1,4-dihydroxy quininib attenuates growth of colorectal cancer cells and xenografts and regulates the TIE-2 signaling pathway in patient tumours.

1,4-dihydroxy quininib attenuates growth of colorectal cancer cells and xenografts and regulates the TIE-2 signaling pathway in patient tumours. Oncotarget. 2019 Jun 04;10(38):3725-3744 Authors: Butler CT, Kennedy SA, Buckley A, Doyle R, Conroy E, Gallagher WM, O'Sullivan J, Kennedy BN Abstract 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 comp...
Source: Oncotarget - Category: Cancer & Oncology Tags: Oncotarget Source Type: research