A novel inhibitor of hypoxia-inducible factor-1α P3155 also modulates PI3K pathway and inhibits growth of prostate cancer cells.
A novel inhibitor of hypoxia-inducible factor-1α P3155 also modulates PI3K pathway and inhibits growth of prostate cancer cells.
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DOI：
10.1186/1471-2407-11-338
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发表时间：
2011-08-05
期刊：
影响因子：
3.8
通讯作者：
Joshi KS
中科院分区：
文献类型：
--
作者：
Manohar SM;Padgaonkar AA;Jalota-Badhwar A;Sonawane V;Rathos MJ;Kumar S;Joshi KS
缺氧诱导因子 1 (HIF-1) 是缺氧转录反应的主要调节因子。它对于血管生成至关重要，并且与肿瘤进展相关，并且 HIF-1α 的过度表达已在许多常见的人类癌症中得到证实。因此，HIF-1α是最引人注目的抗癌靶点之一。为了鉴定 HIF-1α 抑制剂，使用缺氧和常氧下的荧光素酶报告基因测定。进行了蛋白质印迹、RT-PCR、免疫荧光等详细研究以阐明其作用机制。通过迁移测定和管形成测定证明了 P3155 的抗血管生成活性。 P3155 的功效研究是在 PC-3 异种移植模型上进行的。 P3155 在缺氧条件下表现出特异性 HIF-1α 抑制作用，IC50 为 1.4 μM。它抑制 HIF-1α 表达以及 PI3K/Akt 通路，并消除 HIF-1 诱导基因的表达。血管内皮生长因子（VEGF）。 P3155与HIF-1α siRNA联合显示出显着的协同效应。此外，它在前列腺癌细胞系中表现出显着的体内功效和抗血管生成潜力。我们发现了一种新型 HIF-1α 抑制剂 P3155，它也调节 PI3K/Akt 通路，这可能有助于其显着的体外和体内抗肿瘤活性。
Hypoxia-inducible factor-1 (HIF-1) is a master regulator of the transcriptional response to hypoxia. It is essential for angiogenesis and is associated with tumor progression and overexpression of HIF-1α has been demonstrated in many common human cancers. Therefore, HIF-1α is one of the most compelling anticancer targets. To identify HIF-1α inhibitors, luciferase reporter gene assay under hypoxia and normoxia was used. Detailed studies such as western blotting, RT-PCR, immunofluorescence were carried out to elucidate its mechanism of action. Antiangiogenic activity of P3155 was demonstrated by migration assay and tube formation assay. Efficacy study of P3155 was performed on PC-3 xenograft model. P3155 showed specific HIF-1α inhibition with IC50 of 1.4 μM under hypoxia. It suppressed HIF-1α expression as well as PI3K/Akt pathway and abrogated expression of HIF-1-inducible gene viz. vascular endothelial growth factor (VEGF). P3155 in combination with HIF-1α siRNA showed significant synergistic effect. In addition, it demonstrated significant in vivo efficacy and antiangiogenic potential in prostate cancer cell lines. We have identified a novel HIF-1α inhibitor P3155 that also modulates PI3K/Akt pathway, which may contribute to its significant in vitro and in vivo antitumor activity.
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