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新型一氧化氮供体型鬼臼毒素衍生物作为潜在抗多药耐药白血病细胞增殖剂的设计、合成及生物学评价

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

作者信息

Zhang Lei, Rong Ying, Zheng Jie, Yang Chengli, Chen Yongzheng, Wang Jing, Wei Gang

机构信息

Generic Drug Research Center of Guizhou Province, Green Pharmaceuticals Engineering Research Center of Guizhou Province, School of Pharmacy, Zunyi Medical University Zunyi 563003 PR China

Second Department of Pediatrics, Affiliated Hospital of Zunyi Medical University Zunyi 563003 PR China.

出版信息

RSC Adv. 2018 Oct 5;8(60):34266-34274. doi: 10.1039/c8ra06360e. eCollection 2018 Oct 4.

DOI:10.1039/c8ra06360e
PMID:35548612
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9087117/
Abstract

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 . 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 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 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.

摘要

多药耐药性仍然是有效治疗癌症的主要障碍。为了寻找用于耐药白血病化疗的新药，在本研究中，合成了两种新型的一氧化氮供体型鬼臼毒素衍生物并进行了初步评估。生物学评估表明，活性更强的分子S1提高了细胞内一氧化氮水平，并显著抑制了耐药K562/VCR和K562/ADR细胞的增殖，其IC值分别为0.008±0.001和0.007±0.001μM，与敏感K562细胞相似。此外，观察到S1通过破坏微管组织以及抑制CDK1和CDK2表达来阻断K562/ADR细胞周期的G2期。同时，S1诱导K562/ADR细胞凋亡、线粒体去极化并激活caspase-3。此外，S1抑制P-糖蛋白表达，通过调节Beclin1和LC3-II诱导自噬，并抑制K562/ADR细胞中的mTOR和STAT3信号传导。总体而言，S1可能是一种有前景的抗耐药白血病候选药物。

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