title: Synergistic induction of cancer cell death and reduction of clonogenic resistance by cisplatin and FK228.
abstract: Human urinary bladder cancer is the fifth most common cancer in the United States, and the long-term disease-free survival in patients is still suboptimal with current chemotherapeutic regimens. Development of effective chemotherapeutic regimens is crucial to decrease the morbidity and mortality of this cancer. The goal of this study was to investigate the effectiveness of FK228 in increasing cisplatin's ability to induce bladder cancer cell death and reduce drug resistance. Our study revealed that FK228 combined with cisplatin synergistically induced cell death and reduced clonogenic survival of human urinary bladder cancer cells. The Erk-Nox pathway played an important role in mediating signals highly increased by this combined treatment to induce significantly-elevated levels of reactive oxygen species, leading to substantially-induced caspase activation and synergistically-increased death in cancer cells. Cisplatin was able to enhance the ability of FK228 to significantly reduce glutathione, indicating a novel activity of combined FK228 and cisplatin in reducing drug resistance. The ability of combined FK228 and cisplatin to synergistically induce cell death and reduce clonogenic survival was also applicable to colon cancer cells. Hence, combined use of FK228 with cisplatin should be considered in development of therapeutic strategies to control urinary bladder cancer and other cancer development and recurrence.
authors.affiliation: Anticancer Molecular Oncology Laboratory, Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, The University of Tennessee, Knoxville, TN 37996, United States.
authors.forename: Shambhunath
authors.initials: S
authors.lastname: Choudhary
authors.forename: Shilpa
authors.initials: S
authors.lastname: Sood
authors.forename: Hwa-Chain Robert
authors.initials: HC
authors.lastname: Wang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D047630:Depsipeptides / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D019073:HT29 Cells; D006801:Humans; D015151:Immunoblotting; D000074624:NADPH Oxidase 1; D019255:NADPH Oxidases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014410:Tumor Stem Cell Assay; D001749:Urinary Bladder Neoplasms / Q000378:metabolism / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D047630:Depsipeptides; D017382:Reactive Oxygen Species; C087123:romidepsin; D000074624:NADPH Oxidase 1; D019255:NADPH Oxidases; C402799:NOX1 protein, human; D048049:Extracellular Signal-Regulated MAP Kinases; D053148:Caspase 3; D053179:Caspase 7; D005978:Glutathione; D002945:Cisplatin