Sorafenib induces preferential apoptotic killing of a drug- and radio-resistant Hep G2 cells through a mitochondria-dependent oxidative stress mechanism

Jeng Fong Chiou, Cheng Jeng Tai, Yu Huei Wang, Tsan Zon Liu, Yee Min Jen, Chia Yang Shiau

Research output: Contribution to journalArticle

46 Citations (Scopus)

Abstract

Sorafenib (Nexavar, BAY43-9006), a bi-arylurea, is a newly established anti-cancer drug and its functional attribute of cytotoxicity is based on the multi-kinase inhibitory action. here, we report yet another novel pathway in which sorafenib can induce apoptotic cell death preferentially and efficaciously on an experimentally proven drug- and radio-resistant human hep G2 cells via a mitochondria-dependent oxidative stress mechanism. a real-time confocal imaging assay revealed that sorafenib could rapidly provoke the production of ROS plethorically, mainly concentrating in the mitochondria, albeit substantial amounts of ROS could also be detected in cytosol and nucleus. The rapid production of ROS could simultaneously induce intracellular glutathione (iGSH) depletion. a nearly 90% of iGSH was found to be depleted in 1h period after the cells received the drug treatment. Besides mitochondria, iGSH depletion could also be detected in other cellular compartment including cytoplasm and nucleus. Interestingly, we also demonstrated that sorafenib could trigger mitochondrial Ca2+ overload. all these events compoundedly serve as the final arbitrator to initiate lethal apoptotic process through the release of cytochrome c and caspase 3/7 activation. Collectively, we provide first evidence here that sorafenib can provoke an alternative pathway for apoptosis induction of Hep G2 cells through a mitochondria-dependent oxidative stress mechanism which is independent of original kinase inhibitory attribute of the drug action. Most importantly, we also demonstrate that sorafenib can effectively eradicate a highly drug- and radio-resistant HCC cells. Thus, our data can provide the basis for a potential applicability of sorafenib in a combined treatment modality.

Original languageEnglish
Pages (from-to)1904-1913
Number of pages10
JournalCancer Biology and Therapy
Volume8
Issue number20
DOIs
Publication statusPublished - Oct 15 2009

Keywords

  • Anti-cancer drug
  • Apoptosis
  • Confocal
  • Hepatocellular carcinoma cell
  • Mitochondria
  • Oxidative stress mechanism
  • Sorafenib

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Molecular Medicine
  • Pharmacology

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