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Toxicol Appl Pharmacol. 2017 Jun 15;325:48-60. doi: 10.1016/j.taap.2017.04.003. Epub 2017 Apr 10.

4-Acetylantroquinonol B suppresses autophagic flux and improves cisplatin sensitivity in highly aggressive epithelial cancer through the PI3K/Akt/mTOR/p70S6K signaling pathway.

Author information

1
Graduate Institute of Biomedical Materials and Tissue Engineering, College of biomedical engineering, Taipei Medical University, Taipei, Taiwan; Department of Urology, Taipei Medical University Hospital, Taipei, Taiwan; Department of Urology, School of Medicine, college of Medicine, Taipei Medical University, Taipei, Taiwan.
2
Department of Hematology and Oncology, Cancer Center, Taipei Medical University-Shuang Ho Hospital, New Taipei City, Taiwan; Department of Medical Research & Education, Taipei Medical University-Shuang Ho Hospital, New Taipei City, Taiwan.
3
Institute of Traditional Medicine, School of Medicine, National Yang Ming University, Taipei, Taiwan; Department of Surgery, Division of Thoracic Surgery, MacKay Memorial Hospital, Taipei, Taiwan.
4
Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan.
5
Biostatistics and Research Consultation Center, Taipei Medical University, Taipei 11031, Taiwan.
6
The Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
7
Center for General Education, National Taitung University, Taitung, Taiwan.
8
Department of Pathology, Taipei Medical University-Shuang Ho Hospital, Taipei, Taiwan.
9
Obstetrics and Gynecology Department, Taipei Medical University-Shuang Ho Hospital, Taipei, Taiwan.
10
Genomics Research Center, Academia Sinica, Taipei, Taiwan.
11
Beijing Bioprocess Key Laboratory, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, China; Amoy-BUCT Industrial Bio-technovation Institute, Amoy, China.
12
Center for General Education, National Taitung University, Taitung, Taiwan; Department of Appiled Chemistry, Chaoyang University of Technology, Taichung, Taiwan. Electronic address: ymtzeng@nttu.edu.tw.
13
Department of Hematology and Oncology, Cancer Center, Taipei Medical University-Shuang Ho Hospital, New Taipei City, Taiwan; Department of Medical Research & Education, Taipei Medical University-Shuang Ho Hospital, New Taipei City, Taiwan. Electronic address: ctyeh@s.tmu.edu.tw.

Abstract

Targeting residual self-renewing, chemoresistant cancerous cells may represent the key to overcoming therapy resistance. The entry of these quiescent cells into an activated state is associated with high metabolic demand and autophagic flux. Therefore, modulating the autophagy pathway in aggressive carcinomas may be beneficial as a therapeutic modality. In this study, we evaluated the anti-tumor activities of 4-acetylantroquinonol B (4-AAQB) in chemoresistant ovarian cancer cells, particularly its ability to modulate autophagy through autophagy-related genes (Atg). Atg-5 was overexpressed in invasive ovarian cancer cell lines and tissue (OR: 5.133; P=0.027) and depleting Atg-5 in ES-2 cell lines significantly induced apoptosis. 4-AAQB effectively suppressed viability of various subtypes of ovarian cancer. Cells with higher cisplatin-resistance were more responsive to 4-AAQB. For the first time, we demonstrate that 4-AAQB significantly suppress Atg-5 and Atg-7 expression with decreased autophagic flux in ovarian cancer cells via inhibition of the PI3K/Akt/mTOR/p70S6K signaling pathway. Similar to Atg-5 silencing, 4-AAQB-induced autophagy inhibition significantly enhanced cell death in vitro. These results are comparable to those of hydroxychloroquine (HCQ). In addition, 4-AAQB/cisplatin synergistically induced apoptosis in ovarian cancer cells. In vivo, 4-AAQB/cisplatin also significantly induced apoptosis and autophagy in an ES-2 mouse xenografts model. This is the first report demonstrating the efficacy of 4-AAQB alone or in combination with cisplatin on the suppression of ovarian cancer via Atg-5-dependent autophagy. We believe these findings will be beneficial in the development of a novel anti-ovarian cancer therapeutic strategy.

KEYWORDS:

4-AAQB; 4-Acetylantroquinonol B; Atg-5; Autophagy; Chemoresistance; Cisplatin; LC3B-II; Ovarian cancer

PMID:
28408137
DOI:
10.1016/j.taap.2017.04.003
[Indexed for MEDLINE]

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