Role of DNA hypomethylation in the development of the resistance to doxorubicin in human MCF-7 breast adenocarcinoma cells

• Published in: Cancer letters Vol. 231; no. 1; pp. 87 - 93
• Main Authors: Chekhun, Vasil F., Kulik, Galina I., Yurchenko, Olga V., Tryndyak, Volodymyr P., Todor, Igor N., Luniv, Liliana S., Tregubova, Nadiya A., Pryzimirska, Tamara V., Montgomery, Beverly, Rusetskaya, Nataliya V., Pogribny, Igor P.
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier Ireland Ltd 08.01.2006; Elsevier Limited
• Subjects: Adenocarcinoma - pathology; Antibiotics, Antineoplastic - pharmacology; Breast cancer; Breast Neoplasms - pathology; Cancer therapies; Cell culture; Chemotherapy; Deoxyribonucleic acid; DNA; DNA hypomethylation; DNA Methylation; Doxorubicin - pharmacology; Doxorubicin resistance; Drug resistance; Drug Resistance, Neoplasm - genetics; Female; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Genes, MDR; Glutathione Transferase - genetics; Humans; MCF-7 cells; Molecular weight; O-Methylguanine-DNA Methyltransferase - genetics; Promoter Regions, Genetic; Urokinase-Type Plasminogen Activator - genetics; Doxorubicin resistance; MCF-7 cells; DNA hypomethylation
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2005.01.038

The resistance of cancer cells to chemotherapeutic agents is a major clinical problem and an important cause of treatment failure in cancer. Mechanisms that have developed to guard cancer cells against anti-cancer drugs are major barriers to successful anti-cancer therapy. Therefore, the identification of novel mechanisms of cellular resistance holds the promise of leading to better treatments for cancer patients. In the present study, we used human MCF-7 breast adenocarcinoma cell line and its doxorubicin-resistant variant MCF-7/R to determine the role of alterations of DNA methylation of chemoresitance-related genes, such as multidrug resistance 1 ( MDR1), glutathione- S-transferase ( GSTπ), O 6-methylguanine DNA methyltransferase ( MGMT), and urokinase ( Upa), in the development of drug resistance. The promoter regions of MDR1, GSTπ, MGMT, and Upa genes were highly methylated in MCF-7 cell line but not in its MCF-7/R drug resistant variant. The hypomethylated status of MDR1 gene was associated with overexpression of P-glycoprotein. We hypothesize that acquirement of doxorubicin resistance of MCF-7 cells is associated with DNA hypomethylation of the promoter regions of the MDR1, GSTπ, MGMT, and Upa genes.