N',N'-Dimethyl-N',N'-bis(phenylcarbonothioyl) Propanedihydrazide (Elesclomol) Selectively Kills Cisplatin Resistant Lung Cancer Cells through Reactive Oxygen Species (ROS).
N',N'-Dimethyl-N',N'-bis(phenylcarbonothioyl) Propanedihydrazide (Elesclomol) Selectively Kills Cisplatin Resistant Lung Cancer Cells through Reactive Oxygen Species (ROS).
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DOI：
10.3390/cancers1010023
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发表时间：
2009
期刊：
影响因子：
5.2
通讯作者：
Savaraj N
中科院分区：
文献类型：
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作者：
Wangpaichitr M;Wu C;You M;Maher JC;Dinh V;Feun LG;Savaraj N
顺铂是肺癌治疗中重要的化疗药物。顺铂的耐药机制很复杂，历史上一直难以克服。我们在此报告，与正常细胞及其亲本细胞对应物相比，顺铂耐药肺癌细胞系具有高基础水平的活性氧（ROS）。这些耐药细胞的硫氧还蛋白 (TRX) 水平也较低，这可能是导致高 ROS 的因素之一。 N'1,N'3-二甲基-N'1,N'3-双(苯基碳硫酰基)丙二酰肼 (elesclomol) 是一种已知会增加 ROS 的药物，对顺铂耐药细胞具有选择性毒性，但不会影响正常细胞和亲代细胞。艾司洛莫在耐药细胞中的细胞毒性作用伴随着 TRX 和谷胱甘肽 (GSH) 抗氧化系统的进一步降低，而在亲代细胞中发现了相反的结果。艾司氯醇在顺铂耐药细胞中的 ID50 范围为 5-10 nM，完全在临床可实现的范围内。 N-乙酰半胱氨酸 (NAC) 已知可以中和 ROS，可以消除艾司洛莫的细胞毒性作用，表明细胞毒性作用是由 ROS 增加引起的。总体而言，我们的数据表明艾司氯醇通过增加 ROS 选择性杀死顺铂耐药肿瘤细胞。该药物可能具有克服顺铂耐药性的潜力，应进一步探索以治疗顺铂治疗失败的患者。
Cisplatin is an important chemotherapeutic agent in lung cancer treatment. The mechanism of drug resistance to cisplatin is complex and historically has been difficult to overcome. We report here that cisplatin resistant lung cancer cell lines possess high basal levels of reactive oxygen species (ROS) when compared to normal cells and their parental cell counterparts. These resistant cells also have low thioredoxin (TRX) levels which may be one of the contributory factors to high ROS. N′1,N′3-dimethyl-N′1,N′3-bis(phenylcarbonothioyl) propanedihydrazide (elesclomol), an agent known to increase ROS is selectively toxic to cisplatin-resistant cells, while sparing normal cells and the parental counterpart. The cytotoxic effect of elesclomol in resistant cells is accompanied by further decreases in TRX and glutathione (GSH) antioxidant systems, while opposite results were found in parental cells. The ID50 of elesclomol in cisplatin-resistant cells ranged from 5–10 nM, which is well within clinically achievable ranges. N-Acetylcysteine (NAC), which is known to neutralize ROS, can abolish the cytotoxic effect of elesclomol, suggesting that the cytotoxic effect results from increased ROS. Overall, our data suggest that elesclomol selectively kills cisplatin-resistant tumor cells through increased ROS. This agent may hold potential to overcome cisplatin resistance and should be further explored to treat patients who have failed cisplatin therapy.