Dual inhibition of PI3Kalpha and mTOR as an alternative treatment for Kaposi's sarcoma.
Dual inhibition of PI3Kalpha and mTOR as an alternative treatment for Kaposi's sarcoma.
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DOI：
10.1158/0008-5472.can-08-0878
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发表时间：
2008-10-15
期刊：
影响因子：
11.2
通讯作者：
Montaner, Silvia
中科院分区：
文献类型：
--
作者：
Chaisuparat, Risa;Hu, Jiadi;Jham, Bruno C.;Knight, Zachary A.;Shokat, Kevan M.;Montaner, Silvia
雷帕霉素（或西罗莫司）是哺乳动物雷帕霉素靶点（mTOR）的典型抑制剂，也是一种用于预防肾移植排斥反应的免疫抑制剂，最近已成为卡波西肉瘤（KS）的有效治疗方法，卡波西肉瘤是一种神秘的血管肿瘤，也是病理性血管生成的模型。事实上，最近的研究支持 mTOR 在 KS 相关疱疹病毒 (KSHV) 编码的 G 蛋白偶联受体 (vGPCR) 转化内皮细胞中发挥着核心作用，这种病毒癌基因被认为是引起 KS 的原因。然而，新出现的证据表明雷帕霉素可能会暂时促进 Akt 的激活，这可能会限制其作为抗 KS 疗法的用途。在这里，我们证明了表达 vGPCR 的内皮细胞中 Akt 的激活通过雷帕霉素处理而增强，从而导致多个 Akt 增殖和存活途径的上调。然而，使用新型 PI3Kα/mTOR 双重抑制剂 PI-103，可以有效且独立地阻断表达 vGPCR 的内皮细胞中 PI3K 和 mTOR 的激活。这导致更有效地抑制体外内皮细胞增殖和存活以及体内肿瘤生长。我们的结果表明 PI-103 可能是治疗 KS 患者的有效治疗选择。此外，由于KS可能作为病理性血管生成的模型，我们的结果进一步为PI-103作为抗血管生成化疗药物的早期评估提供了基础。
Rapamycin (or sirolimus), the prototypical inhibitor of the mammalian target of rapamycin (mTOR) and an immunosuppressant used for the prevention of renal transplant rejection, has recently emerged as an effective treatment for Kaposi's sarcoma (KS), an enigmatic vascular tumor and a model for pathological angiogenesis. Indeed, recent work supports a role for mTOR as a central player in the transformation of endothelial cells by the KS-associated herpesvirus (KSHV)-encoded G protein-coupled receptor (vGPCR), the viral oncogene believed to be responsible for causing KS. However, emerging evidence that rapamycin may transiently promote the activation of Akt may limit its use as an anti-KS therapy. Here we demonstrate that activation of Akt in endothelial cells expressing vGPCR is augmented by treatment with rapamycin, resulting in the upregulation of several Akt proliferative and survival pathways. However, use of a novel dual PI3Kα/mTOR inhibitor, PI-103, effectively and independently blocked activation of both PI3K and mTOR in vGPCR-expressing endothelial cells. This resulted in more effective inhibition of endothelial cell proliferation and survival in vitro and tumor growth in vivo. Our results suggest that PI-103 may be an effective therapeutic option for the treatment of patients with KS. Moreover, as KS may serve as a model for pathological angiogenesis, our results further provide the basis for the early assessment of PI-103 as an anti-angiogenic chemotherapeutic.