Mini-reviewProstate cancer chemoprevention by natural agents: Clinical evidence and potential implications
Introduction
Despite the advances in prostate cancer (PCa) biology and therapeutics, according to the American Cancer Society's estimates, about 164,690 new cases of PCa will be diagnosed and about 29,430 deaths will occur in 2018, in the United States alone [1]. Traditionally, PCa development and progression is thought to be motivated by androgen and androgen receptor (AR), and therefore first-line of treatment androgen deprivation therapy (ADT) is used. However, the “saturation model” proposed by Morgentaler and Traish suggests that there is a limit to the capability of androgens to promote PCa growth, and this limit is based on maximal androgen-AR binding, which is achieved at well below the physiologic concentrations of serum testosterone [2]. Nevertheless, after initial ADT success, most patients with advanced disease eventually develop resistance and progress to castrate-resistant PCa (CRPC), which remains an incurable disease [3]. Low survival and high mortality of PCa are associated with the emergence of CRPC and subsequent metastatic disease. To advance the battle against PCa, it is necessary to continue both basic and clinical research to improve detection, prevention and treatment practices. However, the preventive approach could be considered as a fundamental strategy to reduce the incidence as well as mortality associated with PCa. To this end, novel strategies are required to be added to existing regimens and standards of care. Epidemiological studies have shown that healthy diet and exercise may significantly influence the pervasiveness of several cancers [4]. Several natural compounds, following promising preclinical testing, have been evaluated in clinics. In this review, we have discussed the data available from the clinical trials regarding several natural chemopreventive agents that have been tested for PCa chemoprevention. Additionally, we also present our thoughts on challenges and opportunities regarding the clinical use of chemopreventive agents for PCa.
Section snippets
Methodology
In this narrative review, we have discussed the PCa chemoprevention by selected natural agents based on available clinical evidence. We searched the NCBI's PubMed database for clinical trials with the key phrases “chemopreventive agents and prostate cancer”, “natural agents and prostate cancer”, and “chemoprevention and prostate cancer”. From these results, we selected all the published clinical studies in which natural agents were used for PCa management. Then we shortlisted those studies
Prostate cancer
According to the most recent estimates by the American Cancer Society, in the United States, PCa is the most common non-skin malignancy and the second leading cause of cancer death in American men, after lung cancer [1]. PCa pathogenesis is highly dependent upon signaling through the androgen receptor (AR), a ligand-dependent transcription factor. Binding of AR with androgen ligands, such as testosterone and dihydrotestosterone (DHT), produces a conformational change in AR to undergo
Chemoprevention for PCa management
PCa, like other cancers, can arise due to mutation(s) in important regulatory genes, most commonly through a carcinogenic or mutagenic agent or because of impaired DNA repair [8], as well as epigenetic modulations such as histone modifications, DNA methylation, and noncoding RNA (reviewed in Ref. [9]). These mutations can result in an unchecked growth of the affected cells through the three steps of cancer development: initiation, promotion, and progression. Cancer chemoprevention involves the
PCa clinical trials with natural chemopreventive agents
Though a number of pre-clinical studies have shown the benefits of chemopreventive agents in the prevention of prostate tumor formation and progression, a limited number of agents have been tested in clinical trials. Out of these, many clinical trials have been conducted to evaluate the safety, tolerability, pharmacokinetics and bioavailability of chemopreventive agents. Although this is a necessary step in testing new chemotherapeutic agents, these studies are not the focus of our review. We
Challenges and opportunities with PCa chemopreventive agents in clinical trials
There are a number of challenges in the translational development of natural chemopreventive agents. Some of these are, i) the lack of immediate effects that are required when chemopreventive agents are used in intervention settings, ii) fear of unexpected toxicity when chemopreventive agents are used in primary prevention settings (long-term supplementation), and iii) low target-organ and/or serum bioavailability of a number of chemopreventive agents. It can be extremely difficult to determine
Conclusions
The available literature on clinical studies using chemopreventive agents against PCa suggests variable outcomes postulating some discrepancies, with favorable, null, and unfavorable results. Some chemopreventive agents that target androgen-signaling have been shown to reduce PCa incidence, but it remains to be investigated if these agents can also reduce PCa mortality. As a concluding remark, we would like to point out that many chemopreventive agents have shown potential for PCa
Conflicts of interest
There is no conflict of interest to declare.
Acknowledgement
This work was partially supported by funding from the National Institutes of Health, United States (R01AR059130 and R01CA176748) and the Department of Veterans Affairs, United States (VA Merit Review Awards I01BX001008 and I01CX001441; and a Research Career Scientist Award IK6BX003780 to NA).
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