title: Sensitization of multidrug-resistant human cancer cells to Hsp90 inhibitors by down-regulation of SIRT1.
abstract: The effectiveness of Hsp90 inhibitors as anticancer agents was limited in multidrug-resistant (MDR) human cancer cells due to induction of heat shock proteins (Hsps) such as Hsp70/Hsp27 and P-glycoprotein (P-gp)-mediated efflux. In the present study, we showed that resistance to Hsp90 inhibitors of MDR human cancer cells could be overcome with SIRT1 inhibition. SIRT1 knock-down or SIRT1 inhibitors (amurensin G and EX527) effectively suppressed the resistance to Hsp90 inhibitors (17-AAG and AUY922) in several MDR variants of human lymphoblastic leukemia and human breast cancer cell lines. SIRT1 inhibition down-regulated the expression of heat shock factor 1 (HSF1) and subsequently Hsps and facilitated Hsp90 multichaperone complex disruption via hyperacetylation of Hsp90/Hsp70. These findings were followed by acceleration of ubiquitin ligase CHIP-mediated mutant p53 (mut p53) degradation and subsequent down-regulation of P-gp in 17-AAG-treated MDR cancer cells expressing P-gp and mut p53 after inhibition of SIRT1. Therefore, combined treatment with Hsp90 inhibitor and SIRT1 inhibitor could be a more effective therapeutic approach for Hsp90 inhibitor-resistant MDR cells via down-regulation of HSF1/Hsps, mut p53 and P-gp.
authors.affiliation: Department of Biochemistry, Pusan National University School of Medicine, Yangsan 626-870, Korea.
authors.forename: Hak-Bong
authors.initials: HB
authors.lastname: Kim
authors.affiliation: Department of Biochemistry, Pusan National University School of Medicine, Yangsan 626-870, Korea.
authors.forename: Su-Hoon
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Korea Mouse Metabolic Phenotyping Center, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 406-840, Korea.
authors.forename: Jee-Hyun
authors.initials: JH
authors.lastname: Um
authors.affiliation: Korea Bioactive Natural Material Bank, College of Pharmacy, Seoul National University, Seoul 151-818, Korea.
authors.forename: Won Keun
authors.initials: WK
authors.lastname: Oh
authors.affiliation: Department of Microbiology, College of Natural Sciences, Chang Won National University, Chang Won 641-773, Korea.
authors.forename: Dong-Wan
authors.initials: DW
authors.lastname: Kim
authors.affiliation: Department of Biochemistry, Pusan National University School of Medicine, Yangsan 626-870, Korea.
authors.forename: Chi-Dug
authors.initials: CD
authors.lastname: Kang
authors.affiliation: Department of Biochemistry, Pusan National University School of Medicine, Yangsan 626-870, Korea.
authors.forename: Sun-Hee
authors.initials: SH
authors.lastname: Kim
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D016227:Benzoquinones / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002227:Carbazoles / Q000494:pharmacology; D045744:Cell Line, Tumor; D003986:Dibenzocycloheptenes / Q000494:pharmacology; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D055785:Gene Knockdown Techniques; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D061986:MCF-7 Cells; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012118:Resorcinols / Q000494:pharmacology; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: C528044:5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide; C550547:6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide; D016227:Benzoquinones; D002227:Carbazoles; D003986:Dibenzocycloheptenes; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D007555:Isoxazoles; D047029:Lactams, Macrocyclic; D012118:Resorcinols; C553921:amurensin G; C112765:tanespimycin; C447939:SIRT1 protein, human; D056564:Sirtuin 1
keywords: Hsp70; Hsp90 inhibitor; MDR; P-gp; SIRT1