Multi-drug resistance (MDR) to anticancer drugs is the primary impediment to successful treatment of cancer. Hunting for new compounds with potent anti-MDR activity is an effectual approach to conquer cancer drug resistance. In this work, 33 new sulfur-containing 1,4-naphthoquinone oxime derivatives were prepared and investigated for their cytotoxicity against a panel of tumor cell lines and fibroblast normal cell line. Cell-based assay showed that most of target compounds displayed more potent cytotoxic potency than positive controls. Meanwhile, all of compounds were non-toxic to normal cells. More importantly, the cytotoxic activity of these oxime derivatives toward drug-resistant cancer cell lines was found to be much stronger than that toward drug-susceptible cell lines (anti-drug resistance coefficient (ADRC) > 1). Of these, compound 12 m was identified as the most effective molecule with IC50 values in the range of 0.29 ± 0.01 to 1.33 ± 0.05 μM toward MDR sublines. Further mechanism studies demonstrated that 12 m could inhibit colony formation, cause G1 phase arrest and promote cell apoptosis mediated by augmenting Bax/Bcl-2 ratio of Bel7402/5-FU cells. Our findings provide promising start points for development of sulfur-containing 1,4-naphthoquinone oxime derivatives as potential anti-MDR agents.

译文

对抗癌药物的多药耐药性 (MDR) 是成功治疗癌症的主要障碍。寻找具有有效抗MDR活性的新化合物是克服癌症耐药性的有效方法。在这项工作中,制备了33种新的含硫1,4-萘醌肟衍生物,并研究了它们对一组肿瘤细胞系和成纤维细胞正常细胞系的细胞毒性。基于细胞的分析表明,大多数目标化合物显示出比阳性对照更有效的细胞毒性。同时,所有化合物均对正常细胞无毒。更重要的是,发现这些肟衍生物对耐药癌细胞系的细胞毒性比对药物敏感细胞系的细胞毒性强得多 (抗耐药系数 (ADRC) >  1)。其中,化合物12 m被鉴定为最有效的分子,其IC50值在0.29   ±   0.01至1.33   ±   0.05  μ m的范围内。进一步的机制研究表明,12 m可以通过增加Bel7402/5-FU细胞的Bax/Bcl-2比值来抑制集落形成,引起G1期阻滞,促进细胞凋亡。我们的发现为开发含硫的1,4-萘醌肟衍生物作为潜在的抗MDR剂提供了有希望的起点。

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