Prostate cancer (PCa) is the second most common type of tumor worldwide and is the fifth leading cause of cancer-related mortality among men. Despite the high morbidity for PCa, its etiology is not yet defined, the only known risk factors are age, race, and family history ^[1][2][1,2]. Other risk factors, such as hormones, diet, physical inactivity, obesity, smoking, sexual factors, and genetic susceptibility have been related to PCa, but the epidemiological evidence is not conclusive. Although the role of these factors is not yet defined, a complex interaction between them is likely to be associated with the development of PCa ^[2][3][4][2,3,4].

PCa is known to be linked to androgens and estrogen receptors [5]. Despite the use of prostate-specific antigen (PSA) and some recent clinical trials testing early biomarkers of PCa onset, the incidence rates of PCa have dramatically increased [4]. To date, endocrine therapy (anti-androgens combined with castration) and classical androgen deprivation (orchiectomy or luteinizing hormone-releasing hormone agonists) represent the most effective treatments for advanced and metastatic PCa. Unfortunately, although most patients favorably respond for a long time, progression to castration-resistant disease is nearly universal, and most patients eventually die from recurrent androgen-independent prostate cancer ^[6][7][6,7].

Increased oxidative stress is a risk factor in the onset and progression of PCa [8]. Oxidative free radicals are produced by several factors and metabolic cellular pathways, such as consumption of saturated fats and refined carbohydrates which can contribute to the development of PCa ^[9][10][9,10]. Oxidative damage is induced by the production of reactive oxygen species (ROS), as well as by other oxidants, such as reactive nitrogen species (RNS). Overproduction of reactive species can lead to protein/lipid oxidation and DNA mutation. The onset and progression of PCa can be prevented by modifying eating habits through modulation of the nuclear factor kappa B (NF-κB), target of rapamycin in mammals (mTOR), mitogen-activated protein kinase (MAPK), Akt, extracellular signaling regulated kinase (ERK), and phosphoinositide 3-kinase (PI3K) signaling pathways. In this context, a diet rich in vitamins A, D, and E, minerals (selenium and zinc), phytochemicals, and dietary fiber could reduce the risk of prostate cancer [11].

Because of the lack of effective drugs, early diagnosis in PCa is fundamental, since only diseases in the early stages are amenable to curative treatment, while patients with advanced disease can only be palliative. In this context, new therapeutic approaches are needed, as well as new specific biomarkers, both for early diagnosis and as tools for prognosis [12]. Several components of the diet are involved in the development and progression of PCa supporting the evidence that PCa incidence and mortality are higher in industrialized countries, where diets are generally high in fat [13]. Many dietary components may play a role in prostate development and progression cancer. Fruits and vegetables rich in antioxidants and phytochemicals have a demonstrable beneficial effect on PCa and can slow down its development and the risk of occurrence [14].

PCa is a malignant tumor of the prostate gland. This tumor tends to develop in older men, aged 50 or older, and it usually develops slowly; however, in some cases, it can be aggressive and metastasize from the prostate to other parts of the body. The human prostate is divided into three zones: peripheral, transitional, and central; in about 80% of cases, prostate adenocarcinoma originates from the peripheral or caudal area of the gland [15]. Transforming cells can be basal or luminal epithelial cells; both can result in high-grade lesions resembling adenocarcinomas [16]. Men between the ages of 50 and 75 undergo a surveillance strategy by assessing the concentration of prostate-specific antigen (PSA) in the blood, along with rectal examination to assess the size of the prostate gland. The first treatment for PCa is based on clinicopathological factors, such as PSA concentrations, clinical stage of the tumor, and histological grade, according to the Gleason score classification to the International Society of Urological Pathology Grade Group Classification [17]. After an initial diagnosis, the neoplasm is divided into low, intermediate, and high risk, and this subdivision includes multiple factors such as the number of positive biopsy specimens, tumor size, imaging results, and molecular signatures [18]. All these parameters determine the management of the disease. Generally, PCa treatment involves surgical therapy, pharmaceutical management, and androgen deprivation (ADT). ADT is frequently associated with sexual dysfunction, diabetes, cognitive dysfunction, cardiovascular disease, and alteration of the bone density [19]. Intense studies have significantly improved the management of the metastatic disease with the addition of new agents.

Several clinical trials have reported better results when androgen deprivation was combined with the use of chemotherapy drugs such as docetaxel or hormonal drugs (abiraterone, enzalutamide, or apalutamide). The introduction of Relugolix, an antagonist of AR, showed a decrease in cardiovascular side effects and suppression of serum testosterone. Poly-ADP ribose polymerase inhibitors (olaparib and rucaparib) have received Food and Drug Administration approval as they have given a significant clinical benefit in patients with deleterious mutations in the genes belonging to the homologous repair path of recombination. Recently, the combination of standard treatment with Lutetium-177 prostate-specific membrane antigen-617 improved survival in men with metastatic castration resistant prostate cancer [20].

PCa is correlated with complex interactions among inherent germline susceptibility, acquired somatic gene alterations, and micro/macroenvironmental factors. Generally, PCa presents multiple foci containing different genetic alterations with different capacity for metastatic seeding and inherent treatment resistance. Some authors argue that chronic microbial inflammation of the urinary tract participates in prostatic carcinogenesis through the generation of reactive oxygen species that induce DNA damage and selection of mutated cells. In addition, during inflammatory processes, the prostate has many proliferative luminal epithelial cells of intermediate phenotype that could be subject to epigenetic and genomic chromatin alterations, which induce malignant transformation [21].

The prostatic intraepithelial neoplasia can be categorized from low-grade to high-grade transformation. The high-grade prostatic intraepithelial neoplasia lesions can be associated with markers of transformation, such as the overexpression of the enzyme alphamethylacyl-CoA racemase (AMACR), which is associated with adenocarcinoma, the loss of the basal markers p63 (TP63), cytokeratin 5 (KRT5), and cytokeratin 14 (KRT14), and the gain of luminal markers, such as cytokeratin 8 (KRT8), while the TMPRSS2 gene is thought to be involved in luminal differentiation ^[15][16][21][15,16,21]. The most common chromosomal aberration present in more than 50% of patients with prostate cancer is represented by a gene fusion between TMPRSS2 and ERG genes [15]. However, it is thought that the epithelial transformation is secondary to a series of phenotypes and genotypic changes within a tumor-permissive inflammatory microenvironment in the prostate. More than 40% of patients showed genomic fusion of TMPRSS2–ERG, 5–15% showed loss-of-function mutations in SPOP, and 3–5% showed gain-of-function mutations in FOXA1 ^[15][22][23][15,22,23], while alterations of the androgen receptor (AR) gene are rare [22]. Furthermore, about 20% of the patients show PTEN deletions and TP53 mutations, and their frequency increases to more than 50% in cases with advanced disease. About 40% of nonmetastatic cancers have increased genetic instability, which is associated with disease recurrence ^[24][25][24,25]. This genomic instability, together with intratumoral hypoxia, causes highly aggressive tumors with a high probability of relapse [26]. The alterations in AR signaling should also be mentioned, which are important drivers of resistance to androgen deprivation therapy. Alterations of the AR pathway are evident in metastatic castration-resistant prostate cancer (MCRPC) [27].

Several studies have reported AR aberrations as mediators of acquired resistance toward targeting agents AR [28]. It is known that the loss of dependence on AR signaling occurs in 15–20% of advanced and treatment-resistant prostate cancers and can evolve into the castration-resistant transformation of the neuroendocrine prostate cancer. Genes involved in repairing DNA errors and breaks are also implicated in prostate cancer; in fact, men with BRCA1 or BRCA2 mutations have a higher probability of getting prostate cancer with a high incidence of disease aggression due to the additional activation of MYC in combination with inactivation of TP53 and PTEN ^[29][30][29,30]. About 12% of patients inherit mutations in the BRCA1, BRCA2, ATM, CHEK2, RAD51D, and PALB2 genes [31].

In particular, there is consolidated evidence from NGS data on several patient cohorts that accumulation of hotspot gain-of-function mutations in the TP53 gene can also be found at a relatively high frequency (28–36%) in primary and, especially, in naïve metastatic prostate cancer ^[32][33][34][32,33,34]. In castration-resistant prostate cancer, the TP53 mutation rate was reported between 53% and 73% [33]. From this point of view, the management of PCa is constantly evolving to try to understand the genomics and biology underlying cancer from primary to metastatic forms. Indeed, mutational perturbations could have strong potential as biomarkers to stratify the risk of the patients and to identify those who could benefit from specific treatment.

Very recently, alternative polyadenylation (APA), which is a molecular mechanism that produces mRNAs that differ in their 3′ end, has been shown to be a novel, interesting and targetable way to affect PCa carcinogenesis [35].

In this context, the development of increasingly sensitive imaging methods has significantly improved diagnostic accuracy and correct staging in order to improve surveillance strategies. The remarkable advances made by research have introduced new therapies into clinical practice, with treatments targeting genomic alterations in DNA repair pathways. A notable improvement in disease management has been achieved in the treatment of metastatic forms, with the use of several new androgen pathway inhibitors that significantly improve patient survival. Molecular typing of localized and recurrent diseases will certainly bring benefits on clinical management. Furthermore, the study of new therapies, such as targeted radioisotopes and immunotherapy, bode well for improving the lives of patients with PCa [2].

As previously remarked, among the different risk factors associated with PCa, differences in the incidence of PCa have been demonstrated as a function of diet, country of residence, and ethnicity ^[11][36][11,36]. These observations have promoted studies that correlate PCa with antioxidant intake from diet and supplements. To date, the effects of antioxidants on the progression of PCa are scarcely known; however, antioxidants play an important role in the body as they prevent damage from free radicals, molecules that attack healthy cells and can contribute to cancer risk.

Antioxidants are substances able to counteract the production of free radicals and the oxidation process; they can be classified according to their source: endogenous sources such as enzymes, and exogenous sources such as beta-carotene, lycopene, and vitamins A, C, and E (tocopherols). The mineral element selenium is generally considered a food antioxidant, but the antioxidant effects of selenium are most likely due to the antioxidant activity of proteins that have this element as an essential component [37]. Several scientists have reported that the use of synthetic antioxidants causes health problems due to the fact that some of these compounds exhibit toxicity after their absorption, and this fact could invalidate numerous clinical studies that have been carried out on patients who have taken these supplements ^[37][38][37,38].

Very recently, thanks to some economic pushes and the novel therapies based on holistic medicine, the literature has reported examples of the use of plant raw materials rich in antioxidants and products derived from their processing to obtain foods fortified with antioxidants compared to their traditional formulations [39]. From this, it appears that it is very important to study the intermediate products deriving from the catabolism of the antioxidant molecules contained in foods, to have knowledge of their stability once ingested and their function as a free-radical scavenger. This step makes it possible to synthesize more functional and easily controllable active ingredients to determine a regimen while also avoiding the thermal processes that can cause modification in the chemical structure of compounds and the bioactive properties of food.

However, only a limited number of studies have been reported for vitamin E, selenium, and a few other antioxidants bioavailability [40]. For example, a very recent paper reported that hydroalcoholic pomace extracts containing high concentrations of anthocyanins, phenolic acids, flavonoids, and stilbenes had a higher antioxidant activity than aqueous extracts [41]. However, the antioxidant activity of aqueous extracts increased after intestinal digestion by promoting the proliferation of probiotic bacteria, while that of hydroalcoholic extracts dramatically decreased [41].

According to some clinical trials and experiments on in vivo models, antioxidants if not carefully administered could help the onset of cancer and interfere with chemotherapy treatments ^[38][42][38,42]. Furthermore, these studies often lack pharmacokinetic experiments to evaluate the presence of functionally active antioxidant molecules in the participants’ serum.

However, there are still numerous positive results of beneficial antioxidant effects during cancer chemotherapies and cancer cachexia pathogenesis ^[38][42][38,42].

The concept of antioxidants is quite complex; in general, an antioxidant is a molecule or drug that hinders an oxidation reaction. Therefore, the definition of oxidation is a chemical process whereby electrons are lost during the reaction by the chemical species that are involved. These electrons are gained from a different chemical species, and this process is called reduction. Oxidation and reduction reactions occur coupled, and these processes are referred to as redox reactions [43]. These reactions are important for cell physiology; however, in some imbalance situations, they are harmful to the system and have deleterious effects. Oxygen is the terminal oxidant of the respiratory or electron transport chain [44]; on the one hand, it is essential for life, while, on the other, it causes various cellular damage during the production of reactive oxygen species (ROS), such as superoxide anion (O₂⁻), hydrogen peroxide (H₂O₂), and hydroxyl radical (HO•). High ROS levels or a decrease in the cellular antioxidant capacity leads to cell oxidative stress, resulting in ROS-mediated damage of nucleic acids, proteins, and lipids. Oxidative stress is implicated in various disease states such as atherosclerosis, cancer, neurodegeneration, and aging [45]. It has been reported that ROS can interact with driver pathways to initiate signaling in a wide variety of cellular processes, such as proliferation and survival (MAP kinase, PI3 kinase, and PTEN), ROS homeostasis and antioxidant gene regulation (thioredoxin, peroxiredoxin, Ref-1, and Nrf-2), mitochondrial oxidative stress, apoptosis, aging, and DNA damage response ^[45][46][47][45,46,47].

Very recent data suggest that natural plant-derived antioxidants could have therapeutic properties by modulating microRNAs (miRNAs), a class of noncoding RNA, that are involved in inflammation and carcinogenesis and are deregulated in diverse tumors, including PCa [48]. These findings implicate that the use of antioxidants may be an attractive miRNA-mediated chemopreventive and therapeutic option in PCa.

Growing evidence points out that PCa is closely associated with aging mechanisms, and high levels of ROS induced by aging activate several pathways which facilitate the onset, development, and progression of PCa [8]. Various sources of intracellular ROS are reported to contribute to the pathogenesis and the progression of PCa. Some of these high levels of reactive oxygen forms result from dysfunctional mitochondrial cellular respiration, the Warburg effect (altered glucose metabolism), overexpression of p66Shc related to age disorders, and the activation of enzymes such as NADPH oxidases, xanthine oxidases, and cytochrome P450. Furthermore, non-physiological ROS levels are associated with oxidative damage of proteins, lipids, and nucleic acids [49]. Other studies have shown that ROS production and oxidative stress led to androgen stimulation in androgen receptor (AR)-positive cells of PCa. In fact, androgens activate AR signaling driving the growth and metastasis, while simultaneously suppressing the apoptosis of PCa cells [50]. Epidemiological studies strongly suggest that a lower risk of cancer is associated with diets that indicated a high consumption of fruit and vegetables; thus, the active ingredients of these foods were tested to verify their preventive and anticancer properties, and to study their molecular mechanism of action [51].