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Anticancer Effects of Ac-Phe-Lys-PABC-Doxorubicin via Mitochondria-centered Intrinsic Apoptosis Involving Reactive Oxidative Stress and ERK1/2Signling Pathway

Author: ZhongYanJun
Tutor: LiYan
School: Wuhan University
Course: Clinical
Keywords: Gastric cancer Cathepsin B Doxorubicin Prodrugs Targeting therapy
CLC: R735.2
Type: PhD thesis
Year: 2013
Downloads: 9
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Abstract

Background and purpose:Ac-Phe-Lys-PABC-DOX (PDOX) was a smart doxorubicin prodrug designed to decrease toxicities and increase effects. This study was aimed to elucidate the molecular mechanisms of action of PDOX using MGC-803gastric cancer cells as a model.Methods:MGC-803cells were cultured; cytotoxicities were determined by MTT assay; cell cycle was measured with flow cytometric analysis; ROS generation probed by DCF-DA and mitochondrial membrane potential probed by Mito Tracker(?) Red CMXRos were assayed by confocal microscopy; mitochondrial morphology was studied by transmission electron microscope; p-ERK1/2, ERK1/2, cytochrome C, and β-actin were detected by western blotting.Results:Abundant cathepsin B expression was observed in MGC-803cell line, PDOX and DOX triggered dose-dependent cytotoxicity and resulted in a significant reduction of cell viability. IC50of PDOX and DOX was14.9and4.9μM respectively. Both PDOX and DOX significantly decreased p-ERK1/2, increased ROS generation, reduced mitochondrial membrane potential, caused mitochondrial swelling, and retarded cell cycle at G2/S phase. Meanwhile, effects of PDOX on mitochondria, ROS generation, p-ERK1/2and cell cycle were more remarkable than DOX.Conclusions:PDOX and DOX have different mechanisms of action, particularly the mitochondria-centered intrinsic apoptosis involving reactive oxidative stress and ERK1/2signaling pathway.

Anticancer Effects of Ac-Phe-Lys-PABC-Doxorubicin via Mitochondria-centered Intrinsic Apoptosis Involving Reactive Oxidative Stress and ERK1/2Signling Pathway

Abstract

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