Encyclopedia
Please note this is a comparison between Version 2 by Jason Zhu and Version 1 by Javad Mottaghipisheh.
As water-soluble flavonoid derivatives, anthocyanidins and anthocyanins are the plants pigments mostly rich in berries, pomegranate, grapes, and dark color fruits. Many bioactivity properties of these advantageous phytochemicals have been reported; among them, their significant abilities in the suppression of tumor cells are of the promising therapeutic features, which have recently attracted great attention. The prostate malignancy, is considered the 2nd fatal and the most distributed cancer type in men worldwide. In general, the anthocyanins (especifically cyanidin-3-O-glucoside) indicated higher activity against prostatic neoplasms compared to their correlated anthocyanidins (e.g., delphinidin); in which potent anti-inflammatory, apoptosis, and anti-proliferative activities were analyzed.
- prostate cancer
- anthocyanidins
- anthocyanins
1. Introduction
Prostate cancer (PC) is known as the 4th commonly diagnosed cancer (7.3% of total cases) in human and the 2nd mortal cancer type in men; moreover, in accordance with the global cancer burden (GLOBOCAN 2020), PC is reported as the most frequent cancer in men prevailing in 112 countries [1].
In the recent years, some systemic chemicals have been developed for the treatment of metastatic castration-resistant PC. Besides mitoxantrone, as the first cytotoxic chemotherapy approved by the US Food and Drug Administration (FDA), cabazitaxel, abiraterone acetate, enzalutamide, pembrolizumab, sipuleucel-T, as well as radioisotopes (e.g., samarium-153 and strontium-89) have been developed as successful PC therapeutic options [2]. Although chemotherapeutic drugs with possible side effects can suppress several tumors types, nature, the major source of diverse natural products, has always been inspiring for discovering healing pathways towards the human ailments. Several plant secondary metabolites (phytochemicals) and their semi-synthetically derivatives have been approved and utilized as anticancer drugs or adjuvant of chemical medications; paclitaxel (syn. taxol), vinblastine, vincristine, camptothecin, and etoposide are the most effective natural-based drugs which widely prescribed for the treatment of various cancer types [3,4,5,6,7][3][4][5][6][7].
Anthocyanidins (ACDs) and anthocyanins (ACNs), as the plant pigments are rich in many fruits and vegetables coloring red, violet, and blue, whilst mainly characterized as unsaturated, water-soluble, and unoxidized flavonoid derivatives. Potential anti-tumor capacities of these compounds have previously been reported [8], whereas they might be caused due to various related bioactivity properties of these compounds comprising anti-inflammation, antioxidant, anti-mutagenesis, anti-proliferation, stimulating autophagy or apoptosis, anti-invasion, anti-metastasis, etc. [9].
2. Metabolic Pathways of Prostate Cancer
The cellular origin of PC is not very clear. However, it was shown that PC develops from normal prostate epithelium through multistep histological transformation processes, under molecular changes. The major signaling pathways that are most frequently altered in prostate cancer include androgen receptor (AR), the PI3K, Ras/Raf/MEK/ERK; and the retinoblastoma (RB) signaling pathway. AR regulates the normal growth and development of the prostate gland. However, in PC, AR is overexpressed to some degree resulting in the serum PSA rising. AR signaling pathway in PC occurs via various mechanisms, including mutation or amplification of AR, the presence of intratumoral testosterone production, and the presence of splice variants of the AR receptor. Briefly, the binding of dihydrotestosterone leads to AR homodimerization, translocation to the nucleus, and recruitment to the androgen response elements (AREs) to initiate transcription [20,21,22][10][11][12]. The PI3K/Akt signaling pathway is part of a complex intracellular cell signaling cascade that regulates cellular metabolism, tumor development, growth, proliferation, metastases, and cytoskeletal reorganization. The PI3K/Akt pathway is initiated through the downstream of receptor tyrosine kinases (RTKs) activation. Next, PI3K catalyzes the phosphorylation of PIP2 to produce PIP3. Generation of PIP3 recruits PDK1 and Akt to the plasma membrane, resulting in subsequent phosphorylation of Akt by PDK1. Phosphorylated Akt starts a wide range of pathways but most importantly activates the mammalian target of rapamycin (mTOR), which is a serine/threonine kinase that plays a critical role in tumorigenesis, regulation of cell growth, survival, and division. Interaction between Akt and AR can lead to AR activation in a ligand-independent manner (androgen-independent manner), ultimately up-regulating genes involved in CRPC tumorigenesis. Also, the activated Akt regulates downstream effectors such as BAD, GSK3β, TSC2, and PRAS40 to control various cellular processes, including protein synthesis, cell proliferation, growth, and survial [23,24,25][13][14][15]. The extracellular molecules such as growth factors, hormones, tumor-promoting substances, and differentiation factors, bind to receptor tyrosine kinases (RTKs) and initiate the intracellular signals for regulating cell proliferation, differentiation, and survival through mitogen-activated protein kinase (MAPK) cascade. RAS proteins are placed on the cytoplasmic side of the cell membrane which is activated in GTP-bound conformation and inactivated in GDP-bound conformation resulting in the accumulation of active RAS proteins in cells followed by stimulation of RAF. RAS causes persistent activation of the ERK-MAPK cascade in human cancers. Activated ERKs translocate to the nucleus, where they phosphorylate and regulate various transcription factors, leading to change in gene expression [26,27][16][17]. The retinoblastoma (Rb) tumor suppressor protein plays a role in the control of the cell cycle, terminal differentiation, control the DNA damage response and promotes cell cycle arrest in G1. Its function is reverted by Rb phosphorylation by cyclin D-CDK, which inactivates Rb and promotes E2F1-mediated transcription [28,29,30][18][19][20]. This situation causes constitutive activation and the induction of uncontrolled cell proliferation. Chemopreventive effect is stated as potency of natural, synthetic, or biological compounds to hinder cancer incidence. These substances are able to protect DNA damage, specifically by reversing or blocking proliferation of these nonmalignant cells [31][21]. In the clinical aspect, dietary phytochemicals and non-steroidal anti-inflammatory drugs (NSAID) can be consumed as chemopreventive agents in the populations with high cancer risk and the normal populations [32][22].3. In Vivo Experiments Evaluating the Effectiveness of Anthocyanidins/Anthocyanins on Prostate Cancer
Preclinical in vivo experimental data was gained from rodent models in mice including athymic nude mice implanted with PC3 and stress provoked benign prostate hyperplasia (BPH); however, animal models in rats include BPH induced by testosterone derivatives such as testosterone enanthate or testosterone propionate. Followings describe the animal studies evaluating the impacts of ACDs/ACNs and natural sources of these compounds on PC cells.
3.1. Mice Model Experiments
Diet with delphinidin suppressed the tumor growth in the athymic nude mice implanted with PC3 cells. In addition, it controlled the protein levels of Bax and Bcl-2, and inhibited the protein levels of cyclin D1 and NF-κB. Furthermore, it suppressed PCNA and Ki67 expression (markers of proliferation) in PC3 originated tumors in athymic nude mice; suggesting the anti-proliferative efficacy of delphinidin [81][23]. Supportively, the delphinidin administration (2 mg, i.p. thrice weekly) to athymic nude mice implanted with PC3 cells showed a significant decrease in the expression of NF-κB/p65, Bcl-2, Ki67, and PCNA [58][24].
Oral administration of sweet potato greens extract (SPGE) significantly inhibited growth and progression of prostate tumor xenografts by 69% in athymic nude mice, as shown by non-invasive real-time bioluminescent imaging and tumor volume measurements. The SPGE treatment reduced the cyclin D, E and D1 expression, and rose the p21 expression in tumor cells. Also, the caspase-3/7 activity and cleaved caspase-3 expression was higher in SPGE-treated tumors in comparison with control, while it proposes the in vivo anti-proliferative response of the SPGE. Moreover, this extract showed no toxicity to quickly divide normal tissues such as bone marrow and gut [52][25]. Sweet potato extract also inactivated Bcl-2 as well as upregulated BAX, cytochrome c release, and triggered downstream apoptotic signaling. Oral administration of 400 mg/kg extract inhibited growth and progression of prostate tumor xenografts by ~70% in nude mice [52][25].
A supplementary diet with the rich ACNs extract (AE) of bilberry (Vaccinium myrtillus L.), administered to stress-provoked BPH in mice, had the protective effects against stress-induced oxidative injury by reducing lipid peroxidation content, elevating glutathione content, oxygen radical absorbance capacity, as well as glutathione peroxidase and superoxide dismutase activities. These results showed the antioxidative activity of AE involved in the amelioration of BPH [84][26].
Wang et al. investigated the antitumor effect of anthocyanin C3G extracted from Chinese bayberry fruit (Myrica rubra Sieb. et Zucc.), on a nude mouse tumor xenograft model. C3G inhibited the growth of SGC-7901 tumor xenografts. The average tumor volume on the 18th day were measured 771.5 mm3, 211.7 mm3, 384.1 mm3 and 276.0 mm3, in the control group, tegafur-treated group (positive control), C3G treatment groups with low dose and high dose, respectively. Moreover, C3G revealed ability to inhibit the cell cycle of SGC-7901 tumor xenografts in the C3G treatment groups by obvious positive p21 staining in cell nuclei in a dose-dependent manner. The mRNA expression and protein expressions of KLF6 and p21 were significantly augmented in the C3G treatment group in comparison with normal group, representing the vital role of KLF6 in the tumor xenograft inhibition in vivo. However, the p53 protein did not alter, but Cyclin D1 and CDK4 mRNA and proteins levels were reduced [91][27].
Ha et al. evaluated the apoptosis and tumor growth of ACNs extracted from the black soybean on DU-145 tumor xenografts established in athymic nude mice. Black soybean (Glycine max L. Merr) has been known for its phenolic rich content mainly flavonoids (i.e., ACDs), stilbenes, lignans, and phenolic acids. It has demonstrated a variety of biological potencies including anti-tumor, anti-diabetic, and for the treatment of cerebrovascular, neurodegenerative, and cardiovascular diseases [92][28]. It has been exhibited that 2 weeks oral treatment with daily 8 mg/kg of ACN increased apoptosis significantly in a dose-dependent manner. Also, the decrease in p53 and Bcl-2 expressions with the increased Bax expression, as well as a lessening in PSA and AR co-expression was observed [87][29].
In another study, Lamas et al. evaluated the impact of two doses of the patented jaboticaba peel extract (PJE) on inflammation and oxidative stress in the prostate of high-fat-fed (HFD) aging or aging mice. The PJE decreased the contents of oxidative-stress parameters (4-hydroxynonenal, glutathione peroxidase 3, glutathione reductase, and catalase), inflammatory mediators phosphorylated signal transducers and activators of transcription 3 (pSTAT-3), tumor necrosis factor α (TNF-α), cyclooxygenase 2 and CD3+ T cells’ number, which were correlated to preservation of the glandular morphological integrity of prostate in HFD-fed aging and aging mice. Nevertheless, merely the high PJE dose ameliorated the toll-like receptor 4 (TLR4), and nuclear factor κB (NF-κB) contents in aging mice, and IL-1β, SOD2, and IL-6 levels in HFD-aging mice. Authors stressed that PJE had a dose-dependent impact on regulating oxidative-stress and inflammation in HFD-fed aging and aging mice prostate [90].
3.2. Rat Model Experiments
Oral administration of the ACNs extracted from black soybeans significantly reduced prostate weight in a rat model of BPH induced by testosterone propionate (TP). The mean prostate weight for the control, BPH-induced rats, and rats receiving 40, 80, and 160 mg/kg ACNs were 674.17 ± 28.24 mg, 1098.33 ± 131.31 mg, 323.00 ± 22.41 mg, 324.00 ± 26.80 mg, and 617.50 ± 31.08 mg, respectively. The average prostate weight in the ACNs-treated groups were markedly lower rather than in the BPH-induced rat, while the apoptotic body counts were significantly higher than in the BPH-induced animal. These findings propose that ACNs may be useful in reducing the volume and inhibiting the proliferation of the prostate [82][30].
In another study, Jang et al. showed that oral administration of an ACN extracted from the seed coat of the black soybean prevented apoptosis in the prostate cells in andropause animal model by bilateral orchiectomy. Despite reporting no remarkable changes in prostate weight between andropause and andropause plus anthocyanin-treated groups, the apoptotic index was meaningfully lesser in andropause plus anthocyanin-treated groups compared to the andropause group. The oxidative stress in the ACN-administered group was reduced rather than in the andropause group [83][31].
A diet with ACNs extracted from black soybean may be useful in treating chronic bacterial prostatitis (CBP) rat model. The ACNs plus ciprofloxacin group indicated a significant reduction in improvement of the prostatic inflammation and bacterial growth in comparison with the ciprofloxacin group; suggesting that ACNs may have antimicrobial and anti-inflammatory effects [85][32].
Seoritae is a black soybean that contains high isoflavone and anthocyanin compounds. Oral administration of seoritae extract (SE) previously demonstrated beneficial effects on the loss of prostate weight and prostate proliferation in the BPH induced by testosterone enanthate in a rat model. The SE treatment groups indicated a significant reduction in prostate weight, apoptosis (caspase-3), oxidative stress markers (8-hydroxy-2-deoxyguanosine and SOD), and 5-α reductase activity compared to the non-treated BPH group [86][33].
In another research, oral administration of polymerized anthocyanin (PA) from grape skin was able to reduce the prostate weight in the TP-induced BPH rats. PA ameliorated serum dihydrotestosterone (DHT) levels, and the 5-α reductase type 2, androgen receptor, steroid receptor coactivator 1, proliferating cell nuclear antigen (PCNA), prostate-specific antigen, and cyclin D1 expression in prostate tissues. Furthermore, PA downregulated and upregulated the expressions of Bcl-2 and Bax, respectively, in the prostate tissues of rats with BPH. Authors stated that PA may be a possible natural agent for BPH treatment [88].
A diet with the extract of Aronia melanocarpa in TP-induced BPH Wistar rats attenuated prostate enlargement and decreased the levels of 5 α-reductase and DHT in prostate tissue and serum. The PCNA expression in prostate tissue was significantly suppressed in the A. melanocarpa-treated group. These results displayed that the extract (including ACNs) weakened the progression of testosterone-induced prostatic hyperplasia, and recommended that A. melanocarpa has beneficial potential to treat prostate enlargement and BPH [89][34].
A diet with 1% hexane insoluble fraction from a purple rice ethanolic extract (PRE-HIF) indicated a reduction in the prevalence of adenocarcinoma in the lateral lobes of the prostate and markedly higher percentage of low-grade prostatic intraepithelial neoplasia in transgenic rat for adenocarcinoma of prostate model. In addition, 1% PRE-HIF diet meaningfully repressed the tumor growth in a rat CRPC xenograft model of the PCai1 cells. Additionally, cyclin D1, androgen receptor, fatty acid synthase, and cdk4 expression were reduced while AMP-activated protein kinase α activation, and p38 mitogen-activated protein kinase upregulated in the prostate tissues of PRE-HIF-treated rats and CRPC tumors. Authors stated that the PRE-HIF can inhibit the progression of CRPC and PC by blocking the cell proliferation and metabolic pathways [60].
4. The Efficacy Assessment of Anthocyanidins/Anthocyanins on Prostate Cancer through Clinical Trials
In three clinical trials, the efficacy of ACDs or ACDs rich fruits have assessed, while 198 prostatic cancer men were targeted in those studies. In a clinical trial, the effect of black raspberry (Rubus occidentalis) in different concentrations were evaluated on 56 men newly diagnosed with resectable prostate cancer. According to the results, during 8 weeks of black raspberry storage, no significant changes in bioactivities were observed, whereas with both dosages of 10 and 20 g black raspberry/day in nectar and confection products were accepted to be considered for further prostate cancer clinical trials [93][35].
Inflammation of the bladder which is called acute radiation cystitis, is defined as a prevalent side effect of external beam radiation therapy, used for the treatment of prostate cancer [94][36]. In two double-blinded randomized placebo-controlled trials, the impact of ACNs on cystitis of the patients during radiation therapy treatment have been investigated.
Hamilton et al. selected 41 patients with normal mainly New Zealand European diet, who were receiving image guided intensity modulated radiation therapy for the treatment of prostate cancer. The patients were taken one capsule of cranberry (Vaccinium macrocarpon) per day after breakfast for two weeks post radiation therapy treatment. Consequently, 65% and 30% of patients taking the capsules developed cystitis and severe cystitis, thus taking of cranberry is suggested for patients receiving radiation therapy, specifically with low hydration regimens or baseline urinary symptoms [94][36].
In another clinical trial, 101 men were chosen, who were receiving beam radiation therapy for the treatment of their prostate or prostate bed. After taking two capsules containing cranberry (Vaccinium macrocarpon) daily, during radiation therapy, no remarkable effect on RICAS (novel radiation induced cystitis assessment scale) was observed in comparison with the taking capsules and placebo groups. Therefore, it is suggested that analysis of RICAS can be implemented for measuring severe cystitis in prostate cancer therapy [95][37]. Since the fruits analysed in the abovementioned studies are well-known as rich sources of ACDs/ACNs, thus the effects can accordingly be related to those compounds, however further studies might be interesting to assess their effects in pure forms.
