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

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• 作者：Prabhu Thirusangu ; V. Vigneshwaran ; T. Prashanth ; B. R. Vijay Avin…
• 关键词：BP ; 1T ; HIF ; 1α ; p53 ; MDM2 ; Solid tumour ; Antiangiogenesis
• 刊名：Angiogenesis
• 出版年：2017
• 出版时间：February 2017
• 年：2017
• 卷：20
• 期：1
• 页码：55-71
• 全文大小：
• 刊物类别：Medicine
• 刊物主题：Cancer Research; Biomedicine, general; Cell Biology; Cardiology; Ophthalmology; Oncology;
• 出版者：Springer Netherlands
• ISSN：1573-7209
• 卷排序：20

文摘

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.