A novel inhibitor of hypoxia-inducible factor-1α P3155 also modulates PI3K pathway and inhibits growth of prostate cancer cells

BMC Cancer

Sonal M Manohar²  Amol A Padgaonkar²  Archana Jalota-Badhwar²  Vinay Sonawane²  Maggie J Rathos²  Sanjay Kumar¹  Kalpana S Joshi³ 

[1] Department of Medicinal Chemistry, Piramal Life Sciences Limited, 1-Nirlon Complex, Goregaon, Mumbai-400 063, India

[2] Department of Pharmacology, Piramal Life Sciences Limited, 1-Nirlon Complex, Goregaon, Mumbai-400 063, India

[3] Target Identification Group, Piramal Life Sciences Limited, 1-Nirlon Complex, Goregaon, Mumbai-400 063, India

关键词: PI3K;    prostate cancer;    HIF-1α;    P3155;   

Others  :  1080797
DOI  :  10.1186/1471-2407-11-338

 received in 2011-03-14, accepted in 2011-08-05,  发布年份 2011

【 摘 要 】

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-1α has been demonstrated in many common human cancers. Therefore, HIF-1α is one of the most compelling anticancer targets.

Methods

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.

Results

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.

Conclusion

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.

【 授权许可】

   
2011 Manohar et al; licensee BioMed Central Ltd.

【 图 表 】

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