title: CHM-1 induces apoptosis via p38-mediated upregulation of DR5 expression in human ovarian cancer SKOV3 cells.
abstract: Ovarian cancer is a leading cause of death due to neoplasm of the female genital tract. Treatment for advanced-stage disease remains limited, and an effective drug for ovarian cancer is urgently needed today. In the present study, MTT assay was used to evaluate the antiproliferative effect of the 2-(substituted phenyl)-6,7-methylenedioxyquinolin-4-one derivatives for developing new anti-ovarian cancer drugs. CHM-1 was the most active compound, and it exhibited potent antiproliferative activity against human ovarian cancer cells. CHM-1 inhibited the growth of SKOV3 cells and induced apoptosis in a concentration-dependent manner, but it was less cytotoxic to human diploid skin fibroblast Detroit 551 cells. The western blot experiments showed that CHM-1 caused the upregulation of death receptor (DR) 5 and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Interestingly, CHM-1-mediated cellular apoptosis was found to be closely involved with the p38-mediated upregulation of DR5 expression. In an SKOV3 subcutaneous xenograft model, both CHM-1 and its phosphate, CHM-1-P caused a significant dose- and time-dependent tumor regression. Furthermore, CHM-1 inhibited tumor growth and prolonged the lifespan in the SKOV3 ip1/luc orthotopic xenograft model. Intravenous administration of CHM-1-P significantly prolonged the survival time in the SKOV3/ICR-Foxn1nu orthotopic xenograft model. Based on their excellent antitumor activity with the interesting mechanism of action, CHM-1 and CHM-1-P were considered new anti-ovarian cancer drug candidates.
authors: Graduate Institute of Pharmaceutical Chemistry, College of Pharmacy, China Medical University, Taichung, Taiwan.
authors: Jang-Chang
authors: JC
authors: Lee
authors: Li-Chen
authors: LC
authors: Chou
authors: Chi-Hung
authors: CH
authors: Huang
authors: Jing-Gung
authors: JG
authors: Chung
authors: Li-Jiau
authors: LJ
authors: Huang
authors: Kuo-Hsiung
authors: KH
authors: Lee
authors: Mien-Chie
authors: MC
authors: Hung
authors: Tzong-Der
authors: TD
authors: Way
authors: Sheng-Chu
authors: SC
authors: Kuo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D053181:Caspase 8 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004149:Dioxoles / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D051379:Mice; D010051:Ovarian Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D011804:Quinolines / Q000737:chemistry; D015363:Quinolones / Q000737:chemistry / Q000494:pharmacology*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D016019:Survival Analysis; D015854:Up-Regulation / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: C525063:2'-fluoro-6,7-methylenedioxy-2-phenyl-4-quinolone; D000970:Antineoplastic Agents; D004149:Dioxoles; D011804:Quinolines; D015363:Quinolones; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D048051:p38 Mitogen-Activated Protein Kinases; D053181:Caspase 8