Design, synthesis and biological evaluation of novel nitric oxide-donating podophyllotoxin derivatives as potential antiproliferative agents against multi-drug resistant leukemia cells

Multidrug resistance remains a major obstacle for the effective treatment of carcinoma. To find new drugs for the chemotherapy of drug-resistant leukemia, in this study, two novel nitric oxide-donating podophyllotoxin derivatives were synthesized and preliminarily evaluated in vitro. Biological evaluation indicated that the more active molecule, S1, enhanced the intracellular NO level and significantly inhibited the proliferation of drug-resistant K562/VCR and K562/ADR cells with IC50 values of 0.008 +/- 0.001 and 0.007 +/- 0.001 mu M, respectively, which were similar to that of sensitive K562 cells. Furthermore, it was observed that S1 blocked the G2 phase of the K562/ADR cell cycle by disruption of the microtubule organization and inhibition of CDK1 and CDK2 expression. Meanwhile, S1 induced apoptosis of K562/ADR cells via mitochondrial depolarization and activation of caspase-3. In addition, S1 suppressed the P-gp expression, induced autophagy by regulation of Beclin1 and LC3-II, and inhibited the mTOR and STAT3 signaling in K562/ADR cells. Overall, S1 may be a promising candidate against drug-resistant leukemia.