title: Suppression of multidrug resistance by treatment with TRAIL in human ovarian and breast cancer cells with high level of c-Myc.
abstract: In this study, we investigated the role of c-Myc in overcoming multidrug resistance (MDR) in human ovarian and breast cancer cells by TRAIL. We showed that P-gp expressing MDR variants (Hey A8-MDR and MCF7-MDR cells) with high level of c-Myc were highly susceptible to TRAIL treatment when compared to their drug-sensitive parental human ovarian cancer Hey A8 and breast MCF-7 cells, respectively. Up-regulation of DR5 TRAIL receptor and down-regulation of c-FLIP and the promotion of caspase-dependent cell death, which contribute to TRAIL sensitization of MDR cells, were regulated by the over-expressed c-Myc in the MDR cells. After targeted inhibition of c-Myc with specific siRNA, these responses to TRAIL disappeared and TRAIL-induced apoptosis was also suppressed in MCF7-MDR cells. Treatment with TRAIL significantly reduced P-glycoprotein (P-gp)-mediated efflux of rhodamine123 in both Hey A8-MDR and MCF7-MDR cells. Furthermore, TRAIL significantly potentiated the cytotoxicity of vinblastine, vincristine, doxorubicin and VP-16 that are P-gp substrate anticancer drugs in both MDR cells, which resulted in the reversal effect of TRAIL on the MDR phenotype. The present study shows for the first time that elevated c-Myc expression in the MDR cells plays a critical role in overcoming MDR by TRAIL that can act as a specific sensitizer for P-gp substrate anticancer drug.
authors.affiliation: Department of Biochemistry, Pusan National University School of Medicine, Yangsan 626-870, South Korea.
authors.forename: Dae-Young
authors.initials: DY
authors.lastname: Kim
authors.forename: Mi-Ju
authors.initials: MJ
authors.lastname: Kim
authors.forename: Hak-Bong
authors.initials: HB
authors.lastname: Kim
authors.forename: Jae-Won
authors.initials: JW
authors.lastname: Lee
authors.forename: Jae-Ho
authors.initials: JH
authors.lastname: Bae
authors.forename: Dong-Wan
authors.initials: DW
authors.lastname: Kim
authors.forename: Chi-Dug
authors.initials: CD
authors.lastname: Kang
authors.forename: Sun-Hee
authors.initials: SH
authors.lastname: Kim
mesh_terms: D001483:Base Sequence; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D017931:DNA Primers; D018432:Drug Resistance, Multiple; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*
chemical_list: D017931:DNA Primers; D016271:Proto-Oncogene Proteins c-myc; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human