gossypol-acetic-acid and Prostatic-Neoplasms

In a phase II multicenter study, men with castration sensitive metastatic prostate cancer were treated with AT-101, a small molecule Bcl-2 inhibitor, and androgen deprivation therapy. At the end of 7 cycles of therapy in 55 patients, an undetectable PSA was achieved in 31%. However, the combination did not meet the pre-specified level of activity for further development.. We conducted a phase II study in men with castration-sensitive metastatic prostate cancer to test the hypothesis that AT-101, a small molecule Bcl-2 inhibitor, has clinical activity in patients initiating androgen deprivation therapy (ADT) for metastatic prostate cancer.. Patients with metastatic prostate cancer scheduled to start, or who had recently (within 6 weeks) initiated, ADT were enrolled. ADT with a luteinizing hormone-releasing hormone agonist and bicalutamide was started 6 weeks before initiation of oral AT-101, 20 mg/day for 21 days of a 28-day cycle. The primary endpoint of the study was the percentage of patients with an undetectable prostate-specific antigen (PSA) level (≤ 0.2 ng/mL) after 7.5 months (1.5 months of ADT alone plus 6 months of combined ADT and AT-101). To assess for an association between chromodomain helicase DNA binding protein 1 (CHD1) and drug sensitivity, fluorescence in situ hybridization with confocal microscopy was assessed in a subgroup of patients.. A total of 55 patients were enrolled, with median age of 61 years and a median PSA level of 27.6 ng/dL. Of the 55 patients, 72% had a Gleason score ≥ 8. Three patients had visceral metastases, and the remaining patients had bone or nodal metastasis. An undetectable PSA level was achieved in 31% of the patients. Of the 31 patients, 12 experienced serious adverse events, 7 of which were considered related to study therapy. Most of the related adverse events were gastrointestinal and nervous system disorders. CHD1 assessment was feasible, with a nonsignificant association with therapeutic sensitivity in a small number of patients.. The combination of ADT and AT-101 did not meet the prespecified level of activity for further development of this combination.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Gossypol; Humans; Lymphatic Metastasis; Male; Middle Aged; Prostatic Neoplasms; Treatment Outcome

AT-101 (A), a small molecule oral inhibitor of the Bcl-2 family, has activity alone and in combination with docetaxel (Taxotere) and prednisone (DP) in metastatic castration-resistant prostate cancer (mCRPC). A randomized, double-blind, placebo-controlled phase II trial compared DP combined with either AT-101 (A) or placebo in chemonaive mCRPC.. Men with progressive mCRPC despite androgen deprivation were eligible and randomized 1:1. Patients received docetaxel (75 mg/m2 day 1) and prednisone 5 mg orally twice daily every 21 days with either AT-101 (40 mg) or placebo twice daily orally on days 1-3. The primary end point was overall survival (OS).. Two hundred and twenty-one patients were randomly assigned. Median OS for AT-101 plus docetaxel-prednisone (ADP) and placebo-DP was 18.1 versus 17.8 months [hazard ratio (HR) 1.07, 95% confidence interval 0.72-1.55, P=0.63]. Secondary end points were also not statistically different. Grade 3/4 toxic effects for ADP versus placebo-DP were cardiac events (5% versus 2%), lymphopenia (23% versus 16%), neutropenia (47% versus 40%), ileus (2% versus 0%) and pulmonary embolism (6% versus 2%). In a subgroup of high-risk mCRPC (n=34), outcomes appeared to favor ADP (median OS 19 versus 14 months).. AT-101 was tolerable but did not extend OS when combined with DP in mCRPC; a potential benefit was observed in high-risk patients.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Docetaxel; Gossypol; Humans; Kaplan-Meier Estimate; Lymphatic Metastasis; Male; Middle Aged; Neoplastic Cells, Circulating; Orchiectomy; Placebos; Prednisone; Prostatic Neoplasms; Proto-Oncogene Proteins c-bcl-2; Taxoids; Treatment Outcome

Docetaxel clearance appears increased in men who are castrated. Neutropenia in cycle 1 may be a pharmacodynamic marker for docetaxel, which may enable tailored dosing in metastatic castration-resistant prostate cancer (mCRPC).. The association of cycle 1 neutropenia with overall survival (OS) was examined post hoc in a randomized phase II trial of 221 men with mCRPC who received docetaxel-prednisone combined with placebo or AT-101 (bcl-2 inhibitor); weekly blood cell counts were performed during the first cycle. Patients from both arms were combined because no outcome and toxicity differences were observed. OS was calculated from randomization by the Kaplan-Meier method, and Cox proportional hazards regression models were used to estimate the association with OS.. The difference in OS between men with day 8 ≥grade 3 neutropenia and those with ≤grade 2 neutropenia was significant after adjusting for trial stratification factors, pain, and performance status (hazard ratio [HR] 0.64; 2P = .048). Results were similar for logarithmic neutrophil counts adjusted for the risk group based on anemia, visceral metastasis, progression by bone scan and pain (HR 1.18; 2P = .07) for stratification factors (HR 1.20; 2P = .052) or both (HR, 1.20; 2P = .046). Men with ≥grade 3 neutropenia and ≥30% prostate-specific antigen level decline by day 90 had improved OS compared with men exhibiting neither (HR 0.51; 2P = .014).. For patients with mCRPC who received docetaxel, ≥grade 3 neutropenia on day 8 was prognostic for improved OS, which suggests its utility as a pharmacodynamic marker, in this hypothesis-generating analysis. Exploration of dose escalation of docetaxel to attain ≥grade 3 neutropenia on day 8 may be warranted.

Topics: Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Docetaxel; Gossypol; Humans; Kaplan-Meier Estimate; Male; Neoplasm Metastasis; Neutropenia; Prednisone; Prognosis; Prostate-Specific Antigen; Prostatic Neoplasms; Retrospective Studies; Survival Analysis; Taxoids

AT-101 binds and inhibits the antiapoptotic function of Bcl-2, Bcl-xL, Mcl-1, and Bcl-w and is a potent stimulator of proapoptotic proteins. In this multi-institution phase I/II trial, we evaluated the safety and efficacy of single-agent AT-101, in men with chemotherapy naïve, castrate-resistant prostate cancer (CRPC).. Patients with progressive CRPC were to be treated with escalating doses of AT-101 on a continuous daily basis until the maximally tolerated dose was achieved. At the recommended phase 2 dose, an additional 21 patients were planned to assess for preliminary evidence of efficacy.. Twenty-three patients were enrolled. The phase I starting dose was 30 mg/day on a continuous basis; however, ongoing trials with AT-101 showed increased gastrointestinal toxicity with this daily schedule when given for repetitive cycles. As a result, the phase II starting dose was chosen to be 30 mg/day for 21 of 28 days. The most frequent observed adverse events (any grade) were diarrhea (43.5%), fatigue (34.8%), nausea (21.7%), anorexia (21.7%), and small intestinal obstruction (21.7%). Due to the high incidence of grade 3 small intestinal obstruction (n = 5; 21.7%), a reduction in dose to 20 mg/day for 21 of 28 days was mandated for all patients. Two patients had a confirmed > or =50% posttherapy prostate-specific antigen decline. No objective responses (Response Evaluation Criteria in Solid Tumors) were observed.. AT-101 administered at 20 mg/day for 21 of 28 days was well-tolerated. Evidence of single-agent clinical activity was observed with prostate-specific antigen declines in some patients. Further investigation of AT-101 in prostate cancer is warranted and trials combining AT-101 with androgen deprivation, as well as with docetaxel chemotherapy are ongoing.

Topics: Adenocarcinoma; Administration, Oral; Aged; Aged, 80 and over; Antineoplastic Agents, Phytogenic; Cohort Studies; Drug Administration Schedule; Gossypol; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Staging; Neoplasms, Hormone-Dependent; Orchiectomy; Prognosis; Prostate-Specific Antigen; Prostatic Neoplasms; Treatment Outcome

The aim of this study was to determine the appropriate doses of AT-101 and resveratrol combination in the in vitro hormone-refractory prostate cancer (PC) cell lines, in order to evaluate the cytotoxic and genotoxic effects of this combination on the proliferation of cancer cells, namely PC-3, DU-145 and LNCAP. Cytotoxicity in PC cell lines was analysed by using the XTT Cell Proliferation Assay. DNA damage was performed with the cell death assay. Apoptotic protein levels were performed by Roche Human Apoptosis Array. IC50 values were determined by XTT analysis. The strongest combined doses (100 µM resveratrol + 5µM AT-101) were found to have the strongest synergistic apoptotic and cytotoxic effects on DU-145 cells at 72 hr. While the combined use of resveratrol and AT-101 increased the expression of markers in apoptotic cell pathways on cells, a decrease in the expression of anti-apoptotic markers was detected (p ˂ 0.05). Combined applications of these compounds showed an important synergism in the hormone-refractory PC cell lines, and it was determined that after the post-translational modification, they were significantly effective on the apoptotic pathway. These results have revealed that the combination of resveratrol and AT-101 holds great expectation as a new chemotherapeutic application in the treatment of human prostate cancer.

Topics: Apoptosis; Cell Line; Cell Line, Tumor; Gossypol; Hormones; Humans; Male; Prostatic Neoplasms; Resveratrol

Gossypol is a yellow polyphenol isolated from cotton seeds. It has the antitumor activity and it is being tested to treat prostate cancer. However, its underlying mechanisms are still not well understood. The present study investigated the inhibitory effects of gossypol acetate on rat 5α-reductase 1, 3α-hydroxysteroid dehydrogenase, and retinol dehydrogenase 2 for androgen metabolism. Rat 5α-reductase 1, 3α-hydroxysteroid dehydrogenase, and retinol dehydrogenase 2 were expressed in COS-1 cells. Immature Leydig cells that contain these enzymes were isolated from 35-day-old male Sprague Dawley rats. The potency and mode of action of gossypol acetate to inhibit these enzymes in both enzyme-expressed preparations and immature Leydig cells were examined. Molecular docking study of gossypol on the crystal structure of 3α-hydroxysteroid dehydrogenase was performed. Gossypol acetate inhibited 5α-reductase 1 and 3α-hydroxysteroid dehydrogenase with IC

Topics: 5-alpha Reductase Inhibitors; Alcohol Oxidoreductases; Animals; Gossypol; Hydroxysteroid Dehydrogenases; Leydig Cells; Male; Molecular Docking Simulation; Molecular Structure; Prostatic Neoplasms; Rats, Sprague-Dawley

Prostate cancer (PCa) is the most common type of cancer among males. Although survival rate of early-stage PCa is high, treatment options are very limited for recurrent disease. In this study, the possible synergistic cytotoxic and apoptotic effect of octreotide in combination with AT-101 was investigated in DU-145 hormone and drug refractory prostate cancer cell line. To enlighten the action mechanisms of the combination treatment, expression levels of somatostatin receptors 2 and 5 (SSTR2 and SSTR5) were also investigated. Cell viability was measured by XTT assay. Apoptosis was assessed through DNA fragmentation analysis and caspase 3/7 assay. mRNA and protein levels of SSTR2 and SSTR5 were evaluated by qRT-PCR and western blot analysis, respectively. Octreotide in combination with AT-101 inhibited cell viability and induced apoptosis synergistically in DU-145 cells as compared to any agent alone. Combination treatment increased both SSTR2 and SSTR5 mRNA and protein levels in DU-145 cells. The data suggest that this combination therapy may be a good candidate for patients with advanced metastatic PCa do not respond to androgen deprivation.

Topics: Androgens; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Resistance, Neoplasm; Drug Synergism; Gene Expression Regulation, Neoplastic; Gossypol; Humans; Male; Octreotide; Prostatic Neoplasms; Receptors, Somatostatin

The optimal number of 3-wk docetaxel plus prednisone (DP) cycles for metastatic castration-resistant prostate cancer (mCRPC) is unclear.. A retrospective analysis of two clinical trials was performed to evaluate the association of the number of cycles with overall survival (OS).. An exploratory analysis compared outcomes of 332 men who received DP in the TAX-327 trial, which stipulated up to 10 cycles, and 220 men who received DP in CS-205, a randomized phase 2 trial comparing DP plus AT-101 (bcl-2 inhibitor) versus DP plus placebo, which allowed up to 17 cycles.. Patients who completed 10 cycles of DP without progression in both trials were included. Men in both arms of CS-205 were combined for analysis, as no significant differences in outcomes were observed. OS was estimated from the date of cycle 10 docetaxel infusion.. The number of men receiving 10 cycles was similar (p=0.26) in the two trials (166 [50.0%] in TAX-327 vs 99 [45.0%] in CS-205; the latter group received a median of five additional cycles). Six- and 12-mo estimated survival after cycle 10 was 92.2% (95% confidence interval [CI], 86.9-95.4%) and 74.6% (CI, 67.2-80.5%) in TAX-327, compared with 92.8% (CI, 85.5-96.5) and 63.4% (CI, 51.8-72.9%) in CS-205. Subanalyses suggested that <10 cycles may have a negative impact and prostate-specific antigen (PSA) declines at cycle 10 may carry a favorable impact. The significance of continued PSA declines up to 17 cycles is unclear. Limitations of a retrospective analysis apply.. A survival benefit was not detected with >10 cycles of DP in men with mCRPC in this retrospective hypothesis-generating analysis.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Clinical Trials as Topic; Disease-Free Survival; Docetaxel; Gossypol; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Prednisone; Prostate-Specific Antigen; Prostatic Neoplasms; Retrospective Studies; Taxoids; Treatment Outcome

Topics: Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Gossypol; Humans; Male; Prednisone; Prostatic Neoplasms; Taxoids

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.

Topics: Androgen Antagonists; Androgens; Anilides; Antineoplastic Agents, Phytogenic; Apoptosis; bcl-X Protein; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dihydrotestosterone; Drug Synergism; Gossypol; Humans; Immunoblotting; Male; Nitriles; Prostatic Neoplasms; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2; Receptors, Androgen; Tosyl Compounds

Upregulation of Bcl-2 family members is a well-established mechanism in the development of androgen-independent prostate cancer. Inhibition of the antiapoptotic proteins Bcl-2 and Mcl-1 may delay the transition to androgen-independent growth.. We have established a prostate cancer model with VCaP prostate cancer cells in vivo to study the transition to androgen independence. Here, we investigated the efficacy of AT-101 (R-(-)-gossypol acetic acid; a pan small molecule inhibitor of Bcl-2, Bcl-x(L), and Mcl-1) in combination with surgical castration to delay the onset of androgen-independent growth in vivo.. AT-101 (15 mg/kg, per os (p.o.) 5 days/week) in combination with surgical castration delayed the onset of androgen-independent prostate cancer growth in vivo. In addition, we demonstrate the induction of caspase-9-and caspase-3-dependent induction of apoptosis following AT-101 treatment in vitro which was accompanied by an AT-101-induced downregulation of Bcl-2 and Mcl-1 mRNA and protein expression.. We conclude that AT-101 in combination with surgical castration delays the onset of androgen-independent prostate cancer in vivo by disrupting the antiapoptotic activity of Bcl-2 upregulation during the transition to androgen independence. Further studies are needed to define the mechanism of action by which AT-101 attenuates the expression of Bcl-2 and Mcl-1 and to characterize the potential for AT-101 in combination with hormone therapy.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Caspases; Combined Modality Therapy; Down-Regulation; Gene Expression Regulation, Neoplastic; Genes, bcl-2; Gossypol; Humans; Male; Mice; Mice, SCID; Myeloid Cell Leukemia Sequence 1 Protein; Neoplasm Proteins; Orchiectomy; Prostatic Neoplasms; Proto-Oncogene Proteins c-bcl-2; RNA, Messenger; RNA, Neoplasm; Xenograft Model Antitumor Assays