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Potent Inhibition of Nitric Oxide-Releasing Bifendate Derivatives against Drug-Resistant K562/A02 Cells in Vitro and in Vivo

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posted on 09.01.2017, 00:00 by Xiaoke Gu, Zhangjian Huang, Zhiguang Ren, Xiaobo Tang, Rongfang Xue, Xiaojun Luo, Sixun Peng, Hui Peng, Bin Lu, Jide Tian, Yihua Zhang
Multidrug resistance is a major obstacle to successful chemotherapy for leukemia. In this study, a series of nitric oxide (NO)-releasing bifendate derivatives (7an) were synthesized. Biological evaluation indicated that the most active compound (7a) produced relatively high levels of NO and significantly inhibited the proliferation of drug-resistant K562/A02 cells in vitro and in vivo. In addition, 7a induced the mitochondrial tyrosine nitration and the intracellular accumulation of rhodamine 123 by inhibiting P-gp activity in K562/A02 cells. Furthermore, 7a remarkably down-regulated AKT, NF-κB, and ERK activation and HIF-1α expression in K562/A02 cells, which are associated with the tumor cell proliferation and drug resistance. Notably, the antitumor effects were dramatically attenuated by an NO scavenger or elimination of the NO-releasing capability of 7a, indicating that NO produced by 7a contributed to, at least partly, its cytotoxicity against drug-resistant K562/A02 cells. Overall, 7a may be a potential agent against drug-resistant myelogenous leukemia.