Abstract
Because multidrug resistance (MDR) is a serious impediment to the use of chemotherapy in treating cancer patients, great efforts have been made to search for effective MDR-reversing agents. We have developed a brand new synthetic ardeemin derivative, 5-N-formylardeemin, and investigated the activity of which in reversing MDR in MDR cancer cell lines derived from human breast cancer (MCF-7-R) or lung cancer (A549-R). 5-N-formylardeemin strongly enhanced the anti-cancer efficacy of doxorubicin, vincristine through potentiation of apoptosis in both MCF-7-R and A549-R at relatively noncytotoxic concentrations in vitro. Mechanistic studies showed that 5-N-formylardeemin inhibited the expression of MDR-1 (P-gp) and increased the intracellular accumulation of cytotoxic drugs in the MDR cells, suggesting that 5-N-formylardeemin reverses MDR activities through inhibiting MDR-1 expression. Interestingly, 5-N-formylardeemin also sensitized the parent wild-type cancer cells toward these chemotherapeutic agents to various extents. Importantly, in vivo studies demonstrated that 5-N-formylardeemin significantly improved the therapeutic effects of doxorubicin in nude mice bearing A549-R xenografts, which was associated with reduced expression of MDR-1 protein level and increased apoptosis in tumor tissues. These results underscore 5-N-formylardeemin as a potential sensitizer for chemotherapy against multidrug resistant cancers.
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Acknowledgments
This study was supported by grants from National Natural Science Foundation of China (81172111 and 81372377) and by Program for New Century Excellent Talents in University (NCET-11-0349) from Chinese Ministry of Education and also partly supported by Program for Changjiang Scholars and Innovative Research Team in University from Chinese Ministry of Education (IRT0935).
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Zheng, X., Li, D., Zhao, C. et al. Reversal of multidrug resistance in vitro and in vivo by 5-N-formylardeemin, a new ardeemin derivative. Apoptosis 19, 1293–1300 (2014). https://doi.org/10.1007/s10495-014-0998-8
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DOI: https://doi.org/10.1007/s10495-014-0998-8