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

Abstract

Background: Doxorubicin (DOX) is the most widely used chemotherapeutic agent that has multimodal cytotoxicity. The main cytotoxic actions of DOX occur in the nucleus. The emergence of drug-resistant cancer cells that have the ability to actively efflux DOX out of the nucleus, and the cytoplasm has led to the search for a more effective derivative of this drug. Materials and methods: We created a new derivative of DOX that was derived via simple conjugation of the 3' amino group of DOX to the dexamethasone molecule. Results: Despite having a lower cytotoxic activity in MCF-7 cells, the conjugated product, DexDOX, exerted its actions in a manner that was different to that of DOX. DexDOX rapidly induced MCF-7 cell apoptosis without entering the nucleus. Further analysis showed that DexDOX increased cytosolic oxidative stress and did not interfere with the cell cycle. In addition, the conjugated product retained its cytotoxicity in multidrug resistance-1-overexpressing MCF-7 cells that had an approximately 16-fold higher resistance to DOX. Conclusion: We have synthesized a new derivative of DOX, which has the ability to overcome multidrug resistance-1-induced resistance. This molecule may have potential as a future chemotherapeutic agent.