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

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• 作者：Vasil F. Chekhun ; Galina I. Kulik ; Olga V. Yurchenko ; Volodymyr P. Tryndyak ; Igor N. Todor ; Liliana S. Luniv ; Nadiya A. Tregubova ; Tamara V. Pryzimirska ; Beverly Montgomery ; Nataliya V. Rusetskaya and
• 关键词：MCF-7 cells ; Doxorubicin resistance ; DNA hypomethylation
• 刊名：Cancer Letters
• 出版年：2006
• 出版时间：8 January 2006
• 年：2006
• 卷：231
• 期：1
• 页码：87-93
• 全文大小：198 K

文摘

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), O⁶-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.