Targeting superoxide dismutase 1 to overcome cisplatin resistance in human ovarian cancer
Targeting superoxide dismutase 1 to overcome cisplatin resistance in human ovarian cancer
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DOI：
10.1007/s00280-008-0791-x
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发表时间：
2009-03-01
影响因子：
3
通讯作者：
Wang, Mu
中科院分区：
文献类型：
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作者：
Brown, Dawn P. G.;Chin-Sinex, Helen;Wang, Mu
目的卵巢癌对铂类化疗药物的耐药性是卵巢癌治疗的主要障碍。许多先前的研究已经提出了与耐药性相关的多个途径。我们的研究小组最近使用全球定量蛋白质组学分析方法报道了参与DNA修复、药物转运、氧化还原调节和凋亡的几种关键蛋白的过表达。超氧化物歧化酶1（SOD 1）是这些蛋白质中的一种，在顺铂耐药的卵巢癌细胞中相对于其敏感的对应物持续过表达，但其在药物抗性中的确切作用尚未被defined.Method在当前的研究中，我们通过使用小分子抑制剂抑制SOD 1在顺铂耐药的卵巢癌细胞中的氧化还原活性来检查SOD 1在药物抗性中的作用，三亚乙基四胺（TETA）。TETA的作用通过细胞增殖测定、克隆形成细胞存活测定、结果SOD1活性的抑制可提高顺铂耐药细胞对顺铂的敏感性，支持SOD1是顺铂耐药的关键决定因素，是克服顺铂耐药的一个可利用的靶点。结论SOD1在顺铂耐药和调节顺铂耐药中起重要作用。其活性可以克服这种抗性并最终导致改善的临床结果。
Purpose Clinical drug resistance to platinum-based chemotherapy is considered a major impediment in the treatment of human ovarian cancer. Multiple pathways associated with drug resistance have been suggested by many previous studies. Over expression of several key proteins involved in DNA repair, drug transport, redox regulation, and apoptosis has been recently reported by our group using a global quantitative proteomic profiling approach. Superoxide dismutase 1 (SOD1) is one of these proteins consistently over-expressed in cisplatin-resistant ovarian cancer cells as compared to their sensitive counterparts, but its precise role in drug resistance is yet to be defined.Method In the current study, we examined the role of SOD1 in drug resistance by inhibiting its redox activity in cisplatin-resistant ovarian cancer cells using a small-molecule inhibitor, triethylenetetramine (TETA). The effect of TETA was determined by the cell proliferation assay, clonogenic cell survival assay, and SOD1 activity assay.Results The inhibition of the SOD1 activity enhanced the cisplatin sensitivity in the resistant cells supporting the hypothesis that SOD1 is a key determinant of cisplatin resistance and is an exploitable target to overcome cisplatin drug resistance.Conclusion SOD1 plays an important role in cisplatin resistance and modulation of its activity may overcome this resistance and ultimately lead to improved clinical outcomes.