Naftopidil, a Selective α1-Adrenoceptor Antagonist, Suppresses Human Prostate Tumor Growth by Altering Interactions between Tumor Cells and Stroma
Naftopidil, a Selective α1-Adrenoceptor Antagonist, Suppresses Human Prostate Tumor Growth by Altering Interactions between Tumor Cells and Stroma
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DOI：
10.1158/1940-6207.capr-10-0189
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发表时间：
2011-01-01
影响因子：
3.3
通讯作者：
Sugimura, Yoshiki
中科院分区：
文献类型：
--
作者：
Hori, Yasuhide;Ishii, Kenichiro;Sugimura, Yoshiki
在前列腺癌中，肿瘤-间质相互作用在促进肿瘤发生中起着关键作用，因此，预防这种相互作用是抑制肿瘤生长的一个有前途的靶点。多项研究表明，治疗良性前列腺增生症的药物α(1)-肾上腺素能受体(α(1)-AR)拮抗剂通过诱导人前列腺癌(Pca)细胞的凋亡或G(1)期细胞周期停滞而抑制其生长。然而，它们对癌细胞周围基质细胞的直接作用尚未阐明。在这项研究中，我们利用商业上可用的成纤维细胞(PRSC)，研究了亚型选择性的α(1)-AR拮抗剂(那托地尔、坦索罗辛和西洛多辛)对前列腺癌生长的影响，重点是基质的作用。体内致瘤性研究表明，当移植有PRSC的E9细胞(一种雄激素低敏感性LNCaP亚系)接受萘哌地尔治疗时，肿瘤生长显著减少。在体外分析中，无论雄激素敏感性和α(1)-AR亚型表达如何，奈哌地尔和西洛多辛对PCa细胞均显示出抑制增殖的作用。在PRSC中，萘哌地尔有较强的生长抑制作用，而西洛多辛无此作用。流式细胞仪分析显示，氟哌地尔诱导PCa细胞和PRSC细胞周期G(1)期停滞，而西洛多辛无此作用。在萘哌地尔处理的PRSC中，总白介素6蛋白显著降低，细胞增殖抑制增强。西洛多辛仅诱导PCa细胞早期微弱的凋亡。这些结果表明，萘哌地尔强烈抑制间质细胞的增殖，导致致瘤可溶性因子降低，提示萘哌地尔可能有效地阻止了肿瘤细胞的间质支持。癌症预防；4(1)；87-96。(C)2011年AACR。
In prostate cancer, tumor-stroma interactions play a critical role in the promotion of tumorigenesis, and thus the prevention of those interactions is a promising target to suppress tumor growth. Several studies demonstrated that alpha(1)-adrenoceptor (alpha(1)-AR) antagonists, therapeutic drugs for benign prostatic hyperplasia, have growth inhibitory effects on human prostate cancer (PCa) cells through induction of apoptosis or G(1) cell-cycle arrest. However, their direct actions on stromal cells surrounding cancer cells have not yet been elucidated. In this study, we investigated the effects of subtype-selective alpha(1)-AR antagonists (naftopidil, tamsulosin, and silodosin) on prostate tumor growth with a focus on the role of stroma, using commercially available fibroblast cells (PrSC). Tumorigenic studies in vivo showed significant reductions in tumor growth when E9 cells (an androgen low-sensitive LNCaP subline) grafted with PrSC were treated with naftopidil. In in vitro analyses, naftopidil and silodosin showed antiproliferative effects on PCa cells regardless of androgen sensitivity and alpha(1)-AR subtype expression. In PrSC, a strong growth inhibitory effect was observed with naftopidil but not silodosin. Flow cytometric analysis revealed that naftopidil, but not silodosin, induced G(1) cell-cycle arrest in both PCa cells and PrSC. In naftopidil-treated PrSC, total interleukin-6 protein was significantly reduced with increased suppression of cell proliferation. Silodosin induced weak early apoptosis only in PCa cells. These findings demonstrated that naftopidil strongly suppressed cell proliferation of stromal cells, resulting in decreased tumorigenic soluble factor, suggesting that naftopidil might be effective in preventing stromal support of tumor cells. Cancer Prev Res; 4(1); 87-96. (C) 2011 AACR.