YM155, a novel small-molecule survivin suppressant, induces regression of established human hormone-refractory prostate tumor xenografts
YM155, a novel small-molecule survivin suppressant, induces regression of established human hormone-refractory prostate tumor xenografts
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DOI：
10.1158/0008-5472.can-07-1343
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发表时间：
2007-09-01
期刊：
影响因子：
11.2
通讯作者：
Sasamata, Masao
中科院分区：
文献类型：
--
作者：
Nakahara, Takahito;Takeuchi, Masahiro;Sasamata, Masao
越来越多的证据表明，凋亡抑制因子（inhibitor of apoptosis，Survivin）家族成员Survivin在包括难治性前列腺癌（hyper-refractory prostate cancer，HRPC）在内的多种癌症的耐药性和癌细胞存活中发挥重要作用。在这里，我们的特点YM 155，一种新的小分子生存素抑制剂，使用生存素基因启动子活性测定。10 nmol/L YM 155可抑制PC-3和PPC-1人HRPC细胞株survivin的表达并诱导其凋亡。与此相反，YM 155高达100 nmol/L的其他IAP或Bcl-2相关蛋白的表达水平几乎没有影响。在一个s.c.在小鼠异种移植PC-3肿瘤模型中，以3至10 mg/kg连续输注3天的YM 155诱导了大量肿瘤消退，伴随着肿瘤内存活素的抑制。YM 155还完全抑制原位异种移植的PC-3肿瘤的生长。在实验期间，在用YM 155处理的小鼠中没有观察到体重的显著降低。药代动力学分析表明，YM 155高度分布于肿瘤中，并且浓度比血浆中的浓度高20倍。我们的研究结果代表了第一次尝试显示肿瘤消退和抑制p53缺陷的人HRPC细胞的生存素的一个单一的小分子化合物治疗。YM 155在包括HRPC在内的多种癌症中的进一步广泛研究似乎值得开发这种新的治疗方法。
Various accumulating evidence suggests that survivin, a member of the inhibitor of apoptosis (LAP) family, plays an important role in drug resistance and cancer cell survival in many types of cancer, including hormone-refractory prostate cancer (HRPC). Here, we characterized YM155, a novel small-molecule survivin suppressant, using a survivin gene promoter activity assay. YM155 suppressed expression of survivin and induced apoptosis in PC-3 and PPC-1 human HRPC cell lines at 10 nmol/L. In contrast, YM155 up to 100 nmol/L showed little effect on expression levels of other IAP- or Bcl-2-related proteins. In a s.c. xenografted PC-3 tumor model in mice, 3-day continuous infusions of YM155 at 3 to 10 mg/kg induced massive tumor regression accompanied by suppression of intratumoral survivin. YM155 also completely inhibited the growth of orthotopically xenografted PC-3 tumors. No significant decreases in body weight were observed in mice treated with YM155 during the experimental period. Pharmacokinetic analyses indicated that YM155 is highly distributed to tumors and at concentrations similar to 20-fold higher than those in plasma. Our findings represent the first attempt to show tumor regression and suppression of survivin in p53-deficient human HRPC cells by a single small molecular compound treatment. Further extensive investigation of YM155 in many types of cancer, including HRPC, seems to be worthwhile to develop this novel therapeutic approach.