DNA methylation and histone modifications of genes influence tumorigenesis and tumor response to drug therapy and are also the main cause of drug resistance. These epigenetic changes lead to silencing of tumor suppressor genes involved in key DNA damage-response pathways, making drug-resistant cancer cells nonresponsive to conventional anticancer drug therapies. Treating drug-resistant cells with epigenetic drugs could restore the sensitivity to anticancer drugs by reactivating previously silenced genes.
We used drug-resistant breast cancer cells (MCF-7/ADR) and two epigenetic drugs that act via different mechanisms DAC and SAHA combination with doxorubicin. DAC can reduce DNA methyl transferase (DNMT) activity and the expression of multidrug resistance-1 (mdr1) efflux protein, thus enhancing intracellular doxorubicin levels. Doxil is not effective in treating drug-resistant breast cancer because of the impaired endocytic function that inhibits effective intracellular drug delivery.
In a word, this work shows that epigenetic drugs, when used sequentially in combination with doxorubicin, induce a highly synergistic effect and overcome drug resistance of cells to a significant extent. The next work would focus on further analyzing the effect of SAHA in resistant and sensitive cells and determine whether DAC and SAHA for pretreatment could be more effective in overcoming doxorubicin resistance than either DAC or SAHA.