Bioactive natural products for chemoprevention and treatment of castration-resistant prostate cancer

Abstract

Prostate cancer (PCa), a hormonally-driven cancer, ranks first in incidence and second in cancer related mortality in men in most Western industrialized countries. Androgen and androgen receptor (AR) are the dominant modulators of PCa growth. Over the last two decades multiple advancements in screening, treatment, surveillance and palliative care of PCa have significantly increased quality of life and survival following diagnosis. However, over 20% of patients initially diagnosed with PCa still develop an aggressive and treatment-refractory disease. Prevention or treatment for hormone-refractory PCa using bioactive compounds from marine sponges, mushrooms, and edible plants either as single agents or as adjuvants to existing therapy, has not been clinically successful. Major advancements have been made in the identification, testing and modification of the existing molecular structures of natural products. Additionally, conjugation of these compounds to novel matrices has enhanced their bio-availability; a big step towards bringing natural products to clinical trials. Natural products derived from edible plants (nutraceuticals), and common folk-medicines might offer advantages over synthetic compounds due to their broader range of targets, as compared to mostly single target synthetic anticancer compounds; e.g. kinase inhibitors. The use of synthetic inhibitors or antibodies that target a single aberrant molecule in cancer cells might be in part responsible for emergence of treatment refractory cancers. Nutraceuticals that target AR signaling (epigallocatechin gallate [EGCG], curcumin, and 5α-reductase inhibitors), AR synthesis (ericifolin, capsaicin and others) or AR degradation (betulinic acid, di-indolyl diamine, sulphoraphane, silibinin and others) are prime candidates for use as adjuvant or mono-therapies. Nutraceuticals target multiple pathophysiological mechanisms involved during cancer development and progression and thus have potential to simultaneously inhibit both prostate cancer growth and metastatic progression (e.g., inhibition of angiogenesis, epithelial-mesenchymal transition (EMT) and proliferation). Given their multi-targeting properties along with relatively lower systemic toxicity, these compounds offer significant therapeutic advantages for prevention and treatment of PCa. This review emphasizes the potential application of some of the well-researched natural compounds that target AR for prevention and therapy of PCa.

Keywords: Androgen receptor inhibitors; Anticancer natural products; Cancer prevention; Protein stability; Regulation.

Figure 1. A schematic of how natural products may affect AR

Binding of DHT to AR results in release of Hsps and subsequent N/C dimerization and exposure of the nuclear localization signal. In the nucleus, AR binds DNA and recruits factors that initiate transcription of target genes. Many chemopreventive natural products mediate their activity though inhibition of AR expression or transcriptional activity. Other compounds interfere with the association of the chaperone Hsp90 with AR, resulting in the degradation of AR. Abbreviations: Akt, RAC serine/threonine protein kinase; AR, androgen receptor; Hsp90, heat shock protein 90; IGF-I, insulin-like growth factor 1; MAPK, mitogen-activated protein kinase; PI3K, phosphoinositide 3-kinase; STAT3, signal transducer and activator of transcription 3; NTD, N-terminal domain; D, DNA binding domain (DBD); L, ligand binding domain (LBD); T, testosterone; DHT, dihydrotestosterone.