Despite advances in cancer therapy, chemoresistance is a major contributor to cancer-related deaths. Aberrant DNA methylation contributes substantially to drug resistance by blocking tumor suppressor genes from being expressed, promoting tumor survival and growth. Furthermore, tumors obtained from chemoresistant patients have dramatically different methylation profiles compared to tumors from chemosensitive patients. There are several compounds known as DNA methylation inhibitors that predominantly function to reverse aberrant DNA methylation. Although there is in vitro evidence that these methylation inhibitors can reverse drug-induced resistance in solid tumor and hematological cancer models, this has not been rigorously tested in ovarian cancer (OvCa). Thus, I hypothesize that blocking DNA methylation will sensitize OvCa cells to chemotherapeutic agents and attenuate drug resistance. To test this hypothesis, fifteen OvCa cell lines, representing all major OvCa histological subtypes, were treated with four different DNA methylation inhibitors: 5-azacytidine, decitabine, zebularine, and RG108, in combination with chemotherapy. It is expected that the cell lines become sensitized to the chemotherapy after drug treatments and lose viability as dosage increases. To determine long-term effects of methylation inhibition we generated growth curves while assessing the drug efficacy via methylation profiling. Together, this data indicates strong efficacy of DNA methylation inhibitors in sensitizing to chemotherapy. In the future, the DNA methylation inhibitors that successfully sensitized the OvCa cells and the best methylation inhibitor for each ovarian cancer subtype could be used in the clinic to bypass resistance.
PROJECT: Epigenetic inhibition sensitizes ovarian cancer to chemotherapy
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