Beyond Androgen Deprivation: Ancillary Integrative Strategies for Targeting the Androgen Receptor Addiction of Prostate Cancer

The large majority of clinical prostate cancers remain dependent on androgen receptor (AR) activity for proliferation even as they lose their responsiveness to androgen deprivation or antagonism. AR activity can be maintained in these circumstances by increased AR synthesis—often reflecting increased NF-B activation; upregulation of signaling pathways that promote AR activity in the absence of androgens; and by emergence of AR mutations or splice variants lacking the ligand-binding domain, which render the AR constitutively active. Drugs targeting the N-terminal transactivating domain of the AR, some of which are now in preclinical development, can be expected to inhibit the activity not only of unmutated ARs but also of the mutant forms and splice variants selected for by androgen deprivation. Concurrent measures that suppress AR synthesis or boost AR turnover could be expected to complement the efficacy of such drugs. A number of nutraceuticals that show efficacy in prostate cancer xenograft models—including polyphenols from pomegranate, grape seed, and green tea, the crucifera metabolite diindolylmethane, and the hormone melatonin—have the potential to suppress AR synthesis via downregulation of NF-B activity; clinical doses of salicylate may have analogous efficacy. The proteasomal turnover of the AR is abetted by diets with a high ratio of long-chain omega-3 to omega-6 fatty acids, which are beneficial in prostate cancer xenograft models; berberine and ...
Source: Integrative Cancer Therapies - Category: Cancer & Oncology Authors: Tags: Articles Source Type: research