The Application of Arsenic Trioxide in Ameliorating ABT-737 Target Therapy on Uterine Cervical Cancer Cells through Unique Pathways in Cell Death.

I-Lun Hsin,Ying-Hsiang Chou,Wei-Li Hung,Po-Hui Wang,Jiunn-Liang Ko

doi:10.3390/cancers12010108

Abstract

ABT-737, a B cell lymphoma-2 (Bcl-2) family inhibitor, activates apoptosis in cancer cells. Arsenic trioxide is an apoptosis activator that impairs cancer cell survival. The aim of this study was to evaluate the effect of a combination treatment with ABT-737 and arsenic trioxide on uterine cervical cancer cells. MTT (3-(4,5-dimethylthiazol-2-yl)-25-diphenyltetrazolium bromide) assay revealed that ABT-737 and arsenic trioxide induced a synergistic effect on uterine cervical cancer cells. Arsenic trioxide enhanced ABT-737-induced apoptosis and caspase-7 activation and the ABT-737-mediated reduction of anti-apoptotic protein Mcl-1 in Caski cells. Western blot assay revealed that arsenic trioxide promoted the ABT-737-mediated reduction of CDK6 and thymidylate synthetase in Caski cells. Arsenic trioxide promoted ABT-737-inhibited mitochondrial membrane potential and ABT-737-inhibited ANT expression in Caski cells. However, ABT-737-elicited reactive oxygen species were not enhanced by arsenic trioxide. The combined treatment induced an anti-apoptosis autophagy in SiHa cells. This study is the first to demonstrate that a combination treatment with ABT-737 and arsenic trioxide induces a synergistic effect on uterine cervical cancer cells through apoptosis. Our findings provide new insights into uterine cervical cancer treatment.

Highlights

B cell lymphoma-2 (Bcl-2) homology 3 (BH3) exhibits pro-apoptotic functions either by directly inducing Bcl-2-associated X protein (Bax) and Bcl-2 homologous antagonist/killer (Bak) or by displacing them away from inhibitory interactions with anti-apoptotic Bcl-2 family members [1].4-[4-[(40 -chloro[1,10 -biphenyl]-2-yl)methyl]-1-piperazinyl]-N-[[4-[[(1R)-3-(dimethylamino)-1-[(phen ylthio)methyl]propyl]amino]-3-nitrophenyl] sulfonyl]-benzamide (ABT-737) is one of the best-characterized BH3 mimetics
We found that Myeloid cell leukemia 1 (Mcl-1) expression in Caski cells obviously decreased after the combined treatment
The combined treatment of ABT-737 and arsenic trioxide may exert a synergistic effect to induce the death of cervical cancer cells

Summary

Introduction

4-[4-[(40 -chloro[1,10 -biphenyl]-2-yl)methyl]-1-piperazinyl]-N-[[4-[[(1R)-3-(dimethylamino)-1-[(phen ylthio)methyl]propyl]amino]-3-nitrophenyl] sulfonyl]-benzamide (ABT-737) is one of the best-characterized BH3 mimetics It targets and inhibits anti-apoptotic Bcl-2 family proteins, such as Bcl-2 [2,3]. Arsenic trioxide (As2 O3 ) has been applied as a therapeutic agent for more than 2400 years, and its preparation (trade name Trisenox) was approved for the treatment of acute promyelocytic leukemia by the U.S Food and Drug Administration in September 2000 [11]. It can trigger the intrinsic pathway of apoptosis in human leukemia cells [12]. As2 O3 can induce apoptosis of the cancer cells of uterine cervix via the mitochondrial pathway [13], suppresses the migration and angiogenesis of gastric cancer cells [14], and reverses chemoresistance in hepatocellular carcinoma [15]

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