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.

Bcl-2 Family of Proteins as Therapeutic Targets in Genitourinary Neoplasms

“…13,84,86,87 In addition, studies indicate that gossypol activates p53 88 and therefore p53 might serve as a predictive biomarker for gossypol efficacy. Bladder cancer cell lines that are resistant to chemotherapeutic agents for metastatic bladder cancer in vitro, including gemcitabine and carboplatin, demonstrated significantly increased apoptosis under cotreatment with gossypol.…”

“…In both non-CRPC and CRPC in vitro and in vivo models, gossypol has been shown to induce apoptosis as a single agent and to interact synergistically with standard therapies, such as docetaxel, radiation, and ADT. 13,84,86,87 In addition, studies indicate that gossypol activates p53 88 and therefore p53 might serve as a predictive biomarker for gossypol efficacy. Bladder cancer cell lines that are resistant to chemotherapeutic agents for metastatic bladder cancer in vitro, including gemcitabine and carboplatin, demonstrated significantly increased apoptosis under cotreatment with gossypol.…”

Obatoclax mesylate: pharmacology and potential for therapy of hematological neoplasms

“…In initial studies, it has shown moderate single agent clinical activity in patients with relapsed and refractory CLL or NHL, but thrombocytopenia is a frequently encountered toxicity [40][41][42]. AT-101 is the isomer of gossypol, another orally available agent with varying affinities for various Bcl-2 family members [43][44][45]. It has shown modest single agent activity in castration-resistant prostate cancer, but significant gastrointestinal toxicity has been encountered [44].…”

A Phase II Study of AT-101 to Overcome Bcl-2–Mediated Resistance to Androgen Deprivation Therapy in Patients With Newly Diagnosed Castration-Sensitive Metastatic Prostate Cancer

“…In the VCap human prostate cancer cell line, Bcl-2 expression was significantly upregulated in androgen independent cells in comparison to androgen-dependent cells, suggesting that abrogating Bcl-2 activity in combination with castration may delay onset of castrate resistant prostate cancer [11]. Further studies confirmed that in vitro , and in the VCaP prostate cancer xenograft, AT-101 was synergistic with androgen deprivation leading to decreased tumor volume, and delayed onset of androgen independence [11, 12]. Furthermore, androgen receptor activation by dihydrotestosterone attenuated AT-101-induced apoptosis, by upregulating Bcl-2 and Bcl-Xl, while inhibition of androgen receptor with bicalutamide restored AT-101-induced apoptosis, demonstrating that androgen deprivation and Bcl-2 inhibition act cooperatively to induce apoptosis.…”