1,4-dihydroxy quininib attenuates growth of colorectal cancer cells and xenografts and regulates the TIE-2 signaling pathway in patient tumours
| Autor: | Amy M. Buckley, Breandán N. Kennedy, William M. Gallagher, Ronan S. Doyle, Emer Conroy, Susan Kennedy, Clare T. Butler, Jacintha O'Sullivan |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Colorectal cancer Angiogenesis business.industry Clone (cell biology) Cancer colorectal cancer medicine.disease drug discovery 03 medical and health sciences angiogenesis 030104 developmental biology 0302 clinical medicine Oncology In vivo 030220 oncology & carcinogenesis medicine Cancer research Gene silencing cysteinyl leukotriene Signal transduction xenograft business Ex vivo Research Paper |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | Colorectal cancer (CRC) is the second leading cause of cancer associated deaths in developed countries. Cancer progression and metastatic spread is reliant on new blood vasculature, or angiogenesis. Tumour-related angiogenesis is regulated by pro- and anti-angiogenic factors secreted from malignant tissue in a stepwise process. Previously we structurally modified the small anti-angiogenic molecule quininib and discovered a more potent anti-angiogenic compound 1, 4 dihydroxy quininib (Q8), an antagonist of cysteinyl leukotriene receptor-1 with VEGF-independent bioactivity. Here, Q8, quininib (Q1) and five structural analogues were assayed for anti-tumorigenic effects in pre-clinical cancer models. Q8 reduced clone formation of the human colorectal cancer cell line HT29-Luc2. Gene silencing of CysLT1 in HT29-Luc2 cells significantly reduced expression of calpain-2. In human ex vivo colorectal cancer tumour explants, Q8 significantly decreased the secretion of both TIE-2 and VCAM-1 expression. In vivo Q8 was well tolerated up to 50 mg/kg by Balb/C mice and significantly more effective at reducing tumour volume in colorectal tumour xenografts compared to the parent drug quininib. In tumour xenografts, Q8 significantly reduced expression of the angiogenic marker calpain-2 in. In summary, we propose Q8 may act on the TIE-2-Angiopoietin signalling pathway to significantly inhibit the process of tumour angiogenesis in colorectal cancer. |
| Databáze: | OpenAIRE |
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