title: BP-1T, an antiangiogenic benzophenone-thiazole pharmacophore, counteracts HIF-1 signalling through p53/MDM2-mediated HIF-1α proteasomal degradation.
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.
authors.affiliation: Molecular Biomedicine Laboratory, Postgraduate Department of Studies and Research in Biotechnology, Sahyadri Science College (Autonomous), Kuvempu University, Shivamogga, Karnataka, 577203, India.
authors.forename: Prabhu
authors.initials: P
authors.lastname: Thirusangu
authors.affiliation: Molecular Biomedicine Laboratory, Postgraduate Department of Studies and Research in Biotechnology, Sahyadri Science College (Autonomous), Kuvempu University, Shivamogga, Karnataka, 577203, India.
authors.forename: V
authors.initials: V
authors.lastname: Vigneshwaran
authors.affiliation: Department of Chemistry, Yuvaraja's College (Autonomous), University of Mysore, Mysore, Karnataka, 570 005, India.
authors.forename: T
authors.initials: T
authors.lastname: Prashanth
authors.affiliation: Molecular Biomedicine Laboratory, Postgraduate Department of Studies and Research in Biotechnology, Sahyadri Science College (Autonomous), Kuvempu University, Shivamogga, Karnataka, 577203, India.|Department of Pharmacology, Center for Lung and Vascular Biology, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: B R
authors.initials: BR
authors.lastname: Vijay Avin
authors.affiliation: Molecular Biomedicine Laboratory, Postgraduate Department of Studies and Research in Biotechnology, Sahyadri Science College (Autonomous), Kuvempu University, Shivamogga, Karnataka, 577203, India.
authors.forename: Vikas H
authors.initials: VH
authors.lastname: Malojirao
authors.affiliation: Molecular Biomedicine Laboratory, Postgraduate Department of Studies and Research in Biotechnology, Sahyadri Science College (Autonomous), Kuvempu University, Shivamogga, Karnataka, 577203, India.
authors.forename: H
authors.initials: H
authors.lastname: Rakesh
authors.affiliation: Department of Chemistry, Yuvaraja's College (Autonomous), University of Mysore, Mysore, Karnataka, 570 005, India.
authors.forename: Shaukath Ara
authors.initials: SA
authors.lastname: Khanum
authors.affiliation: Postgraduate Department of Studies and Research in Biotechnology and Bioinformatics, Kuvempu University, Shankaraghatta, Shivamogga, Karnataka, 577203, India.
authors.forename: Riaz
authors.initials: R
authors.lastname: Mahmood
authors.affiliation: Molecular Biomedicine Laboratory, Postgraduate Department of Studies and Research in Biotechnology, Sahyadri Science College (Autonomous), Kuvempu University, Shivamogga, Karnataka, 577203, India. pbtssc@gmail.com.
authors.forename: B T
authors.initials: BT
authors.lastname: Prabhakar
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D001577:Benzophenones / Q000737:chemistry / Q000494:pharmacology*; D063646:Carcinogenesis / Q000378:metabolism / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D004195:Disease Models, Animal; D018450:Disease Progression; D005786:Gene Expression Regulation / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D020128:Inhibitory Concentration 50; D051379:Mice; D055806:Microvessels / Q000473:pathology; D008954:Models, Biological; D018919:Neovascularization, Physiologic / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D059748:Proteolysis / Q000187:drug effects*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D020533:Angiogenesis Inhibitors; C000626205:BP-1T compound; D001577:Benzophenones; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D013844:Thiazoles; D016159:Tumor Suppressor Protein p53; C047723:benzophenone; D051736:Proto-Oncogene Proteins c-mdm2; D046988:Proteasome Endopeptidase Complex
keywords: Antiangiogenesis; BP-1T; HIF-1α; MDM2; Solid tumour; p53