title: A tumoural angiogenic gateway blocker, Benzophenone-1B represses the HIF-1α nuclear translocation and its target gene activation against neoplastic progression.
abstract: Hypoxia is an important module in all solid tumours to promote angiogenesis, invasion and metastasis. Stabilization and subsequent nuclear localization of HIF-1α subunits result in the activation of tumour promoting target genes such as VEGF, MMPs, Flt-1, Ang-1 etc. which plays a pivotal role in adaptation of tumour cells to hypoxia. Increased HIF-α and its nuclear translocation have been correlated with pronounced angiogenesis, aggressive tumour growth and poor patient prognosis leading to current interest in HIF-1α as an anticancer drug target. Benzophenone-1B ([4-(1H-benzimidazol-2-ylmethoxy)-3,5-dimethylphenyl]-(4-methoxyphenyl) methanone, or BP-1B) is a new antineoplastic agent with potential angiopreventive effects. Current investigation reports the cellular biochemical modulation underlying BP-1B cytotoxic/antiangiogenic effects. Experimental evidences postulate that BP-1B exhibits the tumour specific cytotoxic actions against various cancer types with prolonged action. Moreover BP-1B efficiently counteracts endothelial cell capillary formation in in-vitro, in-vivo non-tumour and tumour angiogenic systems. Molecular signaling studies reveal that BP-1B arrests nuclear translocation of HIF-1α devoid of p42/44 pathway under CoCl2induced hypoxic conditions in various cancer cells thereby leading to abrogated HIF-1α dependent activation of VEGF-A, Flt-1, MMP-2, MMP -9 and Ang-1 angiogenic factors resulting in retarded cell migration and invasions. The in-vitro results were reproducible in the reliable in-vivo solid tumour model. Taken together, we conclude that BP-1B impairs angiogenesis by blocking nuclear localization of HIF-1α which can be translated into a potent HIF-1α inhibitor.
authors.affiliation: Molecular Biomedicine Laboratory, Postgraduate Department of Studies and Research in Biotechnology, Sahyadri Science College (Autonomous), Kuvempu University, Shivamogga 577203, Karnataka, 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 577203, Karnataka, India.
authors.forename: V
authors.initials: V
authors.lastname: Vigneshwaran
authors.affiliation: Department of Chemistry, Yuvaraja's College (Autonomous), University of Mysore, Mysuru 570 005, Karnataka, India; Department of Chemistry, The National Institute of Engineering, Mysuru 570008, Karnataka, India.
authors.forename: V Lakshmi
authors.initials: VL
authors.lastname: Ranganatha
authors.affiliation: Molecular Biomedicine Laboratory, Postgraduate Department of Studies and Research in Biotechnology, Sahyadri Science College (Autonomous), Kuvempu University, Shivamogga 577203, Karnataka, India; Department of Pharmacology and Centre for Lung and Vascular Biology, University of Illinois at Chicago, Chicago, USA.
authors.forename: B R
authors.initials: BR
authors.lastname: Vijay Avin
authors.affiliation: Department of Chemistry, Yuvaraja's College (Autonomous), University of Mysore, Mysuru 570 005, Karnataka, India.
authors.forename: Shaukath Ara
authors.initials: SA
authors.lastname: Khanum
authors.affiliation: Postgraduate Department of Studies and Research in Biotechnology & Bioinformatics, Kuvempu University, Shankaraghatta, Shivamogga 577203, Karnataka, India.
authors.forename: Riaz
authors.initials: R
authors.lastname: Mahmood
authors.affiliation: Department of Pathology, JSS Medical College, JSS University, Mysore 570015, Karnataka, India.
authors.forename: K
authors.initials: K
authors.lastname: Jayashree
authors.affiliation: Molecular Biomedicine Laboratory, Postgraduate Department of Studies and Research in Biotechnology, Sahyadri Science College (Autonomous), Kuvempu University, Shivamogga 577203, Karnataka, India. Electronic address: prabhakarbt@gmail.com.
authors.forename: B T
authors.initials: BT
authors.lastname: Prabhakar
mesh_terms: D000818:Animals; D001577:Benzophenones / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D002642:Chick Embryo; D004195:Disease Models, Animal; D018450:Disease Progression; D005786:Gene Expression Regulation / Q000187:drug effects*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000473:pathology*; D021381:Protein Transport; D051381:Rats; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology
chemical_list: D001577:Benzophenones; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; C047723:benzophenone
keywords: Angiogenesis; Benzimidazole; Benzophenone-1B; HIF-1α; Nuclear translocation; Solid tumour