title: Camptothecin acts synergistically with imatinib and overcomes imatinib resistance through Bcr-Abl independence in human K562 cells.
abstract: In this study, we have tried to find new targets and effective drugs for imatinib-resistant chronic myelogenous leukemia (CML) cells displaying loss of Bcr-Abl kinase target dependence. The imatinib-resistant K562/R1, -R2 and -R3 cells showed profound declines of Bcr-Abl level and concurrently exhibited up-regulation of Bcl-2 and Ku70/80, and down-regulation of Bax, DNA-PKcs and BRCA1, suggesting that loss of Bcr-Abl after exposure to imatinib might be accompanied by other cell survival mechanism. K562/R3 cells were more sensitive to camptothecin (CPT)- and radiation-induced apoptosis than K562 cells, indicating hypersensitivity of imatinib-resistant cells to DNA damaging agents. Moreover, when K562 cells were treated with the combination of imatinib with CPT, the level of Bax and the cleavage of PARP-1 and DNA-PK were significantly increased in comparison with the effects of each drug. Therefore, our study suggests that CPT can be used to treat CML with loss of Bcr-Abl expression.
authors.affiliation: Department of Biochemistry, Pusan National University School of Medicine, Busan 602-739, South Korea.
authors.forename: Dong-Sik
authors.initials: DS
authors.lastname: Ju
authors.forename: Mi-Ju
authors.initials: MJ
authors.lastname: Kim
authors.forename: Jae-Ho
authors.initials: JH
authors.lastname: Bae
authors.forename: Hye-Soon
authors.initials: HS
authors.lastname: Song
authors.forename: Byung-Seon
authors.initials: BS
authors.lastname: Chung
authors.forename: Min-Ki
authors.initials: MK
authors.lastname: Lee
authors.forename: Chi-Dug
authors.initials: CD
authors.lastname: Kang
authors.forename: Hyun-Sun
authors.initials: HS
authors.lastname: Lee
authors.forename: Dong-Wan
authors.initials: DW
authors.lastname: Kim
authors.forename: Sun-Hee
authors.initials: SH
authors.lastname: Kim
mesh_terms: D034961:Antigens, Nuclear / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D019313:BRCA1 Protein / Q000037:antagonists & inhibitors; D001549:Benzamides; D002166:Camptothecin / Q000494:pharmacology*; D045744:Cell Line, Tumor; D045643:DNA Repair Enzymes / Q000378:metabolism; D051747:DNA-Activated Protein Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D016044:Fusion Proteins, bcr-abl; D006801:Humans; D000068877:Imatinib Mesylate; D000072200:Ku Autoantigen; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000378:metabolism*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology*; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D019253:Proto-Oncogene Proteins c-bcl-2; D011743:Pyrimidines / Q000494:pharmacology*; D011836:Radiation Tolerance; D051028:bcl-2-Associated X Protein / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D034961:Antigens, Nuclear; D000970:Antineoplastic Agents; D019313:BRCA1 Protein; D001549:Benzamides; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D011743:Pyrimidines; D051028:bcl-2-Associated X Protein; D000068877:Imatinib Mesylate; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human; C000606509:Xrcc6 protein, human; D000072200:Ku Autoantigen; D045643:DNA Repair Enzymes; D002166:Camptothecin