Reversal to cisplatin sensitivity in recurrent human ovarian cancer cells by NCX-4016, a nitro derivative of aspirin
Reversal to cisplatin sensitivity in recurrent human ovarian cancer cells by NCX-4016, a nitro derivative of aspirin
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DOI：
10.1073/pnas.0511250103
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发表时间：
2006-03-07
影响因子：
11.1
通讯作者：
Kuppusamy, P
中科院分区：
文献类型：
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作者：
Bratasz, A;Weir, NM;Kuppusamy, P
卵巢癌是一种妇科恶性肿瘤，通常通过细胞减灭术和顺铂治疗来治疗。然而，顺铂治疗虽然最初是成功的，但在治疗在初始治疗的几个月内总是出现的复发性疾病方面无效。难治性行为归因于顺铂治疗明显引起的细胞硫醇水平增加。这一观察结果促使我们选择一种细胞毒性药物，其活性通过细胞硫醇增强，对富含硫醇的顺铂耐药细胞具有增强的特异性。我们使用NCX-4016 [2-（乙酰氧基）苯甲酸3-（硝基氧基甲基）苯基酯]，一种含有硝基的阿司匹林衍生物，其在细胞和体内以持续数小时的方式释放一氧化氮，我们研究了其对人卵巢癌细胞（HOCC）的细胞毒性功效。用100 μ M NCX-4016处理顺铂敏感性和顺铂抗性（CR）HOCC 6小时，和/或用0.5 μ g/ml顺铂处理1小时，并测定克隆形成性。NCX-4016显著降低顺铂敏感（63 +/- 6%）和CR（70 - 10%）IHOCC的存活分数。NCX-4016还导致CR HOCC中细胞谷胱甘肽水平降低50%。与单独用NCX-4016或顺铂处理细胞相比，用NCX-4016随后用顺铂处理细胞显示出显著更大程度的毒性。总之，这项研究表明，NCX-4016是CR HOCC增殖的潜在抑制剂，因此可能特异性杀死复发性卵巢癌患者中的顺铂难治性癌细胞。
Ovarian cancer is a gynecological malignancy that is commonly treated by cytoreductive surgery followed by cisplatin treatment. However, the cisplatin treatment, although successful initially, is not effective in the treatment of the recurrent disease that invariably surfaces within a few months of the initial treatment. The refractory behavior is attributed to the increased levels of cellular thiols apparently caused by the cisplatin treatment. This observation prompted us to choose a cytotoxic drug whose activity is potentiated by cellular thiols with enhanced specificity toward the thiol-rich cisplatin-resistant cells. We used NCX-4016 [2-(acetyloxy) benzoic acid 3-(nitrooxymethyl) phenyl ester], a derivative of aspirin containing a nitro group that releases nitric oxide in a sustained fashion for several hours in cells and in vivo, and we studied its cytotoxic efficacy against human ovarian cancer cells (HOCCs). Cisplatin-sensitive and cisplatin-resistant (CR) HOCCs were treated with 100 mu M NCX-4016 for 6 h, and/or 0.5 mu g/ml cisplatin for 1 h and assayed for clonogenecity. NCX-4016 significantly reduced the surviving fractions of cisplatin-sensitive (63 +/- 6%) and CR (70 10%) IHOCCs. NCX-4016 also caused a 50% reduction in the levels of cellular glutathione in CR HOCCs. Treatment of cells with NCX-4016 followed by cisplatin showed a significantly greater extent of toxicity when compared with treatment of cells with NCX-4016 or cisplatin alone. In conclusion, this study showed that NCX-4016 is a potential inhibitor of the proliferation of CR HOCCs and thus might specifically kill cisplatin-refractory cancer cells in patients with recurrent ovarian cancer.