Prostate cancer chemoprevention by natural agents: Clinical evidence and potential implications

Abstract

Prostate cancer (PCa) is the most common non-skin cancer and the second leading cause of cancer-related deaths in American men. Due to its long latency period, PCa is considered as an ideal cancer type for chemopreventive interventions. Chemopreventive agents include various natural or synthetic agents that prevent or delay cancer development, progression and/or recurrence. Pre-clinical studies suggest that many natural products and dietary agents have chemopreventive properties. However, a limited number of these agents have been tested in clinical trials, with varying success. In this review, we have discussed the available clinical studies regarding the efficacy of natural chemopreventive agents against PCa, including tea polyphenols, selenium, soy proteins, vitamins and resveratrol. We have also provided a discussion on the clinical challenges and opportunities for the potential use of chemopreventive agents against PCa. Based on available literature, it appears that the variable outcomes of the chemopreventive clinical studies necessitate a need for additional studies with more rigorous designs and methodical interpretations in order to measure the potential of the natural agents against PCa.

Keywords: Chemoprevention; Clinical trials; Natural agents; Prostate cancer.

Figure 1. Schematic representation of PCa pathogenesis showing androgen receptor (AR) dependent and independent signaling as well the potential targets of the chemopreventive agents

Androgen ligands bind to AR and produce a conformational change in AR to undergo homodimerization that allows for nuclear translocation where AR binds to androgen response elements (ARE). AR binding to the AREs induces androgen-responsive gene expression that supports growth and survival of prostate cells and further progression of the PCa. PSA is one of the downstream AR signaling genes, and a well-known PCa clinical biomarker. AR-independent PCa mechanisms include overexpression of the glucocorticoid receptor (GR) which can substitute AR in binding to AREs, and activation of alternative signaling pathways via cytokines and growth factors. Various chemopreventive agents that are in clinical trials against PCa have been shown to inhibit PCa development and progression through the regulation of major cellular signaling pathways such as the androgen, AR and PSA inhibition as well as affecting AR independent pathways such as inhibiting growth factor and NF-κB. These targets are pointed out in the figure with green arrows.