Original Article

G226, a novel epipolythiodioxopiperazine derivative, induces autophagy and caspase-dependent apoptosis in human breast cancer cells in vitro

Authors: Peng-xing HE, Yong-sheng CHE, Qiao-jun HE, Yi CHEN, Jian DING
DOI: 10.1038/aps.2014.47

Abstract

Peng-xing HE1, Yong-sheng CHE2, Qiao-jun HE1, Yi CHEN3, *, Jian DING3, *
1Institute of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; 2Beijing Institute of Pharmacology & Toxicology, Beijing 100190, China; 3Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China

Aim: To investigate the effects of G226, a novel epipolythiodioxopiperazine derivative, on human breast cancer cells in vitro, and to explore its anticancer mechanisms.
Methods: A panel of human breast cancer cell lines (MDA-MB-231, MDA-MB-468, MCF-7, ZR-75-30, BT474, BT549, SK-BR-3, T47D and HBL100) was examined. Cell proliferation was measured using sulforhodamine B assay, and cell apoptosis was detected with flow cytometry and caspase activity assay. Western blotting, immunofluorescence and targeted gene knockdowns were used to study autophagy in the cells.

Results: G226 suppressed proliferation of the 9 breast cancer cell lines with a mean IC50 value of 48.5 nmol/L (the mean IC50 value of adriamycin, a reference compound, was 170.6 nmol/L). G226 induced dose-dependent apoptosis of MDA-MB-231 and MCF-7 cells, accompanied by markedly increased activities of caspase-8 and caspase-3/7, which were abolished by caspase inhibitors zVAD or zIETD. G226 also induced mitochondrial outer membrane permeabilization, resulted in the caspase-9 activation. Moreover, G226 dose-dependently enhanced the autophagy marker LC3-II and autophagy substrate p62 accumulation in the cells, which were co-localized with caspase-8. Silencing of p62 or LC3 partially diminished caspase-8 and subsequent caspase-3 activation. LC3 silencing partially reversed G226-induced apoptosis, but p62 silencing elicited a subtle effect on G226-induced apoptosis.ted kidneys, which were significantly attenuated by daily administration of resveratrol (100 mg/kg, po).

Conclusion: The novel epipolythiodioxopiperazine derivative G226 exerts potent anticancer action against human breast cancer cells in vitro, via triggering autophagy and caspase-dependent apoptosis.


Keywords: breast cancer; epipolythiodioxopiperazine; dideoxyverticillin; apoptosis; autophagy; LC3; p62; caspase-8; anticancer drug

The project was supported by National Natural Science Foundation of China (81321092) and by a grant from the National Basic Research Program of China (2013CB932503).

* To whom correspondence should be addressed.
E-mail jding@simm.ac.cn (Jian DING);ychen@simm.ac.cn (Yi CHEN)
Received 2014-03-21 Accepted 2014-05-12
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