Original Article

ABT-263 induces G1/G0-phase arrest, apoptosis and autophagy in human esophageal cancer cells in vitro

Authors: LIN Qing-huan1, QUE Fu-chang1, GU Chun-ping1, ZHONG De-sheng1, ZHOU Dan1, KONG Yi1, YU Le1, LIU Shu-wen1
1 State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
Corresponding to: YU Le: yulezy@smu.edu.cn, LIU Shu-wen: liusw@smu.edu.cn,
DOI: 10.1038/aps.2017.78
Received: 8 November 2016
Accepted: 21 February 2017
Advance online: 17 July 2017

Abstract

Abstract
Both the anti- and pro-apoptotic members of the Bcl-2 family are regulated by a conserved Bcl-2 homology (BH3) domain. ABT- 263 (Navitoclax), a novel BH3 mimetic and orally bioavailable Bcl-2 family inhibitor with high affinity for Bcl-xL, Bcl-2 and Bcl-w has entered clinical trials for cancer treatment. But the anticancer mechanisms of ABT-263 have not been fully elucidated. In this study we investigated the effects of ABT-263 on human esophageal cancer cells in vitro and to explore its anticancer mechanisms. Treatment with ABT-263 dose-dependently suppressed the viability of 3 human esophageal cancer cells with IC50 values of 10.7±1.4, 7.1±1.5 and 8.2±1.6 μmol/L, in EC109, HKESC-2 and CaES-17 cells, respectively. ABT-263 (5–20 μmol/L) dose-dependently induced G1/G0-phase arrest in the 3 cancer cell lines and induced apoptosis evidenced by increased the Annexin V-positive cell population and elevated levels of cleaved caspase 3, cleaved caspase 9 and PARP. We further demonstrated that ABT-263 treatment markedly increased the expression of p21Waf1/Cip1 and decreased the expression of cyclin D1 and phospho-Rb (retinoblastoma tumor suppressor protein) (Ser780) proteins that contributed to the G1/G0-phase arrest. Knockdown of p21Waf1/Cip1 attenuated ABT-263-induced G1/G0-phase arrest. Moreover, ABT-263 treatment enhanced pro-survival autophagy, shown as the increased LC3-II levels and decreased p62 levels, which counteracted its anticancer activity. Our results suggest that ABT-263 exerts cytostatic and cytotoxic effects on human esophageal cancer cells in vitro and enhances pro-survival autophagy, which counteracts its anticancer activity.
Keywords: human esophageal cancer cells; ABT-263; G1/G0 phase arrest; p21Waf1/Cip1; cyclin D1 and phospho-Rb (Ser780); apoptosis; autophagy; LC3-II; p62