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.