Doxorubicin-conjugated dexamethasone induced MCF-7 apoptosis without entering the nucleus and able to overcome MDR-1-induced resistance

Abstract

Doxorubicin is a common chemotherapeutic drug that generally uses in many solid and hematologic malignancies. The main mechanism of doxorubicin is inhibition of topoisomerase II that occurs in the nucleus. Currently, doxorubicin resistant cancer cells which have decreased accumulation of intracellular doxorubicin resulting from an efflux pump, P-glycoprotein encoded by multidrug resistant gene. Several studies reported many different ways to overcome doxorubicin resistance. In this study, we conjugated 3’amino group of doxorubicin to dexamethasone molecule. Despite of lower cytotoxic activity in MCF-7 cells, the conjugated product, DexDOX, exerted its actions in the different fashion to doxorubicin. DexDOX rapidly induced MCF-7 cells apoptosis without entering to the nucleus. Further analysis showed that DexDOX increased cytosolic oxidative stress and did not interfere with cell cycle. In addition, DexDOX retained cytotoxicity in MDR-1 over-expressed MCF-7 cells which had ≈16-folds resistance to doxorubicin. We here synthesized a new derivative of doxorubicin, DexDOX, which can overcome MDR-1 induced resistant. This molecule might be useful for future therapy.