Multilevel induction of apoptosis by microtubule-interfering inhibitors 4β-S-aromatic heterocyclic podophyllum derivatives causing multi-fold mitochondrial depolarization and PKA signaling pathways in HeLa cells
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Ya-Xuan Zhang1,*, Wei Zhao1,*, Ya-Jie Tang1
1Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei Key Laboratory of Industrial Microbiology, Hubei Provincial Cooperative Innovation Center of Industrial Fermentation, Hubei University of Technology, Wuhan 430068, China
*These authors have contributed equally to this work
Ya-Jie Tang, e-mail: yajietang@QQ.com
Keywords: podophyllum derivatives, carbon-sulfur and carbon-amine bonds, mitochondrial depolarization, antitumor mechanism
Received: December 06, 2015 Accepted: February 28, 2016 Published: March 17, 2016
Herein is a first effort to study effect of carbon-sulfur (C-S) and carbon-nitrogen (C-N) bonds modification on the antitumor activity of the podophyllum derivatives in HeLa cells. Compared with the derivative modified by the C-N bond, the C-S bond modification exhibited superior antitumor activity by further causing significant mitochondria depolarization from three signaling pathway. First, a large number of microtubules were depolymerized by 4β-S-heterocyclic substituted podophyllum derivatives. The increasing free tubulin bond with voltage-dependent anion-selective channel (VDAC). Second, cAMP-dependent protein kinase A (PKA) was activated by 4β-S-heterocyclic substituted podophyllum derivatives. And then the activated PKA further caused significantly mitochondria depolarization. Third, the activated PKA also activated c-Jun N-terminal kinase (JNK) and further deceased MMP by improving the level of reactive oxygen species. Understanding the molecular events that contribute to drug-induced tumors apoptosis should provide a paradigm for a more rational approach to antitumor drug design.
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