title: 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.
abstract: 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.
authors.affiliation: Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, People's Republic of China ; Department of Oncology, The Affiliated Hospital, North Sichuan Medical College, Sichuan, People's Republic of China ; Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Ren
authors.affiliation: Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, People's Republic of China.
authors.forename: Jinlu
authors.initials: J
authors.lastname: Shan
authors.affiliation: Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, People's Republic of China.
authors.forename: Mengxia
authors.initials: M
authors.lastname: Li
authors.affiliation: Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, People's Republic of China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Qing
authors.affiliation: Department of Oncology, The 97 Hospital of PLA, Jiangsu, People's Republic of China.
authors.forename: Chengyuan
authors.initials: C
authors.lastname: Qian
authors.affiliation: Cancer Diagnosis and Treatment Center, Military District General Hospital of Chengdu Military Region, Sichuan, People's Republic of China.
authors.forename: Guangjie
authors.initials: G
authors.lastname: Wang
authors.affiliation: Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, People's Republic of China ; Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Li
authors.affiliation: Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, People's Republic of China.
authors.forename: Guoshou
authors.initials: G
authors.lastname: Lu
authors.affiliation: Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, People's Republic of China.
authors.forename: Chongyi
authors.initials: C
authors.lastname: Li
authors.affiliation: Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, People's Republic of China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Peng
authors.affiliation: Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, People's Republic of China.
authors.forename: Hao
authors.initials: H
authors.lastname: Luo
authors.affiliation: Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, People's Republic of China.
authors.forename: Shiheng
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, People's Republic of China.
authors.forename: Yuxing
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, People's Republic of China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, People's Republic of China.
authors.forename: Dong
authors.initials: D
authors.lastname: Wang
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA.
authors.forename: Shu-Feng
authors.initials: SF
authors.lastname: Zhou
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology*; D004260:DNA Repair / Q000187:drug effects; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000378:metabolism; D006072:Gossypol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D010084:Oxidation-Reduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D006072:Gossypol; D002945:Cisplatin; C028178:gossypol acetic acid
keywords: AT-101; angiogenesis; apurinic/apyrimidinic endonuclease 1; cisplatin; non-small-cell lung cancer; tumor