KPT-330, a potent and selective exportin-1 (XPO-1) inhibitor, shows antitumor effects modulating the expression of cyclin D1 and survivin [corrected] in prostate cancer models.
KPT-330, a potent and selective exportin-1 (XPO-1) inhibitor, shows antitumor effects modulating the expression of cyclin D1 and survivin [corrected] in prostate cancer models.
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DOI：
10.1186/s12885-015-1936-z
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发表时间：
2015-12-01
期刊：
影响因子：
3.8
通讯作者：
Festuccia C
中科院分区：
文献类型：
--
作者：
Gravina GL;Mancini A;Sanita P;Vitale F;Marampon F;Ventura L;Landesman Y;McCauley D;Kauffman M;Shacham S;Festuccia C
在一些侵袭性肿瘤中，染色体区域维持(CRM-1)/出口蛋白-1(XPO-1)的高表达与预后不良相关，使其成为一个有趣的治疗靶点。选择性核出口抑制剂(SINE)化合物与XPO-1结合并阻断其出口货物蛋白的能力。在这里，我们研究了一类新的正弦化合物在前列腺癌模型中的作用。我们检测了XPO-1在人前列腺癌组织和细胞系中的表达。接下来，6个具有广谱、肿瘤选择性细胞毒性、耐受性和药代动力学特征的具有不同效力的化合物(KPT-127、KPT-185、KPT-205、KPT-225、KPT-251和KPT-330)在一组代表疾病和基因的不同分化/进展状态的前列腺癌细胞中进行测试。两个用于临床试验的Sine候选药物(KPT-251和KPT-330)也在三个移植到雄性裸鼠体内的侵袭性前列腺癌细胞模型中进行了体内测试。与正常或增生性组织相比，XPO-1在前列腺癌中高表达。XPO-1的表达增加，主要是在核间室，与Gleason评分和骨转移潜能的增加有关，支持Sine用于晚期前列腺癌。氨基类化合物抑制肿瘤细胞的增殖和促进细胞的凋亡，但不影响永生化的未转化的前列腺上皮细胞。Sine处理的细胞核显示XPO-1、Survivin和Cyclin D1的蛋白定位增加，随后这些蛋白的降解导致细胞周期停滞和细胞凋亡。KPT-251和KPT-330在PC3、DU145和22Rv1荷瘤裸鼠体内灌胃给药可抑制肿瘤细胞增殖、血管生成和诱导细胞凋亡。我们的结果为在晚期前列腺癌/去势耐药前列腺癌的治疗中使用Sine化合物提供了支持性证据，并值得进一步的临床研究。
Increased expression of Chromosome Region Maintenance (CRM-1)/exportin-1 (XPO-1) has been correlated with poor prognosis in several aggressive tumors, making it an interesting therapeutic target. Selective Inhibitor of Nuclear Export (SINE) compounds bind to XPO-1 and block its ability to export cargo proteins. Here, we investigated the effects of a new class of SINE compounds in models of prostate cancer. We evaluated the expression of XPO-1 in human prostate cancer tissues and cell lines. Next, six SINE (KPT-127, KPT-185, KPT-205, KPT-225, KPT-251 and KPT-330) compounds having different potency with broad-spectrum, tumor-selective cytotoxicity, tolerability and pharmacokinetic profiles were tested in a panel of prostate cancer cells representing distinct differentiation/progression states of disease and genotypes. Two SINE candidates for clinical trials (KPT-251 and KPT-330) were also tested in vivo in three cell models of aggressive prostate cancer engrafted in male nude mice. XPO-1 is overexpressed in prostate cancer compared to normal or hyperplastic tissues. Increased XPO-1 expression, mainly in the nuclear compartment, was associated with increased Gleason score and bone metastatic potential supporting the use of SINEs in advanced prostate cancer. SINE compounds inhibited proliferation and promoted apoptosis of tumor cells, but did not affect immortalized non-transformed prostate epithelial cells. Nuclei from SINE treated cells showed increased protein localization of XPO-1, survivin and cyclin D1 followed by degradation of these proteins leading to cell cycle arrest and apoptosis. Oral administration of KPT-251 and KPT-330 in PC3, DU145 and 22rv1 tumor-bearing nude mice reduced tumor cell proliferation, angiogenesis and induced apoptosis. Our results provide supportive evidence for the therapeutic use of SINE compounds in advanced/castration resistant prostate cancers and warrants further clinical investigation.