title: Sensitization of chemo-resistant human chronic myeloid leukemia stem-like cells to Hsp90 inhibitor by SIRT1 inhibition.
abstract: Development of effective therapeutic strategies to eliminate cancer stem-like cells (CSCs), which play a major role in drug resistance and disease recurrence, is critical to improve cancer treatment outcomes. The current investigation was undertaken to examine the effectiveness of the combination treatment of Hsp90 inhibitor and SIRT1 inhibitor in inhibiting the growth of chemo-resistant stem-like cells isolated from human chronic myeloid leukemia K562 cells. Inhibition of SIRT1 by use of SIRT1 siRNA or SIRT1 inhibitors (amurensin G and EX527) effectively potentiated sensitivity of Hsp90 inhibitors (17-AAG and AUY922) in CD44(high) K562 stem-like cells expressing high levels of CSC-related molecules including Oct4, CD34, β-catenin, c-Myc, mutant p53 (mut p53), BCRP and P-glycoprotein (P-gp) as well as CD44. SIRT1 depletion caused significant down-regulation of heat shock factor 1 (HSF1)/heat shock proteins (Hsps) as well as these CSC-related molecules, which led to the sensitization of CD44(high) K562 cells to Hsp90 inhibitor by SIRT1 inhibitor. Moreover, 17-AAG-mediated activation of HSF1/Hsps and P-gp-mediated efflux, major causes of Hsp90 inhibitor resistance, was suppressed by SIRT1 inhibitor in K562-CD44(high) cells. Our data suggest that combined treatment with Hsp90 inhibitor and SIRT1 inhibitor could be an effective therapeutic approach to target CSCs that are resistant to current therapies.
authors.affiliation: 1. 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: 1. 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: 2. 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: 1. Department of Biochemistry, Pusan National University School of Medicine, Yangsan 626-870, Korea.
authors.forename: Mi-Ju
authors.initials: MJ
authors.lastname: Kim
authors.affiliation: 1. Department of Biochemistry, Pusan National University School of Medicine, Yangsan 626-870, Korea.
authors.forename: Suh-Kyung
authors.initials: SK
authors.lastname: Hyun
authors.affiliation: 1. Department of Biochemistry, Pusan National University School of Medicine, Yangsan 626-870, Korea.
authors.forename: Eun-Ji
authors.initials: EJ
authors.lastname: Gong
authors.affiliation: 3. College of Pharmacy, Seoul National University, Seoul 151-818, Korea.
authors.forename: Won Keun
authors.initials: WK
authors.lastname: Oh
authors.affiliation: 1. 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: 1. 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: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors; D016227:Benzoquinones / Q000494:pharmacology; D002227:Carbazoles / Q000494:pharmacology; D003986:Dibenzocycloheptenes / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology; D020014:K562 Cells; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000473:pathology*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D012118:Resorcinols / Q000494:pharmacology; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors*; D015854:Up-Regulation
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; C116614:ABCG2 protein, human; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D016227:Benzoquinones; D002227:Carbazoles; D003986:Dibenzocycloheptenes; D018841:HSP90 Heat-Shock Proteins; D007555:Isoxazoles; D047029:Lactams, Macrocyclic; D009363:Neoplasm Proteins; D012118:Resorcinols; C553921:amurensin G; C112765:tanespimycin; C447939:SIRT1 protein, human; D056564:Sirtuin 1
keywords: CD44; Hsp90 inhibitor; K562; SIRT1 inhibitor; cancer stem-like cells; multidrug resistance