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

Multidrug resistance is a major obstacle
to successful chemotherapy for leukemia. In this study, a series of
nitric oxide (NO)-releasing bifendate derivatives (7a–n) 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.