title: Role of DNA hypomethylation in the development of the resistance to doxorubicin in human MCF-7 breast adenocarcinoma cells.
abstract: 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 (GSTpi), O(6)-methylguanine DNA methyltransferase (MGMT), and urokinase (Upa), in the development of drug resistance. The promoter regions of MDR1, GSTpi, 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, GSTpi, MGMT, and Upa genes.
authors.affiliation: Department of Mechanisms of Anticancer Therapy, R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, Kyiv, Ukraine.
authors.forename: Vasil F
authors.initials: VF
authors.lastname: Chekhun
authors.forename: Galina I
authors.initials: GI
authors.lastname: Kulik
authors.forename: Olga V
authors.initials: OV
authors.lastname: Yurchenko
authors.forename: Volodymyr P
authors.initials: VP
authors.lastname: Tryndyak
authors.forename: Igor N
authors.initials: IN
authors.lastname: Todor
authors.forename: Liliana S
authors.initials: LS
authors.lastname: Luniv
authors.forename: Nadiya A
authors.initials: NA
authors.lastname: Tregubova
authors.forename: Tamara V
authors.initials: TV
authors.lastname: Pryzimirska
authors.forename: Beverly
authors.initials: B
authors.lastname: Montgomery
authors.forename: Nataliya V
authors.initials: NV
authors.lastname: Rusetskaya
authors.forename: Igor P
authors.initials: IP
authors.lastname: Pogribny
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology*; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000473:pathology*; D019175:DNA Methylation; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D019450:Genes, MDR; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000235:genetics; D011401:Promoter Regions, Genetic; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics
chemical_list: D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin; D019853:O(6)-Methylguanine-DNA Methyltransferase; D005982:Glutathione Transferase; D014568:Urokinase-Type Plasminogen Activator