Vinca alkaloids cause aberrant ROS-mediated JNK activation, Mcl-1 downregulation, DNA damage, mitochondrial dysfunction, and apoptosis in lung adenocarcinoma cells.

Abstract

Vinca alkaloids are clinically used to inhibit the growth of malignancy by interfering with microtubule polymerization. The purpose of this study was to identify the molecular mechanisms underlying growth inhibition as well as apoptosis in vinca alkaloid-treated lung adenocarcinoma cells. Consistent with nocodazole, treatment with vinorelbine (VNR) caused mitotic prometaphase arrest in a time-dependent manner, accompanied by cell apoptosis, dependent on both dose and time. VNR sequentially induced mitochondrial transmembrane potential (MTP) loss and caspase-dependent apoptosis following myeloid cell leukemia (Mcl) 1 downregulation. Prolonged activation of c-Jun N-terminal kinase (JNK) was required for vinca alkaloid- and nocodazole-induced apoptosis but not cell cycle arrest. Vinca alkaloids and nocodazole caused glutathione/reactive oxygen species (ROS) imbalance, and inhibiting ROS prevented prolonged JNK activation, decreased Mcl-1 levels, MTP loss, and apoptosis. Notably, cell size and granularity were enlarged in stimulated cells; unexpectedly, many ROS-producing mitochondria were accumulated followed by aberrant JNK-mediated mitochondrial dysfunction. Unlike cisplatin, which causes DNA damage in each phase of the cell cycle, VNR and nocodazole induced aberrant JNK-regulated DNA damage in prometaphase; however, inhibiting ATM (ataxia telangiectasia, mutated) and ATR (ATM and Rad3-related) did not reverse mitotic arrest or apoptosis. These results demonstrate an essential role of ROS in vinca alkaloid-induced aberrant JNK-mediated Mcl-1 downregulation and DNA damage followed by mitochondrial dysfunction-related apoptosis but not mitotic arrest.

• Authors: Wei-Hsin Chiu, Sheng-Jei Luo, Chia-Ling Chen, Jai-Hong Cheng, Chia-Yuan Hsieh, Chi-Yun Wang, Wei-Ching Huang, Wu-Chou Su, Chiou-Feng Lin
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 83 Issue 9 Pg. 1159-71 (May 01 2012) ISSN: 1873-2968 [Electronic] England
• PMID: 22285910 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents, Phytogenic
• Myeloid Cell Leukemia Sequence 1 Protein
• Proto-Oncogene Proteins c-bcl-2
• Reactive Oxygen Species
• Vinca Alkaloids
• Vinblastine
• JNK Mitogen-Activated Protein Kinases
• Caspases
• Vinorelbine

Topics

• Adenocarcinoma (drug therapy, metabolism, pathology)
• Antineoplastic Agents, Phytogenic (pharmacology)
• Apoptosis (drug effects)
• Caspases (metabolism)
• Cell Line, Tumor
• DNA Damage
• Down-Regulation
• Humans
• JNK Mitogen-Activated Protein Kinases (metabolism)
• Lung Neoplasms (drug therapy, metabolism, pathology)
• Mitochondria (drug effects, metabolism)
• Myeloid Cell Leukemia Sequence 1 Protein
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Reactive Oxygen Species (metabolism)
• Vinblastine (analogs & derivatives, pharmacology)
• Vinca Alkaloids (pharmacology)
• Vinorelbine