Reversal of epigenetic aberrations associated with the acquisition of doxorubicin resistance restores drug sensitivity in breast cancer cells

European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences
Logeswari PonnusamyKamaleshwar P Singh

Abstract

Acquired resistance against doxorubicin is a major limitation in clinical treatment of breast cancer. The molecular mechanism behind the aberrant expression of genes leading to doxorubicin resistance is not clear. Epigenetic changes play an important role in the regulation of gene expression. Therefore, the objective of this study was to identify the epigenetic mechanism underlying acquired doxorubicin resistance in breast cancer cells. Doxorubicin-resistant cells were selected by repeated exposure of MCF-7 and MDA-MB-231 breast cancer cell lines to clinically relevant doses of doxorubicin for 18 months. MTT assay, cell cycle analysis, colony formation, qRT-PCR, and Western blot analyses were used to characterize the epigenetic and molecular mechanism. Pyrosequencing was used to detect MSH2 promoter hypermethylation. Aberrant expression of epigenetic regulatory genes, a significant increase in H3 acetylation and methylation, as well as promoter hypermethylation-mediated inactivation of MSH2 gene were associated with the acquired resistant phenotype. Demethylating agent 5-Aza-deoxycytidine and HDAC inhibitor Trichostatin A significantly re-sensitized resistant cells to doxorubicin. Findings of this study revealed that epigenetic...Continue Reading

Citations

Aug 28, 2020·Frontiers in Oncology·Susana Romero-GarciaAngeles Carlos-Reyes
Jul 17, 2020·Frontiers in Oncology·Anthony QuaglianoSonali P Barwe
Oct 5, 2019·Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy·Yehuda G AssarafM Helena Vasconcelos
Nov 19, 2020·Breast Cancer : Targets and Therapy·Andrea Luque-BolivarMilena Rondón-Lagos
May 10, 2021·Life Sciences·Amin MahoutforoushSoheil Abbaspour-Ravasjani
Aug 25, 2021·Cellular & Molecular Biology Letters·Ghazaleh Khalili-Tanha, Meysam Moghbeli
Aug 29, 2020·Seminars in Cancer Biology·Gulab SherShahab Uddin

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