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Chem Biol Interact. 2016 Jan 25;244:94-104. doi: 10.1016/j.cbi.2015.11.013. Epub 2015 Nov 21.

SZC015, a synthetic oleanolic acid derivative, induces both apoptosis and autophagy in MCF-7 breast cancer cells.

Author information

1
Pharmacology Department, Dalian Medical University, Dalian, China.
2
Pharmaceutical Biology Department, Groningen Research Institute of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
3
Department of Internal Medicine, First Hospital Affiliated to Dalian Medical University, Dalian, China.
4
College of Pharmaceutical Science and Technology, Dalian University of Technology, Dalian, China.
5
Pharmacology Department, Dalian Medical University, Dalian, China. Electronic address: tangzeyao@aliyun.com.

Abstract

Breast cancer is one of the most common cancers among women with high mortality and morbidity. The present study was aimed to investigate the cytotoxic mechanism of SZC015, a synthetic oleanolic acid (OA) derivative, in MCF-7 human breast cancer cells. SZC015 reduced MCF-7 cell viability with an IC50 value of only 24.19 μM at 24 h by activating both apoptosis and autophagy pathways. More specifically, we found that SZC015 was able to activate intrinsic apoptosis, which was proved by activations of caspase3, caspase9, release of cytochrome C, cleavage of PARP and increasing ratio of Bax/Bcl-2. SZC015 induced autophagy in MCF-7 cells evidenced by the increase of LC3II/LC3I and up-regulation of Atg5 and beclin1. Moreover, these two cell death pathways were modulated by inhibiting phosphatidylinositide 3-kinase/protein kinase B/mammalian target of rapamycin/nuclear factor-κB (PI3K/Akt/mTOR/NF-κB), mitogen-activated protein kinase (MAPK) signaling pathways. SZC015 also induced S phase cell cycle arrest in MCF-7 cells. Furthermore, analysis of topoisomerase I (Top I) and topoisomerase IIα (Top IIα) proteins suggested that SZC015 may interfere the DNA topological phenomenon. The computer-assisted molecular docking study also showed SZC015 had lower interaction energy with Top I and Top IIα than that of OA. In conclusion, the current study revealed SZC015 played an important role in the regulation of autophagy and apoptosis in breast cancer cells.

KEYWORDS:

Apoptosis; Autophagy; Breast cancer; SZC015

PMID:
26612655
DOI:
10.1016/j.cbi.2015.11.013
[Indexed for MEDLINE]

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