Role of DNA hypomethylation in the development of the resistance to doxorubicin in human MCF-7 breast adenocarcinoma cells.
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.
Chekhun
Vasil F
VF
Department of Mechanisms of Anticancer Therapy, R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, Kyiv, Ukraine.
Kulik
Galina I
GI
Yurchenko
Olga V
OV
Tryndyak
Volodymyr P
VP
Todor
Igor N
IN
Luniv
Liliana S
LS
Tregubova
Nadiya A
NA
Pryzimirska
Tamara V
TV
Montgomery
Beverly
B
Rusetskaya
Nataliya V
NV
Pogribny
Igor P
IP
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
D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin; D019853:O(6)-Methylguanine-DNA Methyltransferase; D005982:Glutathione Transferase; D014568:Urokinase-Type Plasminogen Activator