title: 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.
abstract: 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.
authors.affiliation: Key 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.
authors.forename: Ya-Xuan
authors.initials: YX
authors.lastname: Zhang
authors.affiliation: Key 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.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Key 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.
authors.forename: Ya-Jie
authors.initials: YJ
authors.lastname: Tang
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects*; D008870:Microtubules / Q000187:drug effects* / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D011034:Podophyllotoxin / Q000031:analogs & derivatives / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D050995:Voltage-Dependent Anion Channel 1 / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D017382:Reactive Oxygen Species; C494762:VDAC1 protein, human; D050995:Voltage-Dependent Anion Channel 1; D017868:Cyclic AMP-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D011034:Podophyllotoxin
keywords: antitumor mechanism; carbon-sulfur and carbon-amine bonds; mitochondrial depolarization; podophyllum derivatives