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 IC 50 values of 0.008 ± 0.001 and 0.007 ± 0.001 μM, 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.
Keyphrases
- drug resistant
- induced apoptosis
- endoplasmic reticulum stress
- multidrug resistant
- signaling pathway
- acinetobacter baumannii
- oxidative stress
- cell cycle
- nitric oxide
- cell cycle arrest
- cell death
- poor prognosis
- cell proliferation
- bone marrow
- emergency department
- pseudomonas aeruginosa
- radiation therapy
- high resolution
- mass spectrometry
- rectal cancer
- diabetic rats
- stress induced
- chemotherapy induced
- tandem mass spectrometry
- solid phase extraction