a novel inhibitor of hypoxia-inducible factor-1α p3155 also modulates pi3k pathway and inhibits growth of prostate cancer cells一种新型抑制剂的低氧factor-1αp3155也调节pi3k通路,抑制前列腺癌细胞的生长.pdfVIP

Manohar et al. BMC Cancer 2011, 11:338 /1471-2407/11/338 RESEARCH ARTICLE Open Access A novel inhibitor of hypoxia-inducible factor-1a P3155 also modulates PI3K pathway and inhibits growth of prostate cancer cells 1† 1† 1 1 1 Sonal M Manohar , Amol A Padgaonkar , Archana Jalota-Badhwar , Vinay Sonawane , Maggie J Rathos , Sanjay Kumar2 and Kalpana S Joshi3* Abstract Background: 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-1a has been demonstrated in many common human cancers. Therefore, HIF-1a is one of the most compelling anticancer targets. Methods: To identify HIF-1a 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. Results: P3155 showed specific HIF-1a inhibition with IC50 of 1.4 μM under hypoxia. It suppressed HIF-1a 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-1a siRNA showed significant synergistic effect. In addition, it demonstrated significant in vivo efficacy and antiangiogenic potential in prostate cancer cell lines. Conclusion: We have identified a novel HIF-1a inhibitor P3155 that also modulates PI3K/Akt pathway, which may contribute to its significant in vitro and in vivo antitumor