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

Abstract

// Clare T. Butler 1 , Susan A. Kennedy 2 , Amy Buckley 2 , Ronan Doyle 3 , Emer Conroy 1 , William M. Gallagher 1 , Jacintha O’Sullivan 2 , * and Breandán N. Kennedy 1 , * 1 UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, Dublin, Ireland 2 Trinity Translational Medicine Institute, Department of Surgery, Trinity College Dublin, St. James’s Hospital, Dublin, Ireland 3 Department of Histopathology, Trinity College Dublin Central Pathology Laboratory, St James’s Hospital, Dublin, Ireland * These authors contributed equally to this work Correspondence to: Breandán N. Kennedy, email: brendan.kennedy@ucd.ie Keywords: colorectal cancer; angiogenesis; cysteinyl leukotriene; drug discovery; xenograft Received: January 01, 2019     Accepted: April 21, 2019     Published: June 04, 2019 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 CysLT 1 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 summary, we propose Q8 may act on the TIE-2-Angiopoietin signalling pathway to significantly inhibit the process of tumour angiogenesis in colorectal cancer.