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Angiogenesis

, Volume 20, Issue 1, pp 55–71 | Cite as

BP-1T, an antiangiogenic benzophenone-thiazole pharmacophore, counteracts HIF-1 signalling through p53/MDM2-mediated HIF-1α proteasomal degradation

  • Prabhu Thirusangu
  • V. Vigneshwaran
  • T. Prashanth
  • B. R. Vijay Avin
  • Vikas H. Malojirao
  • H. Rakesh
  • Shaukath Ara Khanum
  • Riaz Mahmood
  • B. T. Prabhakar
Original Paper

Abstract

Hypoxia is a feature of all solid tumours, contributing to tumour progression. Activation of HIF-1α plays a critical role in promoting tumour angiogenesis and metastasis. Since its expression is positively correlated with poor prognosis for cancer patients, HIF-1α is one of the most convincing anticancer targets. BP-1T is a novel antiproliferative agent with promising antiangiogenic effects. In the present study, the molecular mechanism underlying cytotoxic/antiangiogenic effects of BP-1T on tumour/non-tumour angiogenesis was evaluated. Evidences show that BP-1T exhibits potent cytotoxicity with prolonged activity and effectively regressed neovessel formation both in reliable non-tumour and tumour angiogenic models. The expression of CoCl2-induced HIF-1α was inhibited by BP-1T in various p53 (WT)-expressing cancer cells, including A549, MCF-7 and DLA, but not in mutant p53-expressing SCC-9 cells. Mechanistically, BP-1T mediates the HIF-1α proteasomal degradation by activating p53/MDM2 pathway and thereby downregulated HIF-1α-dependent angiogenic genes such as VEGF-A, Flt-1, MMP-2 and MMP-9 under hypoxic condition of in vitro and in vivo solid tumour, eventually leading to abolition of migration and invasion. Based on these observations, we conclude that BP-1T acts on HIF-1α degradation through p53/MDM2 proteasome pathway.

Keywords

BP-1T HIF-1α p53 MDM2 Solid tumour Antiangiogenesis 

Notes

Acknowledgments

B.T. Prabhakar gratefully acknowledges the grant extended by DBT (6242-P37/RGCB/PMD/DBT/PBKR/2015), UGC (F.No.41-507/2012 (SR) and VGST (VGST/GRD231/CISEE/2013-14). B.T. Prabhakar expresses sincere thanks to UGC, Government of India for Raman post doctoral research internship at Medical University South Carolina (MUSC), Charleston, USA. Prabhu Thirusangu acknowledges the Lady Tata Memorial Trust (LTMT) (JRS/2014-15/LTMT dated 11-08-2014), Mumbai, for financial assistance and support. Shaukath Ara Khanum expresses their sincere gratitude to VGST [VGST/CISEE/2012-13/2882], Government of Karnataka for the financial assistance and support.

Compliance with ethical standards

Conflict of interest

The authors declare that there are no conflicts of interest.

Supplementary material

10456_2016_9528_MOESM1_ESM.pdf (723 kb)
Supplementary material 1 (PDF 723 kb)

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Copyright information

© Springer Science+Business Media Dordrecht 2016

Authors and Affiliations

  • Prabhu Thirusangu
    • 1
  • V. Vigneshwaran
    • 1
  • T. Prashanth
    • 2
  • B. R. Vijay Avin
    • 1
    • 3
  • Vikas H. Malojirao
    • 1
  • H. Rakesh
    • 1
  • Shaukath Ara Khanum
    • 2
  • Riaz Mahmood
    • 4
  • B. T. Prabhakar
    • 1
  1. 1.Molecular Biomedicine Laboratory, Postgraduate Department of Studies and Research in Biotechnology, Sahyadri Science College (Autonomous)Kuvempu UniversityShivamoggaIndia
  2. 2.Department of Chemistry, Yuvaraja’s College (Autonomous)University of MysoreMysoreIndia
  3. 3.Department of Pharmacology, Center for Lung and Vascular BiologyUniversity of Illinois at ChicagoChicagoUSA
  4. 4.Postgraduate Department of Studies and Research in Biotechnology and BioinformaticsKuvempu UniversityShankaraghatta, ShivamoggaIndia

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