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

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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.

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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.

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Authors and Affiliations

  1. Molecular Biomedicine Laboratory, Postgraduate Department of Studies and Research in Biotechnology, Sahyadri Science College (Autonomous), Kuvempu University, Shivamogga, Karnataka, 577203, India

    Prabhu Thirusangu, V. Vigneshwaran, B. R. Vijay Avin, Vikas H. Malojirao, H. Rakesh & B. T. Prabhakar

  2. Department of Chemistry, Yuvaraja’s College (Autonomous), University of Mysore, Mysore, Karnataka, 570 005, India

    T. Prashanth & Shaukath Ara Khanum

  3. Department of Pharmacology, Center for Lung and Vascular Biology, University of Illinois at Chicago, Chicago, IL, USA

    B. R. Vijay Avin

  4. Postgraduate Department of Studies and Research in Biotechnology and Bioinformatics, Kuvempu University, Shankaraghatta, Shivamogga, Karnataka, 577203, India

    Riaz Mahmood

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  1. Prabhu Thirusangu
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Thirusangu, P., Vigneshwaran, V., Prashanth, T. et al. BP-1T, an antiangiogenic benzophenone-thiazole pharmacophore, counteracts HIF-1 signalling through p53/MDM2-mediated HIF-1α proteasomal degradation. Angiogenesis 20, 55–71 (2017). https://doi.org/10.1007/s10456-016-9528-3

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