Abstract: Doxorubicin (DOX), an anthracycline antibiotic, is one of the most active anticancer chemotherapeutic agents. The clinical use of DOX, however, is limited by the dose-dependant P-glycoprotein (P-gp)-mediated resistance. Herein, a 3′-azido analogue of DOX (ADOX) was prepared from daunorubicin (DNR). ADOX exhibited potent antitumor activities in drug-sensitive (MCF-7 and K562) and drug-resistant cell lines (MCF-7/DNR, K562/DOX), respectively. The drug resistance index (DRI) values of ADOX were much lower than that of DOX. The cytotoxicity experiments of ADOX or DOX against K562/DOX, with or without P-gp inhibitor, indicated that ADOX circumvents resistance by abolishing the P-gp recognition. This conclusion was further supported by drug influx/efflux flow cytometry experiments, as well as by molecular docking of ADOX to P-gp. In vivo animal tests, ADOX exhibited higher activity and less toxicity than DOX. The current data warranted ADOX for additional pre-clinical evaluations for new drug development.
Keywords: anthracycline; Azido; multidrug resistance; ADOX; P-gp
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Yu, S.; Zhang, G.; Zhang, W.; Luo, H.; Qiu, L.; Liu, Q.; Sun, D.; Wang, P.-G.; Wang, F. Synthesis and Biological Activities of a 3'-Azido Analogue of Doxorubicin Against Drug-Resistant Cancer Cells. Int. J. Mol. Sci. 2012, 13, 3671-3684.
Yu S, Zhang G, Zhang W, Luo H, Qiu L, Liu Q, Sun D, Wang P-G, Wang F. Synthesis and Biological Activities of a 3'-Azido Analogue of Doxorubicin Against Drug-Resistant Cancer Cells. International Journal of Molecular Sciences. 2012; 13(3):3671-3684.
Yu, Shuwen; Zhang, Guisheng; Zhang, Wenpeng; Luo, Huanhua; Qiu, Liyun; Liu, Qingfeng; Sun, Duxin; Wang, Peng-George; Wang, Fengshan. 2012. "Synthesis and Biological Activities of a 3'-Azido Analogue of Doxorubicin Against Drug-Resistant Cancer Cells." Int. J. Mol. Sci. 13, no. 3: 3671-3684.