NCX-4040, a nitric oxide-releasing aspirin, sensitizes drug-resistant human ovarian xenograft tumors to cisplatin by depletion of cellular thiols.
NCX-4040, a nitric oxide-releasing aspirin, sensitizes drug-resistant human ovarian xenograft tumors to cisplatin by depletion of cellular thiols.
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DOI：
10.1186/1479-5876-6-9
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发表时间：
2008-02-26
影响因子：
7.4
通讯作者：
Kuppusamy P
中科院分区：
文献类型：
--
作者：
Bratasz A;Selvendiran K;Wasowicz T;Bobko A;Khramtsov VV;Ignarro LJ;Kuppusamy P
卵巢癌是妇科恶性肿瘤中死亡率最高的一种。高死亡率与缺乏早期诊断和耐药性的发展有关。研究了一氧化氮释放型阿司匹林衍生物NCX-4040对卵巢癌的抗肿瘤作用及其机制。在顺铂敏感（A2780 WT）和顺铂耐药（A2780 cDDP）细胞系以及裸鼠中生长的异种移植瘤中研究了NCX-4040单独或与顺铂（顺式二氨二氯铂，cDDP）联合使用。电子顺磁共振（EPR）用于测量一氧化氮和氧化还原状态。来自小鼠的A2780 cDDP肿瘤异种移植物的免疫印迹分析用于机制研究。用NCX-4040（25 μM）处理的细胞显示出细胞活力的显著降低（A2780 WT，34.9 ± 8.7%; A2780 cDDP，41.7 ± 7.6%; p < 0.05）。此外，NCX-4040显著增强了A2780 cDDP细胞（单独顺铂，80.6 ± 11.8%相对于NCX-4040+顺铂，26.4 ± 7.6%; p < 0.01）和异种移植肿瘤（单独顺铂，74.0 ± 4.4%相对于NCX-4040+顺铂，56.4 ± 7.8%; p < 0.05）对顺铂治疗的敏感性。组织氧化还原和巯基测量的EPR成像显示，与未处理的对照相比，NCX-4040处理的A2780 cDDP肿瘤中谷胱甘肽减少5.5倍（p < 0.01）。用NCX-4040和顺铂处理的小鼠的A2780 cDDP肿瘤异种移植物的免疫印迹分析显示pEGFR（Tyr 845和Tyr 992）和pSTAT 3（Tyr 705和Ser 727）表达显著下调。结果表明，NCX-4040可能通过耗尽细胞巯基而使卵巢癌耐药细胞对顺铂重新敏感。因此，NCX-4040似乎是一个潜在的治疗剂，用于治疗人卵巢癌和顺铂耐药的恶性肿瘤。
Ovarian carcinoma is the leading cause of mortality among gynecological cancers in the world. The high mortality rate is associated with lack of early diagnosis and development of drug resistance. The antitumor efficacy and mechanism of NCX-4040, a nitric oxide-releasing aspirin derivative, against ovarian cancer is studied. NCX-4040, alone or in combination with cisplatin (cis-diamminedichloroplatinum, cDDP), was studied in cisplatin-sensitive (A2780 WT) and cisplatin-resistant (A2780 cDDP) cell lines as well as xenograft tumors grown in nude mice. Electron paramagnetic resonance (EPR) was used for measurements of nitric oxide and redox state. Immunoblotting analysis of A2780 cDDP tumor xenografts from mice was used for mechanistic studies. Cells treated with NCX-4040 (25 μM) showed a significant reduction of cell viability (A2780 WT, 34.9 ± 8.7%; A2780 cDDP, 41.7 ± 7.6%; p < 0.05). Further, NCX-4040 significantly enhanced the sensitivity of A2780 cDDP cells (cisplatin alone, 80.6 ± 11.8% versus NCX-4040+cisplatin, 26.4 ± 7.6%; p < 0.01) and xenograft tumors (cisplatin alone, 74.0 ± 4.4% versus NCX-4040+cisplatin, 56.4 ± 7.8%; p < 0.05), to cisplatin treatment. EPR imaging of tissue redox and thiol measurements showed a 5.5-fold reduction (p < 0.01) of glutathione in NCX-4040-treated A2780 cDDP tumors when compared to untreated controls. Immunoblotting analysis of A2780 cDDP tumor xenografts from mice treated with NCX-4040 and cisplatin revealed significant downregulation of pEGFR (Tyr845 and Tyr992) and pSTAT3 (Tyr705 and Ser727) expression. The results suggested that NCX-4040 could resensitize drug-resistant ovarian cancer cells to cisplatin possibly by depletion of cellular thiols. Thus NCX-4040 appears to be a potential therapeutic agent for the treatment of human ovarian carcinoma and cisplatin-resistant malignancies.
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DOI：
10.1073/pnas.0511250103
发表时间：
2006-03-07
影响因子：
11.1
作者：
Bratasz, A;Weir, NM;Kuppusamy, P
通讯作者：
Kuppusamy, P
DOI：
10.1016/j.bbrc.2007.05.038
发表时间：
2007-07-13
影响因子：
3.1
作者：
Kashfi, Khosrow;Rigas, Basil
通讯作者：
Rigas, Basil
影响因子：
4.1
作者：
Dunlap, Tareisha;Chandrasena, R. Esala P.;Thatcher, Gregory R. J.
通讯作者：
Thatcher, Gregory R. J.
影响因子：
7.2
作者：
Fabbri, F;Brigliadori, G;Zoli, W
通讯作者：
Zoli, W
影响因子：
3.3
作者：
Ilangovan, G;Bratasz, A;Kuppusamy, P
通讯作者：
Kuppusamy, P