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

Authors Chaikomon K, Chattong S, Chaiya T, Tiwawech D, Sritana-Anant Y, Sereemaspun A, Manotham K

Received 19 March 2018

Accepted for publication 3 May 2018

Published 1 August 2018 Volume 2018:12 Pages 2361—2369

DOI https://doi.org/10.2147/DDDT.S168588

Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 2

Editor who approved publication: Dr Tuo Deng


Kamontip Chaikomon,1,2 Supreecha Chattong,1,3 Theerasak Chaiya,1 Danai Tiwawech,4 Yongsak Sritana-Anant,5 Amornpun Sereemaspun,6 Krissanapong Manotham1

1Molecular and Cellular Biology Unit, Department of Medicine, Lerdsin General Hospital, Bangkok, Thailand; 2Medical Sciences Program, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; 3EST Laboratory, SS Manufacturing, Nonthaburi, Thailand; 4Research Division, National Cancer Institute, Bangkok, Thailand; 5Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok, Thailand; 6Department of Anatomy, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand

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.

Keywords:
doxorubicin, dexamethasone, drug-resistant tumor, bioconjugation, multidrug resistance, reactive oxygen species

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