Antitumor Activity of YM155, a Selective Small-Molecule Survivin Suppressant, Alone and in Combination with Docetaxel in Human Malignant Melanoma Models
Antitumor Activity of YM155, a Selective Small-Molecule Survivin Suppressant, Alone and in Combination with Docetaxel in Human Malignant Melanoma Models
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DOI：
10.1158/1078-0432.ccr-10-3410
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发表时间：
2011-08-15
影响因子：
11.5
通讯作者：
Sasamata, Masao
中科院分区：
文献类型：
--
作者：
Yamanaka, Kentaro;Nakahara, Takahito;Sasamata, Masao
目的：侵袭性细胞生长和化疗耐药性是黑色素瘤治疗中众所周知的障碍。越来越多的证据表明，生存素在癌细胞中优先表达，并在细胞分裂和凋亡功能障碍中起关键作用。在这里，我们评估的治疗潜力YM 155，选择性生存素抑制剂，单独和多西他赛联合使用人类melanoma models.Experimental Design：A375和SK-MEL-5人类恶性黑色素瘤细胞与siRNA，YM 155，和/或多西他赛，细胞活力，mRNA和蛋白质表达水平，细胞周期分布，免疫组化染色，然后进行了评价。结果：抑制Survivin表达可诱导黑色素瘤细胞自发凋亡，抑制Survivin表达可诱导黑色素瘤细胞自发凋亡。YM 155在建立的黑素瘤异种移植模型中显示出纳摩尔级的抗增殖作用并诱导肿瘤消退。多西他赛对黑色素瘤细胞显示出抗肿瘤活性，尽管它也诱导生存素上调和G（2）/M有丝分裂阻滞;然而，与YM 155共同处理使生存素表达低于基础水平。YM 155和多西他赛的联合治疗诱导了更大的细胞凋亡率比单一治疗率的总和，并促进肿瘤消退，而没有增强体重减轻的黑色素瘤异种移植models.Conclusions：生存素是负责黑色素瘤细胞自发凋亡的固有低水平。YM 155与多西他赛联合用药减少了G（2）/M期有丝分裂阻滞中生存素的积累，并诱导了更强烈的细胞凋亡。YM 155与多西他赛的组合耐受性良好，并且在小鼠异种移植模型中显示出比单独的任一药剂更大的功效。临床癌症研究; 17（16）; 5423-31。（C）2011年《非洲标准化评论》。
Purpose: Aggressive cell growth and chemoresistance are notorious obstacles in melanoma therapy. Accumulating evidence suggests that survivin is preferentially expressed in cancer cells and plays a crucial role in cell division and apoptosis dysfunction. Here, we evaluated the therapeutic potential of YM155, a selective survivin suppressant, alone and in combination with docetaxel using human melanoma models.Experimental Design: A375 and SK-MEL-5 human malignant melanoma cells were treated with siRNA, YM155, and/or docetaxel, and cell viability, mRNA and protein expression levels, cell-cycle distribution, and immunohistochemical staining were then evaluated. Furthermore, the efficacy of YM155 combined with docetaxel was further examined in established xenograft models.Results: Survivin suppression was sufficient to induce spontaneous apoptosis of melanoma cells. YM155 showed nanomolar antiproliferative effects and induced tumor regression in established melanoma xenograft models. Docetaxel showed antitumor activity against melanoma cells, although it also induced survivin upregulation and G(2)/M mitotic arrest; however, cotreatment with YM155 decreased survivin expression below basal levels. Combination treatment of YM155 and docetaxel induced a greater rate of apoptosis than the sum of the single-treatment rates and promoted tumor regression without enhanced body weight loss in the melanoma xenograft models.Conclusions: Survivin is responsible for the inherent low levels of spontaneous apoptosis in melanoma cells. The concomitant combination of YM155 with docetaxel diminished the accumulation of survivin in G(2)/M mitotic arrest, and induced more intense apoptosis compared with each single treatment. YM155 in combination with docetaxel is well tolerated and shows greater efficacy than either agent alone in mouse xenograft models. Clin Cancer Res; 17(16); 5423-31. (C)2011 AACR.