AT-101 (R-(-)-gossypol acetic acid) enhances the effectiveness of androgen deprivation therapy in the VCaP prostate cancer model.

Abstract

Prostate cancer remains a leading cause of cancer death in American men. Androgen deprivation therapy (ADT) is the most common treatment for advanced prostate cancer patients; however, ADT fails in nearly all cases resulting in castration resistant or androgen-insensitive (AI) disease. In many cases, this progression results from dysregulation of the pro-survival Bcl-2 family proteins. Inhibition of pro-survival Bcl-2 family proteins, therefore, may be an effective strategy to delay the onset of AI disease. Gossypol, a small molecule inhibitor of pro-survival Bcl-2 family proteins, has been demonstrated to inhibit AI prostate cancer growth. The apoptotic effect of gossypol, however, has been demonstrated to be attenuated by the presence of androgen in a prostate cancer xenograft mouse model (Vertebral Cancer of Prostate [VCaP]) treated with AT-101 (R-(-)-gossypol acetic acid). This study was undertaken to better understand the in vitro effects of androgen receptor (AR) on AT-101-induced apoptosis. VCaP cells treated with AT-101 demonstrated an increase in apoptosis and downregulation of Bcl-2 pro-survival proteins. Upon AR activation in combination with AT-101 treatment, apoptosis is reduced, cell survival increases, and caspase activation is attenuated. Akt and X inhibitor of apoptosis (XIAP) are downregulated in the presence of AT-101, and AR stimulation rescues protein expression. Combination treatment of bicalutamide and AT-101 increases apoptosis by reducing the expression of these pro-survival proteins. These data suggest that combination therapy of AT-101 and ADT may further delay the onset of AI disease, resulting in prolonged progression-free survival of prostate cancer patients.

• Authors: Natalie McGregor, Lalit Patel, Matthew Craig, Savannah Weidner, Shaomeng Wang, Kenneth J Pienta
• Journal: Journal of cellular biochemistry (J Cell Biochem) Vol. 110 Issue 5 Pg. 1187-94 (Aug 01 2010) ISSN: 1097-4644 [Electronic] United States
• PMID: 20589722 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Published 2010 Wiley-Liss, Inc.

Chemical References

• Androgen Antagonists
• Androgens
• Anilides
• Antineoplastic Agents, Phytogenic
• Nitriles
• Proto-Oncogene Proteins c-bcl-2
• Receptors, Androgen
• Tosyl Compounds
• bcl-X Protein
• Dihydrotestosterone
• bicalutamide
• Proto-Oncogene Proteins c-akt
• Gossypol
• gossypol acetic acid

Topics

• Androgen Antagonists (pharmacology)
• Androgens (pharmacology)
• Anilides (pharmacology)
• Antineoplastic Agents, Phytogenic (pharmacology)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Dihydrotestosterone (pharmacology)
• Drug Synergism
• Gossypol (analogs & derivatives, pharmacology)
• Humans
• Immunoblotting
• Male
• Nitriles (pharmacology)
• Prostatic Neoplasms (drug therapy, metabolism, pathology)
• Proto-Oncogene Proteins c-akt (metabolism)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Receptors, Androgen (metabolism)
• Tosyl Compounds (pharmacology)
• bcl-X Protein (metabolism)