Verrucarin A induces apoptosis through ROS-mediated EGFR/MAPK/Akt signaling pathways in MDA-MB-231 breast cancer cells.

Abstract

The present study was carried out to elucidate the mechanisms underlying Verrucarin A (VA)-induced cytotoxicity in human breast cancer cell line MDA-MB-231. VA inhibited the growth of MDA-MB-231 cells by induction of reactive oxygen species (ROS)-dependent mitochondrial apoptosis. Elevation of ROS production, associated with changes in Bax/Bcl-2 ratio, led to loss of mitochondrial membrane potential (Δψm) and cytochrome c release in VA-treated cells. Release of cytochrome c from mitochondria to cytosol triggered activation of caspase-3, PARP cleavage, DNA fragmentation, and finally apoptotic cell death. Furthermore, VA-induced apoptosis was accompanied by the activation of p38MAPK and inhibition of phosphorylation of EGFR as well as of Akt and ERK1/2. However, pre-treatment with n-acetyl cysteine, an ROS scavenger, and SB202190, a p38MAPK inhibitor, significantly inhibited VA-induced ROS generation, EGFR inhibition, p38MAPK activation and apoptosis. Moreover, pharmacological inhibition of EGFR and ERK1/2 significantly accelerated the VA-induced apoptosis in MDA-MB-231 cells. Collectively, these results indicate that VA-induces ROS elevation in cancer cells, which results in the activation of p38MAPK and inhibition of EGFR/Akt/ERK signaling cascade and, ultimately, cancer cell death.

• Authors: Kandasamy Palanivel, Veerasamy Kanimozhi, Balamuthu Kadalmani, Mohammad Abdulkader Akbarsha
• Journal: Journal of cellular biochemistry (J Cell Biochem) Vol. 115 Issue 11 Pg. 2022-32 (Nov 2014) ISSN: 1097-4644 [Electronic] United States
• PMID: 24963595 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 Wiley Periodicals, Inc.

Chemical References

• Antibiotics, Antineoplastic
• Reactive Oxygen Species
• Trichothecenes
• muconomycin A

Topics

• Antibiotics, Antineoplastic (pharmacology)
• Apoptosis
• Breast Neoplasms (metabolism, pathology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• MAP Kinase Signaling System (drug effects)
• Membrane Potential, Mitochondrial (drug effects)
• Reactive Oxygen Species (metabolism)
• Trichothecenes (pharmacology)