Drug resistance in cancer therapy and the possible role of epigenetics

Abstract

Effective leukemia treatment is seriously hampered by drug resistance. The possible roles of epigenetic mechanisms have recently been considered in cancer drug resistance. With conventional anti-cancer drugs, including alkylating drugs, anti-metabolite drugs, topoisomerase inhibitors, and microtubule inhibitors, which have been available for half a century, the drug resistance often occurs due to decreased expression of target enzymes, with increased expression of drug export pumps. The alterations of target gene expression and increased export pump function might be caused by epigenetic changes, such as changes of methylation status, as well as changes of histone acetylation status. In addition, newly developed anti-cancer drugs, including small molecule drugs such as kinase inhibitors, antibody drugs, and immune modulatory drugs, also showed development of drug resistance within a year, although these drugs show significant efficacy in conventional anti-cancer drug-resistant patients. The resistant cells showed increased expression of bypass pathways, activation of downstream cascades, decreased expression of antigens of tumor cells, increased DNA repair activity, and increased expression of drug export pumps, also suggesting epigenetic changes. In this paper, drug resistance to cancer therapy and the possible roles of epigenetic mechanisms are reviewed.