title: Anticancer effects of Ac‑Phe‑Lys‑PABC‑doxorubicin via mitochondria‑centered apoptosis involving reactive oxidative stress and the ERK1/2 signaling pathway in MGC‑803 cells.
abstract: Ac‑Phe‑Lys‑PABC‑DOX (PDOX) is a smart doxorubicin (DOX) prodrug designed to decrease toxicities while maintaining the potent anticancer effects of DOX. The present study aimed to elucidate the molecular mechanisms of action of PDOX using MGC‑803 gastric cancer cells as a model. The cells were treated with both PDOX and DOX, and cytotoxicities, cell cycle analysis, reactive oxygen species (ROS) generation, mitochondrial damage and ERK1/2 signaling pathway alterations were studied. Abundant cathepsin B expression was observed in the MGC‑803 cells, and treatment with PDOX and DOX triggered dose‑dependent cytotoxicity and resulted in a significant reduction in cell viability. IC50 of PDOX and DOX was 14.9 and 4.9 µM, respectively. Both PDOX and DOX significantly decreased p‑ERK1/2, increased ROS generation, reduced mitochondrial membrane potential, caused mitochondrial swelling and arrested the cell cycle at the G2/S phase, and these effects were more pronounced for PDOX than for DOX. PDOX and DOX have different mechanisms of action, particularly the mitochondria‑centered intrinsic apoptosis involving reactive oxidative stress and the ERK1/2 signaling pathway.
authors.affiliation: Department of Oncology, Zhongnan Hospital of Wuhan University, Hubei Key Laboratory of Tumor Biological Behaviors and Hubei Cancer Clinical Study Center, Wuhan, Hubei 430071, P.R. China.
authors.forename: Yan-Jun
authors.initials: YJ
authors.lastname: Zhong
authors.forename: Shao-Ping
authors.initials: SP
authors.lastname: Liu
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Firestone
authors.forename: Ya-Ping
authors.initials: YP
authors.lastname: Hong
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002401:Cathepsin B / Q000096:biosynthesis; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism*; D008933:Mitochondrial Swelling / Q000187:drug effects; D009842:Oligopeptides / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D059807:S Phase Cell Cycle Checkpoints / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D009842:Oligopeptides; D017382:Reactive Oxygen Species; C573848:acetyl-phenylalanyl-lysyl-para-aminobenzyloxycarbonyl-adriamycin; D004317:Doxorubicin; D048049:Extracellular Signal-Regulated MAP Kinases; D002401:Cathepsin B