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.

Genistein promotes ionizing radiation-induced cell death by reducing cytoplasmic Bcl-xL levels in non-small cell lung cancer

“…Nuclear Bcl-xL also plays an important role in DNA damage. Nuclear Bcl-xL can inhibit the DNA damage repair gene APE1 by interacting with APE1, thus enhancing oncotherapy-induced DNA damage and apoptosis 30 . This suggests that not only total Bcl-xL levels but the distribution of Bcl-xL are also an important factor in oncotherapy-induced apoptosis.…”

Targeting MCL-1 sensitizes human esophageal squamous cell carcinoma cells to cisplatin-induced apoptosis

“…It has been reported that obatoclax (GX15–070) induces apoptosis and enhances cisplatin-induced apoptosis in NSCLC cells [ 38 ]. Ren et al [ 39 ] reported that (−)-Gossypol enhances the antitumor efficacy of cisplatin through inhibition of APE1 repair and redox activity in non-small cell lung cancer. Furthermore, synergistic antitumor effects have been observed when MCL-1 inhibitors combined not only with cytoxic drugs but also with other chemotherapeutic agents.…”

Base excision repair and its implications to cancer therapy

“…For example, E3330 (an NF-κB inhibitor) and Gossypol/AT101 (BCL2 inhibitors) can bind APE1 making it less redox active [ 45 , 46 ]. These agents can induce cytotoxicity as single agents [ 47 ] or in combination [ 46 , 48 ] in lung, lymphoma, prostate, adrenocortical and glioblastoma cancers, and more than 20 clinical trials are currently investigating their suitability.…”