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Cracking the Cytotoxicity Code: Apoptotic Induction of 10-Acetylirciformonin B is Mediated through ROS Generation and Mitochondrial Dysfunction

Authors :
Huei-Chuan Shih
Mohamed El-Shazly
Yung-Shun Juan
Chao-Yuan Chang
Jui-Hsin Su
Yu-Cheng Chen
Shou-Ping Shih
Huei-Mei Chen
Yang-Chang Wu
Mei-Chin Lu
Source :
Marine Drugs, Vol 12, Iss 5, Pp 3072-3090 (2014)
Publication Year :
2014
Publisher :
MDPI AG, 2014.

Abstract

A marine furanoterpenoid derivative, 10-acetylirciformonin B (10AB), was found to inhibit the proliferation of leukemia, hepatoma, and colon cancer cell lines, with selective and significant potency against leukemia cells. It induced DNA damage and apoptosis in leukemia HL 60 cells. To fully understand the mechanism behind the 10AB apoptotic induction against HL 60 cells, we extended our previous findings and further explored the precise molecular targets of 10AB. We found that the use of 10AB increased apoptosis by 8.9%–87.6% and caused disruption of mitochondrial membrane potential (MMP) by 15.2%–95.2% in a dose-dependent manner, as demonstrated by annexin-V/PI and JC-1 staining assays, respectively. Moreover, our findings indicated that the pretreatment of HL 60 cells with N-acetyl-l-cysteine (NAC), a reactive oxygen species (ROS) scavenger, diminished MMP disruption and apoptosis induced by 10AB, suggesting that ROS overproduction plays a crucial rule in the cytotoxic activity of 10AB. The results of a cell-free system assay indicated that 10AB could act as a topoisomerase catalytic inhibitor through the inhibition of topoisomerase IIα. On the protein level, the expression of the anti-apoptotic proteins Bcl-xL and Bcl-2, caspase inhibitors XIAP and survivin, as well as hexokinase II were inhibited by the use of 10AB. On the other hand, the expression of the pro-apoptotic protein Bax was increased after 10AB treatment. Taken together, our results suggest that 10AB-induced apoptosis is mediated through the overproduction of ROS and the disruption of mitochondrial metabolism.

Details

Language :
English
ISSN :
16603397
Volume :
12
Issue :
5
Database :
Directory of Open Access Journals
Journal :
Marine Drugs
Publication Type :
Academic Journal
Accession number :
edsdoj.fffcaa13a2a54a1f8014331e00de2a85
Document Type :
article
Full Text :
https://doi.org/10.3390/md12053072