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

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

Research output: Contribution to journalArticle

68 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1159-1171
Number of pages13
JournalBiochemical Pharmacology
Volume83
Issue number9
DOIs
Publication statusPublished - May 1 2012

Keywords

  • Apoptosis
  • Caspase
  • JNK
  • Lung adenocarcinoma
  • Mcl-1
  • Mitochondria
  • Mitotic arrest
  • ROS
  • Vinca alkaloids

ASJC Scopus subject areas

  • Pharmacology
  • Biochemistry

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