A tumoural angiogenic gateway blocker, Benzophenone-1B represses the HIF-1α nuclear translocation and its target gene activation against neoplastic progression

• Published in: Biochemical pharmacology Vol. 125; pp. 26 - 40
• Main Authors: Thirusangu, Prabhu, Vigneshwaran, V., Ranganatha, V. Lakshmi, Vijay Avin, B.R., Khanum, Shaukath Ara, Mahmood, Riaz, Jayashree, K., Prabhakar, B.T.
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 01-02-2017
• Subjects: Angiogenesis; Animals; Benzimidazole; Benzophenone-1B; Benzophenones - pharmacology; Cell Line, Tumor; Cell Nucleus - metabolism; Chick Embryo; Disease Models, Animal; Disease Progression; Gene Expression Regulation - drug effects; HIF-1α; Human Umbilical Vein Endothelial Cells; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Male; Mice; Mice, Inbred BALB C; Neoplasms - pathology; Nuclear translocation; Protein Transport; Rats; Solid tumour; Vascular Endothelial Growth Factor A - pharmacology; Angiogenesis; HIF-1α; Benzophenone-1B; Nuclear translocation; Benzimidazole; Solid tumour
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2016.11.009

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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 CoCl2 induced 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.