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

被引：5

作者：

Zhang, Lei ^{[1
]}

Rong, Ying ^{[2
]}

Zheng, Jie ^{[3
]}

Yang, Chengli ^{[1
]}

Chen, Yongzheng ^{[1
]}

Wang, Jing ^{[1
]}

Wei, Gang ^{[4
]}

机构：

[1] Zunyi Med Univ, Green Pharmaceut Engn Res Ctr Guizhou Prov, Gener Drug Res Ctr Guizhou Prov, Sch Pharm, Zunyi 563003, Peoples R China

[2] Zunyi Med Univ, Affiliated Hosp, Dept Pediat 2, Zunyi 563003, Peoples R China

[3] Zunyi Med Univ, Affiliated Hosp, Dept Nephrol & Rheumatol, Zunyi 563003, Peoples R China

[4] CSIRO Mfg, POB 218, Lindfield, NSW 2070, Australia

来源：

RSC ADVANCES | 2018年 / 8卷 / 60期

基金：

中国国家自然科学基金;

关键词：

ANTI-MDR AGENTS; COLON-CANCER CELLS; ANTITUMOR AGENTS; SIGNALING PATHWAYS; IN-VITRO; AUTOPHAGY; CHEMOTHERAPY; DOXORUBICIN; APOPTOSIS; CYTOTOXICITY;

D O I：

10.1039/c8ra06360e

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

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.

引用

页码：34266 / 34274

页数：9

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