TGF-beta-RI kinase inhibitor SD-208 reduces the development and progression of melanoma bone metastases.
TGF-beta-RI kinase inhibitor SD-208 reduces the development and progression of melanoma bone metastases.
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DOI：
10.1158/0008-5472.can-10-2651
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发表时间：
2011-01-01
期刊：
影响因子：
11.2
通讯作者：
Guise TA
中科院分区：
文献类型：
--
作者：
Mohammad KS;Javelaud D;Fournier PG;Niewolna M;McKenna CR;Peng XH;Duong V;Dunn LK;Mauviel A;Guise TA
黑色素瘤通常转移到骨，在那里它暴露于高浓度的TGF-β。组成性Smad信号传导发生在人黑素瘤中。由于TGF-β促进几种类型的实体瘤（包括乳腺癌）向骨转移，我们假设TGF-β信号通路的药理学阻断可能会干扰黑色素瘤细胞向骨转移的能力。在这项研究中，我们测试了TGF-β受体I激酶（TβRI）的小分子抑制剂SD-208对体外和人黑色素瘤骨转移小鼠模型中影响黑色素瘤发生和进展的各种参数的影响。在黑色素瘤细胞系中，SD-208阻断TGF-β诱导Smad 3磷酸化、Smad 3/4特异性转录、Matrigel侵袭和TGF-β靶基因PTHrP、IL-11、CTGF和RUNX 2的表达。为了评估SD-208对黑色素瘤发展和转移的影响，将1205 Lu黑色素瘤细胞接种到裸鼠左心室中，并根据预防或治疗方案通过经口灌胃给予药物。与溶媒相比，在肿瘤接种前2天开始的SD-208（60 mg/kg/天）可预防溶骨性骨转移的发生。在已建立骨转移的小鼠中，与溶剂处理的小鼠相比，SD-208处理4周后溶骨性病变的大小显著减小。我们的研究结果表明，TGF-β的治疗靶向可以防止黑色素瘤骨转移的发展，并减少已建立的溶骨性病变的进展。
Melanoma often metastasizes to bone where it is exposed to high concentrations of TGF-β. Constitutive Smad signaling occurs in human melanoma. Because TGF-β promotes metastases to bone by several types of solid tumors including breast cancer, we hypothesized that pharmacologic blockade of the TGF-β signaling pathway may interfere with the capacity of melanoma cells to metastasize to bone. In this study, we tested the effect of a small molecule inhibitor of TGF-β receptor I kinase (TβRI), SD-208, on various parameters affecting the development and progression of melanoma, both in vitro and in a mouse model of human melanoma bone metastasis. In melanoma cell lines, SD-208 blocked TGF-β induction of Smad3 phosphorylation, Smad3/4-specific transcription, Matrigel invasion and expression of the TGF-β target genes PTHrP, IL-11, CTGF and RUNX2. To assess effects of SD-208 on melanoma development and metastasis, nude mice were inoculated with 1205Lu melanoma cells into the left cardiac ventricle and drug was administered by oral gavage on prevention or treatment protocols. SD-208 (60mg/kg/day), started 2 days before tumor inoculation prevented the development of osteolytic bone metastases compared with vehicle. In mice with established bone metastases, the size of osteolytic lesions was significantly reduced after 4 weeks treatment with SD-208 compared to vehicle-treated mice. Our results demonstrate that therapeutic targeting of TGF-β may prevent the development of melanoma bone metastases and decrease the progression of established osteolytic lesions.