YM155 reverses cisplatin resistance in head and neck cancer by decreasing cytoplasmic survivin levels.
YM155 reverses cisplatin resistance in head and neck cancer by decreasing cytoplasmic survivin levels.
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DOI：
10.1158/1535-7163.mct-12-0167
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发表时间：
2012-09
影响因子：
5.7
通讯作者：
Kumar P
中科院分区：
文献类型：
--
作者：
Kumar B;Yadav A;Lang JC;Cipolla MJ;Schmitt AC;Arradaza N;Teknos TN;Kumar P
顺铂是治疗头颈部鳞状细胞癌的常用化疗药物之一。然而，获得顺铂耐药是常见的HNSCC患者，它往往导致局部和远端失败。在这项研究中，我们证明，生存素的表达显着上调HNSCC原发性肿瘤和细胞系。此外，在通常对顺铂治疗反应较差的HPV阴性患者中，生存素水平显著较高。与其亲本细胞（CAL 27）相比，Survivin表达在顺铂抗性细胞（CAL 27-CisR）中进一步增加。因此，我们假设靶向HNSCC中的存活素可以逆转肿瘤细胞中的耐药表型，从而增强顺铂的治疗功效。我们使用体外和体内模型来测试YM 155（一种小分子存活素抑制剂）作为单一药剂或与顺铂组合的功效。YM 155以剂量依赖性方式显著降低存活素水平和细胞增殖。此外，YM 155预处理显著逆转了癌细胞中的顺铂耐药性。有趣的是，YM 155处理通过诱导细胞质生存素的快速减少来改变生存素在细胞中的动态定位，而生存素在其抗凋亡功能中发挥着关键作用。在SCID小鼠异种移植模型中，YM 155显著增强顺铂的抗肿瘤和抗血管生成作用，而没有增加全身毒性。综上所述，我们的研究结果提示了一种潜在的新策略，即使用YM 155克服肿瘤细胞的耐药性，从而增强HNSCC中化疗的有效性。
Cisplatin is one of the commonly used chemotherapeutic drugs for the treatment of head and neck squamous cell carcinoma (HNSCC). However, acquisition of cisplatin resistance is common in patients with HNSCC and it often leads to local and distant failure. In this study, we demonstrate that survivin expression is significantly upregulated in HNSCC primary tumors and cell lines. In addition, survivin levels were significantly higher in HPV negative patients that normally respond poorly to cisplatin treatment. Survivin expression was further increased in cisplatin resistant cells (CAL27-CisR) as compared to its parent cells (CAL27). Therefore, we hypothesize that targeting of survivin in HNSCC could reverse the resistant phenotype in tumor cells thereby enhancing the therapeutic efficacy of cisplatin. We used both in vitro and in vivo models to test the efficacy of YM155, a small molecule survivin inhibitor, either as a single agent or in combination with cisplatin. YM155 significantly decreased survivin levels and cell proliferation in a dose-dependent manner. In addition, YM155 pretreatment significantly reversed cisplatin resistance in cancer cells. Interestingly, YM155 treatment altered the dynamic localization of survivin in cells by inducing a rapid reduction in cytoplasmic survivin, which plays a critical role in its anti-apoptotic function. In a SCID mouse xenograft model, YM155 significantly enhanced the anti-tumor and anti-angiogenic effects of cisplatin with no added systemic toxicity. Taken together, our results suggest a potentially novel strategy to use YM155 to overcome the resistance in tumor cells thereby enhancing the effectiveness of the chemotherapy in HNSCC.