Department of Pharmacology, Piramal Life Sciences Limited, 1-Nirlon Complex, Goregaon, Mumbai-400 063, India.
BMC Cancer. 2011 Aug 5;11:338. doi: 10.1186/1471-2407-11-338.
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.
缺氧诱导因子-1（HIF-1）是对缺氧的转录反应的主要调节因子。它对血管生成至关重要，与肿瘤进展有关，并且在许多常见的人类癌症中已经证明 HIF-1α的过表达。因此，HIF-1α 是最引人注目的抗癌靶标之一。
为了鉴定 HIF-1α 抑制剂，在低氧和常氧条件下使用荧光素酶报告基因检测。进行了详细的研究，如 Western blot、RT-PCR、免疫荧光，以阐明其作用机制。通过迁移试验和管形成试验证明了 P3155 的抗血管生成活性。在 PC-3 异种移植模型上进行了 P3155 的疗效研究。
P3155 在低氧条件下表现出对 HIF-1α 的特异性抑制，IC50 为 1.4μM。它抑制了 HIF-1α 的表达以及 PI3K/Akt 通路，并消除了 HIF-1 诱导基因，即血管内皮生长因子（VEGF）的表达。P3155 与 HIF-1α siRNA 联合使用显示出显著的协同作用。此外，它在前列腺癌细胞系中表现出显著的体内疗效和抗血管生成潜力。
我们已经鉴定出一种新型的 HIF-1α 抑制剂 P3155，它还调节 PI3K/Akt 通路，这可能有助于其在体外和体内的显著抗肿瘤活性。
