DNA damage response in imatinib resistant chronic myeloid leukemia K562 cells

• Published in: Leukemia & lymphoma Vol. 53; no. 10; pp. 2004 - 2014
• Main Authors: Dinis, Joana, Silva, Vânia, Gromicho, Marta, Martins, Célia, Laires, António, Tavares, Purificação, Rendeiro, Paula, Torres, Fátima, Rueff, José, Rodrigues, António
• Format: Journal Article
• Language: English
• Published: United States Informa Healthcare 01.10.2012; Taylor & Francis
• Subjects: Antineoplastic Agents - pharmacology; Benzamides; Cell Survival - drug effects; Cell Survival - genetics; Chronic myeloid leukemia; Deoxyribonuclease (Pyrimidine Dimer) - genetics; DNA Damage - drug effects; DNA Damage - genetics; DNA repair; Drug Resistance, Neoplasm - genetics; Endodeoxyribonucleases - genetics; Gene Expression Regulation, Leukemic - drug effects; Gene Silencing; genotoxicity; Humans; Hydrogen Peroxide - pharmacology; Imatinib Mesylate; K562 Cells; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - metabolism; Oxidants - pharmacology; oxidative damage; Piperazines - pharmacology; Protein Kinase Inhibitors - pharmacology; Pyrimidines - pharmacology; resistance to imatinib
• ISSN: 1042-8194; 1029-2403
• DOI: 10.3109/10428194.2012.681654

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 H2O2 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 H2O2 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.