expression of key cell cycle regulatory proteins. Nutr. Cancer 2014, 66, 1154–1164.
    219. Li, M.; Ma, H.; Yang, L.; Li, P. Mangiferin inhibition of proliferation and induction of apoptosis in human prostate cancer cells is correlated with downregulation of b-cell lymphoma-2 and upregulation of microrna-182. Oncol. Lett. 2016, 11, 817–822.
    220. Nunez Selles, A.J.; Daglia, M.; Rastrelli, L. The potential role of mangiferin in cancer treatment through its immunomodulatory, anti-angiogenic, apoptopic, and gene regulatory effects. Biofactors 2016, 42, 475–491.
    221. Lee, J.; Lee, S.; Kim, S.L.; Choi, J.W.; Seo, J.Y.; Choi, D.J.; Park, Y.I. Corn silk maysin induces apoptotic cell death in pc-3 prostate cancer cells via mitochondria-dependent pathway. Life Sci. 2014, 119, 47–55.
    222. Shokoohinia, Y.; Hosseinzadeh, L.; Alipour, M.; Mostafaie, A.; Mohammadi-Motlagh, H.-R. Comparative evaluation of cytotoxic and apoptogenic effects of several coumarins on human cancer cell lines: Osthole induces apoptosis in p53-deficient h1299 cells. Adv. Pharmacol. Sci. 2014, 2014, 8.
    223. Liu, Y.; Zhang, X.; Kelsang, N.; Tu, G.; Kong, D.; Lu, J.; Zhang, Y.; Liang, H.; Tu, P.; Zhang, Q. Structurally diverse cytotoxic dimeric chalcones from Oxytropis chiliophylla. J. Nat. Prod. 2018, 81, 307–315.
    224. Xu, Y.; Zhu, J.Y.; Lei, Z.M.; Wan, L.J.; Zhu, X.W.; Ye, F.; Tong, Y.Y. Anti-proliferative effects of paeonol on human prostate cancer cell lines du145 and pc-3. J. Physiol. Biochem. 2017, 73, 157–165.
    225. Tsai, C.C.; Chuang, T.W.; Chen, L.J.; Niu, H.S.; Chung, K.M.; Cheng, J.T.; Lin, K.C. Increase in apoptosis by combination of metformin with silibinin in human colorectal cancer cells. World J. Gastroenterol. 2015, 21, 4169–4177.
    226. Sun, C.P.; Qiu, C.Y.; Yuan, T.; Nie, X.F.; Sun, H.X.; Zhang, Q.; Li, H.X.; Ding, L.Q.; Zhao, F.; Chen, L.X.; et al. Antiproliferative and anti-inflammatory withanolides from Physalis angulata. J. Nat. Prod. 2016, 79, 1586–1597.
    227. Aziz, M.H.; Dreckschmidt, N.E.; Verma, A.K. Plumbagin, a medicinal plant-derived naphthoquinone, is a novel inhibitor of the growth and invasion of hormone refractory prostate cancer. Cancer Res. 2008, 68, 9024–9032.
    228. Adaramoye, O.; Erguen, B.; Nitzsche, B.; Hopfner, M.; Jung, K.; Rabien, A. Punicalagin, a polyphenol from pomegranate fruit, induces growth inhibition and apoptosis in human pc-3 and lncap cells. Chem. Biol. Interact. 2017, 274, 100–106.
    229. Al-Jabban, S.M.; Zhang, X.; Chen, G.; Mekuria, E.A.; Rakotondraibe, L.H.; Chen, Q.H. Synthesis and anti-proliferative effects of quercetin derivatives. Nat. Prod. Commun. 2015, 10, 2113–2118.
    230. Li, X.; Chen, G.; Zhang, X.; Zhang, Q.; Zheng, S.; Wang, G.; Chen, Q.H. A new class of flavonol-based anti-prostate cancer agents: Design, synthesis, and evaluation in cell models. Bioorg. Med. Chem. Lett. 2016, 26, 4241–4245.
    231. Yang, F.; Song, L.; Wang, H.; Wang, J.; Xu, Z.; Xing, N. Quercetin in prostate cancer: Chemotherapeutic and chemopreventive effects, mechanisms and clinical application potential (review). Oncol. Rep. 2015, 33, 2659–2668.
    232. Li, J.; Chong, T.; Wang, Z.; Chen, H.; Li, H.; Cao, J.; Zhang, P.; Li, H. A novel anticancer effect of resveratrol: Reversal of epithelialmesenchymal transition in prostate cancer cells. Mol. Med. Rep. 2014, 10, 1717–1724.
    233. Wang, T.T.Y.; Hudson, T.S.; Wang, T.-C.; Remsberg, C.M.; Davies, N.M.; Takahashi, Y.; Kim, Y.S.; Seifried, H.; Vinyard, B.T.; Perkins, S.N.; et al. Differential effects of resveratrol on androgen-responsive lncap human prostate cancer cells in vitro and in vivo. Carcinogenesis 2008, 29, 2001–2010.
    234. Berman, A.Y.; Motechin, R.A.; Wiesenfeld, M.Y.; Holz, M.K. The therapeutic potential of resveratrol: A review of clinical trials. NPJ Precis. Oncol. 2017, 1, 35.
    235. Lee, C.L.; Hwang, T.L.; Peng, C.Y.; Chen, C.J.; Kuo, C.L.; Chang, W.Y.; Wu, Y.C. Anti-inflammatory and cytotoxic compounds from solanum macaonense. Nat. Prod. Commun. 2015, 10, 345–348.
    236. Karakurt, S.; Adali, O. Tannic acid inhibits proliferation, migration, invasion of prostate cancer and modulates drug metabolizing and antioxidant enzymes. Anti-Cancer Agents Med. Chem. 2016, 16, 781–789.
    237. Ghasemi, S.; Lorigooini, Z.; Wibowo, J.; Amini-Khoei, H. Tricin isolated from allium atroviolaceum potentiated the effect of docetaxel on pc3 cell proliferation: Role of mir-21. Nat. Prod. Res. 2018, 33, 1828–1831.
    238. Klosek, M.; Mertas, A.; Krol, W.; Jaworska, D.; Szymszal, J.; Szliszka, E. Tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in prostate cancer cells after treatment with xanthohumol-a natural compound present in Humulus lupulus L. Int. J. Mol. Sci. 2016, 17, 837.
    239. Ikemoto, K.; Shimizu, K.; Ohashi, K.; Takeuchi, Y.; Shimizu, M.; Oku, N. Bauhinia purprea agglutinin-modified liposomes for human prostate cancer treatment. Cancer Sci. 2016, 107, 53–59.
    240. Hu, E.; Wang, D.; Chen, J.; Tao, X. Novel cyclotides from Hedyotis diffusa induce apoptosis and inhibit proliferation and migration of prostate cancer cells. Int. J. Clin. Exp. Med. 2015, 8, 4059–4065.
    241. Gondim, A.C.S.; Romero-Canelon, I.; Sousa, E.H.S.; Blindauer, C.A.; Butler, J.S.; Romero, M.J.; Sanchez-Cano, C.; Sousa, B.L.; Chaves, R.P.; Nagano, C.S.; et al. The potent anti-cancer activity of Dioclea lasiocarpa lectin. J. Inorg. Biochem. 2017, 175, 179–189.
    242. Santha, S.; Dwivedi, C. Anticancer effects of sandalwood (Santalum album). Anticancer Res. 2015, 35, 3137–3145.
    243. Farimani, M.M.; Taleghani, A.; Aliabadi, A.; Aliahmadi, A.; Esmaeili, M.A.; Namazi Sarvestani, N.; Khavasi, H.R.; Smiesko, M.; Hamburger, M.; Nejad Ebrahimi, S. Labdane diterpenoids from Salvia leriifolia: Absolute configuration, antimicrobial and cytotoxic activities. Planta Med. 2016, 82, 1279–1285.
    244. Wang, W.; Rayburn, E.R.; Hao, M.; Zhao, Y.; Hill, D.L.; Zhang, R.; Wang, H. Experimental therapy of prostate cancer with novel natural product anti-cancer ginsenosides. Prostate 2008, 68, 809–819.
    245. Chun, J.Y.; Tummala, R.; Nadiminty, N.; Lou, W.; Liu, C.; Yang, J.; Evans, C.P.; Zhou, Q.; Gao, A.C. Andrographolide, an herbal medicine, inhibits interleukin-6 expression and suppresses prostate cancer cell growth. Genes Cancer 2010, 1, 868–876.
    246. Kuchta, K.; Xiang, Y.; Huang, S.; Tang, Y.; Peng, X.; Wang, X.; Zhu, Y.; Li, J.; Xu, J.; Lin, Z.; et al. Celastrol, an active constituent of the TCM plant Tripterygium wilfordii hook. F. inhibits prostate cancer bone metastasis. Prostate Cancer Prostatic Dis. 2017, 20, 156–164.
    247. Nie, C.; Zhou, J.; Qin, X.; Shi, X.; Zeng, Q.; Liu, J.; Yan, S.; Zhang, L. Diosgenininduced autophagy and apoptosis in a human prostate cancer cell line. Mol. Med. Rep. 2016, 14, 4349–4359.
    248. Silva, V.A.O.; Rosa, M.N.; Tansini, A.; Oliveira, R.J.S.; Martinho, O.; Lima, J.P.; Pianowski, L.F.; Reis, R.M. In vitro screening of cytotoxic activity of euphol from Euphorbia tirucalli on a large panel of human cancer-derived cell lines. Exp. Ther. Med. 2018, 16, 557–566.
    249. Guo, Y.X.; Lin, Z.M.; Wang, M.J.; Dong, Y.W.; Niu, H.M.; Young, C.Y.; Lou, H.X.; Yuan, H.Q. Jungermannenone a and b induce ros-and cell cycle-dependent apoptosis in prostate cancer cells in vitro. Acta Pharmacol. Sin. 2016, 37, 814–824.
    250. Sun, S.; Liu, J.; Zhou, N.; Zhu, W.; Dou, Q.P.; Zhou, K. Isolation of three new annonaceous acetogenins from graviola fruit (Annona muricata) and their anti-proliferation on human prostate cancer cell pc-3. Bioorg. Med. Chem. Lett. 2016, 26, 4382–4385.
    251. Younis, T.; Khan, M.I.; Khan, M.R.; Rasul, A.; Majid, M.; Adhami, V.M.; Mukhtar, H. Nummularic acid, a triterpenoid, from the medicinal plant Fraxinus xanthoxyloides, induces energy crisis to suppress growth of prostate cancer cells. Mol. Carcinog. 2018, 57, 1267–1277.
    252. Singh, S.; Dubey, V.; Singh, D.K.; Fatima, K.; Ahmad, A.; Luqman, S. Antiproliferative and antimicrobial efficacy of the compounds isolated from the roots of Oenothera biennis L. J. Pharm. Pharmacol. 2017, 69, 1230–1243.
    253. Akhtar, N.; Syed, D.N.; Khan, M.I.; Adhami, V.M.; Mirza, B.; Mukhtar, H. The pentacyclic triterpenoid, plectranthoic acid, a novel activator of ampk induces apoptotic death in prostate cancer cells. Oncotarget 2016, 7, 3819–3831.
    254. Piao, L.; Canguo, Z.; Wenjie, L.; Xiaoli, C.; Wenli, S.; Li, L. Lipopolysaccharides-stimulated macrophage products enhance withaferin a-induced apoptosis via activation of caspases and inhibition of nf-kappab pathway in human cancer cells. Mol. Immunol. 2017, 81, 92–101.
    255. Perabo, F.G.E.; von Löw, E.C.; Siener, R.; Ellinger, J.; Müller, S.C.; Bastian, P.J. [a critical assessment of phytotherapy for prostate cancer]. Urol. A 2009, 48, 270–271, 274–283.
    256. Wu, C.Y.; Yang, Y.H.; Lin, Y.Y.; Kuan, F.C.; Lin, Y.S.; Lin, W.Y.; Tsai, M.Y.; Yang, J.J.; Cheng, Y.C.; Shu, L.H.; et al. Anti-cancer effect of danshen and dihydroisotanshinone i on prostate cancer: Targeting the crosstalk between macrophages and cancer cells via inhibition of the stat3/ccl2 signaling pathway. Oncotarget 2017, 8, 40246–40263.
    257. Liu, J.-M.; Lin, P.-H.; Hsu, R.-J.; Chang, Y.-H.; Cheng, K.-C.; Pang, S.-T.; Lin, S.-K. Complementary traditional chinese medicine therapy improves survival in patients with metastatic prostate cancer. Medicine 2016, 95, e4475.
    258. Pantuck, A.J.; Leppert, J.T.; Zomorodian, N.; Aronson, W.; Hong, J.; Barnard, R.J.; Seeram, N.; Liker, H.; Wang, H.; Elashoff, R.; et al. Phase ii study of pomegranate juice for men with rising prostate-specific antigen following surgery or radiation for prostate cancer. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2006, 12, 4018–4026.
    259. Pantuck, A.J.; Leppert, J.T.; Zomorodian, N.; Seeram, N.; Seiler, D.; Liker, H.; Wang, H.-j.; Elashoff, R.; Heber, D.; Belldegrun, A.S. 831: Phase ii study of pomegranate juice for men with rising PSA following surgery or radiation for prostate cancer. J. Urol. 2005, 173, 225–226.
    260. Paller, C.J.; Ye, X.; Wozniak, P.J.; Gillespie, B.K.; Sieber, P.R.; Greengold, R.H.; Stockton, B.R.; Hertzman, B.L.; Efros, M.D.; Roper, R.P.; et al. A randomized phase ii study of pomegranate extract for men with rising psa following initial therapy for localized prostate cancer. Prostate Cancer Prostatic Dis. 2013, 16, 50–55.
    261. Thomas, R.; Williams, M.; Sharma, H.; Chaudry, A.; Bellamy, P. A double-blind, placebo-controlled randomised trial evaluating the effect of a polyphenol-rich whole food supplement on psa progression in men with prostate cancer—The UK NCRN pomi-t study. Prostate Cancer Prostatic Dis. 2014, 17, 180.
    262. Kjaer, T.N.; Ornstrup, M.J.; Poulsen, M.M.; Jorgensen, J.O.; Hougaard, D.M.; Cohen, A.S.; Neghabat, S.; Richelsen, B.; Pedersen, S.B. Resveratrol reduces the levels of circulating androgen precursors but has no effect on, testosterone, dihydrotestosterone, psa levels or prostate volume. A 4-month randomised trial in middle-aged men. Prostate 2015, 75, 1255–1263.
    263. Paller, C.J.; Rudek, M.A.; Zhou, X.C.; Wagner, W.D.; Hudson, T.S.; Anders, N.; Hammers, H.J.; Dowling, D.; King, S.; Antonarakis, E.S.; et al. A phase i study of muscadine grape skin extract in men with biochemically recurrent prostate cancer: Safety, tolerability, and dose determination. Prostate 2015, 75, 1518–1525.
    264. De La Taille, A.; Buttyan, R.; Hayek, O.; Bagiella, E.; Shabsigh, A.; Burchardt, M.; Burchardt, T.; Chopin, D.K.; Katz, A.E. Herbal therapy pc-spes: In vitro effects and evaluation of its efficacy in 69 patients with prostate cancer. J. Urol. 2000, 164, 1229–1234.
    More