Combination therapy with epigenetic-targeted and chemotherapeutic drugs delivered by nanoparticles to enhance the chemotherapy response and overcome resistance by breast cancer stem cells.

Aberrant DNA hypermethylation is critical in the regulation of renewal and maintenance of cancer stem cells (CSCs), which represent targets for carcinogenic initiation by chemical and environmental agents. The administration of decitabine (DAC), which is a DNA hypermethylation inhibitor, is an attractive approach to enhancing the chemotherapeutic response and overcoming drug resistance by CSCs. In this study, we investigated whether low-dose DAC encapsulated in nanoparticles could be used to sensitize bulk breast cancer cells and CSCs to chemotherapy. In vitro studies revealed that treatment with nanoparticles loaded with low-dose DAC (NPDAC) combined with nanoparticles loaded with doxorubicin (NPDOX) better reduced the proportion of CSCs with high aldehyde dehydrogenase activity (ALDH(hi)) in the mammospheres of MDA-MB-231 cells, and better overcame the drug resistance by ALDH(hi) cells. Subsequently, systemic delivery of NPDAC significantly down-regulated the expression of DNMT1 and DNMT3b in a MB-MDA-231 xenograft murine model and induced increased caspase-9 expression, which contributed to the increased sensitivity of the bulk cancer cells and CSCs to NPDOX treatment. Importantly, the combined treatment of NPDAC and NPDOX resulted in the lowest proportion of ALDH(hi) CSCs and the highest proportion of apoptotic tumor cells, and the best tumor suppressive effects in inhibiting breast cancer growth.