Small-molecule BH3 mimetic and pan-Bcl-2 inhibitor AT-101 enhances the antitumor efficacy of cisplatin through inhibition of APE1 repair and redox activity in non-small-cell lung cancer

• Published in: Drug design, development and therapy development and therapy, 2015, Vol.9, p.2887-2910
• Main Authors: Ren, Tao, Shan, Jinlu, Li, Mengxia, Qing, Yi, Qian, Chengyuan, Wang, Guangjie, Li, Qing, Lu, Guoshou, Li, Chongyi, Peng, Yu, Luo, Hao, Zhang, Shiheng, Yang, Yuxing, Cheng, Yi, Wang, Dong, Zhou, Shu-Feng
• Format: Article
• Language: English
• Subjects: Accounting; Angiogenesis; Animal models; Animal tissues; Animals; Anticancer properties; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Antitumor activity; Apoptosis; Apoptosis - drug effects; Autophagy; Bcl-2 protein; Bone cancer; Cancer therapies; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - pathology; Cell Line, Tumor; Cell migration; Cell proliferation; Cell Proliferation - drug effects; Chemotherapy; Cisplatin; Cisplatin - administration & dosage; Cisplatin - pharmacology; Deoxyribonucleic acid; DNA; DNA repair; DNA Repair - drug effects; DNA-(Apurinic or Apyrimidinic Site) Lyase - metabolism; Drug synergism; Drug therapy; Effectiveness; Endonuclease; Endothelial cells; Enzyme inhibitors; Genetic aspects; Gossypol - administration & dosage; Gossypol - analogs & derivatives; Gossypol - pharmacology; Human Umbilical Vein Endothelial Cells; Humans; Hypoxia; Inhibition; Inhibitors; Interleukin 6; Lung cancer; Lung cancer, Non-small cell; Lung Neoplasms - drug therapy; Lung Neoplasms - pathology; Lymphoma; Medical prognosis; Mice; Mice, Inbred BALB C; Mice, Nude; Neovascularization, Pathologic - drug therapy; Non-small cell lung carcinoma; Original Research; Oxidation-Reduction - drug effects; Patient outcomes; Prostate; Proteins; Redox properties; Repair; Signal transduction; Stat3 protein; Transcription; Transcription factors; Tumors; Umbilical vein; Vascular endothelial growth factor; Xenograft Model Antitumor Assays
• ISSN: 1177-8881; 1177-8881
• DOI: 10.2147/DDDT.S82724

AT-101 is a BH3 mimetic and pan-Bcl-2 inhibitor that has shown potent anticancer activity in non-small-cell lung cancer (NSCLC) in murine models, but failed to show clinical efficacy when used in combination with docetaxel in NSCLC patients. Our recent study has demonstrated that AT-101 enhanced the antitumor effect of cisplatin (CDDP) in a murine model of NSCLC via inhibition of the interleukin-6/signal transducer and activator of transcription 3 (STAT3) pathway. This study explored the underlying mechanisms for the enhanced anticancer activity of CDDP by AT-101. Our results show that, when compared with monotherapy, AT-101 significantly enhanced the inhibitory effects of CDDP on proliferation and migration of A549 cells and on tube formation and migration in human umbilical vein endothelial cells. AT-101 promoted the proapoptotic activity of CDDP in A549 cells. AT-101 also enhanced the inhibitory effect of CDDP on DNA repair and redox activities of apurinic/apyrimidinic endonuclease 1 (APE1) in A549 cells. In tumor tissues from nude mice treated with AT-101 plus CDDP or monotherapy, the combination therapy resulted in greater inhibition of angiogenesis and tumor cell proliferation than the monotherapy. These results suggest that AT-101 can enhance the antitumor activity of CDDP in NSCLC via inhibition of APE1 DNA repair and redox activities and by angiogenesis and induction of apoptosis, but other mechanisms cannot be excluded. We are now conducting a Phase II trial to examine the clinical efficacy and safety profile of combined use of AT-101 plus CDDP in advanced NSCLC patients.