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

• Published in: Angiogenesis (London) Vol. 20; no. 1; pp. 55 - 71
• Main Authors: Thirusangu, Prabhu, Vigneshwaran, V., Prashanth, T., Vijay Avin, B. R., Malojirao, Vikas H., Rakesh, H., Khanum, Shaukath Ara, Mahmood, Riaz, Prabhakar, B. T.
• Format: Journal Article
• Language: English
• Published: Dordrecht Springer Netherlands 01.02.2017
• Subjects: Angiogenesis Inhibitors - pharmacology; Animals; Benzophenones - chemistry; Benzophenones - pharmacology; Biomedical and Life Sciences; Biomedicine; Cancer Research; Carcinogenesis - metabolism; Carcinogenesis - pathology; Cardiology; Cell Biology; Cell Death - drug effects; Cell Line; Cell Movement - drug effects; Disease Models, Animal; Disease Progression; Gene Expression Regulation - drug effects; Human Umbilical Vein Endothelial Cells - drug effects; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Inhibitory Concentration 50; Mice; Microvessels - pathology; Models, Biological; Neovascularization, Physiologic - drug effects; Oncology; Ophthalmology; Original Paper; Proteasome Endopeptidase Complex - metabolism; Proteolysis - drug effects; Proto-Oncogene Proteins c-mdm2 - metabolism; Rats; Signal Transduction - drug effects; Thiazoles - chemistry; Thiazoles - pharmacology; Tumor Suppressor Protein p53 - metabolism; MDM2; HIF-1α; BP-1T; Antiangiogenesis; Solid tumour; p53
• ISSN: 0969-6970; 1573-7209
• DOI: 10.1007/s10456-016-9528-3

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 CoCl 2 -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.