title: DNA damage response in imatinib resistant chronic myeloid leukemia K562 cells.
abstract: Resistance to imatinib in patients with chronic myeloid leukemia can lead to advanced disease and blast crisis. Conventional chemotherapy with DNA damaging agents is then used, alone or in combination with other tyrosine kinase inhibitors (TKIs). Our aim was to assess whether imatinib resistant K562 cells were also resistant to DNA damaging agents. After treatment with H(2)O(2) and doxorubicin, but not camptothecin, cell survival was higher in imatinib resistant cells compared to parental cells. DNA damage, measured by comet and γ-H2AX assays, was lower in imatinib resistant cells. mRNA expression levels of 50 genes of the DNA damage response pathway showed increased expression of the base excision repair (BER) genes MBD4 and NTHL1. Knockdown of MBD4 and NTHL1 expression in resistant cells using siRNA decreased cell survival after treatment with H(2)O(2) and doxorubicin. Our results indicate that imatinib resistant cells display cross-resistance to oxidative agents, partly through up-regulation of BER genes. Expression of these genes in imatinib resistant patients was not significantly different compared to sensitive patients. However, the strategy followed in this study could help identify chemotherapeutic agents that are more effective as alternative agents in cases of resistance to TKIs.
authors.affiliation: CIGMH Human Molecular Genetics Research Center, Department of Genetics, Faculty of Medical Sciences, Universidade Nova de Lisboa, Lisboa, Portugal.
authors.forename: Joana
authors.initials: J
authors.lastname: Dinis
authors.forename: Vânia
authors.initials: V
authors.lastname: Silva
authors.forename: Marta
authors.initials: M
authors.lastname: Gromicho
authors.forename: Célia
authors.initials: C
authors.lastname: Martins
authors.forename: António
authors.initials: A
authors.lastname: Laires
authors.forename: Purificação
authors.initials: P
authors.lastname: Tavares
authors.forename: Paula
authors.initials: P
authors.lastname: Rendeiro
authors.forename: Fátima
authors.initials: F
authors.lastname: Torres
authors.forename: José
authors.initials: J
authors.lastname: Rueff
authors.forename: António
authors.initials: A
authors.lastname: Rodrigues
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004249:DNA Damage / Q000187:drug effects / Q000235:genetics; D043224:Deoxyribonuclease (Pyrimidine Dimer) / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004706:Endodeoxyribonucleases / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D020868:Gene Silencing; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D000068877:Imatinib Mesylate; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics* / Q000378:metabolism*; D016877:Oxidants / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D016877:Oxidants; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D006861:Hydrogen Peroxide; D004706:Endodeoxyribonucleases; C118712:MBD4 protein, human; D043224:Deoxyribonuclease (Pyrimidine Dimer); C468347:NTHL1 protein, human