Apoptosis induction by alantolactone in breast cancer MDA-MB-231 cells through reactive oxygen species-mediated mitochondrion-dependent pathway.

Abstract

Alantolactone is a sesquiterpene lactone isolated from Inula helenium L. Although alantolactone possesses anti-inflammation and apoptosis-induction activities, the underlying mechanism of anti-cancer effect on human breast cancer cells remains largely unknown. In this study, we explored the possibility of alantolactone as an apoptosis-inducing cytotoxic agent using MDA-MB-231 cells as in vitro model. Alantolactone significantly induced its apoptosis, demonstrated by cell cycle analysis, annexin V-APC/7-AAD double staining and dUTP nick end labeling. Additionally, alantolactone triggered the mitochondrial-mediated caspase cascade apoptotic pathway, which was confirmed by increased Bax/Bcl-2 ratio, loss of MMP, release of cytc from mitochondria to cytoplasm, activation of caspase 9/3, and subsequent cleavage of PARP. Z-VAD-FMK partially prevented apoptosis induced by alantolactone. Alantolactone provoked the production of ROS, while NAC (a scavenger of ROS) reversed alantolactone-mediated depolarization of MMP and apoptosis. Alantolactone modulated the activities of MAPKs. As expected, cotreatment with SB203580, SP600125 or U0126 could reduced the apoptotic rate. Furthermore, alantolactone decreased the protein expressions of p-NF-kB p65 and p-STAT3, increased p-c-Jun level in a dose-dependent manner. These findings suggested that alantolactone possessed anticancer activity via ROS-mediated mitochondrial dysfunction involving MAPK pathway, and had an effect on the transcription factors of NF-kB, AP-1 and STAT3.

• Authors: Li Cui, Weiquan Bu, Jie Song, Liang Feng, Tingting Xu, Dan Liu, Wenbo Ding, Jianhua Wang, Changyang Li, Binge Ma, Yi Luo, Ziyu Jiang, Chengcheng Wang, Juan Chen, Jian Hou, Hongmei Yan, Lei Yang, Xiaobin Jia
• Journal: Archives of pharmacal research (Arch Pharm Res) Vol. 41 Issue 3 Pg. 299-313 (Mar 2018) ISSN: 1976-3786 [Electronic] Korea (South)
• PMID: 29214600 (Publication Type: Journal Article)

Chemical References

• Lactones
• Reactive Oxygen Species
• Sesquiterpenes, Eudesmane
• alantolactone

Topics

• Apoptosis (drug effects, physiology)
• Breast Neoplasms (metabolism)
• Cell Death (drug effects, physiology)
• Cell Line, Tumor
• Dose-Response Relationship, Drug
• Female
• Humans
• Lactones (pharmacology)
• MCF-7 Cells
• Mitochondria (drug effects, metabolism)
• Reactive Oxygen Species (metabolism)
• Sesquiterpenes, Eudesmane (pharmacology)