期刊
DRUG DESIGN DEVELOPMENT AND THERAPY
卷 12, 期 -, 页码 2361-2369出版社
DOVE MEDICAL PRESS LTD
DOI: 10.2147/DDDT.S168588
关键词
doxorubicin; dexamethasone; drug-resistant tumor; bioconjugation; multidrug resistance; reactive oxygen species
资金
- Lerdsin Foundation
- SS Manufacturing
- 90th and 100th Anniversary of Chulalongkorn University Funds
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 Dex-DOX 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 over-come multidrug resistance-1-induced resistance. This molecule may have potential as a future chemotherapeutic agent.
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