2. Academic Validation
  3. Pyrazinib (P3), [(E)-2-(2-Pyrazin-2-yl-vinyl)-phenol], a small molecule pyrazine compound enhances radiosensitivity in oesophageal adenocarcinoma

Pyrazinib (P3), [(E)-2-(2-Pyrazin-2-yl-vinyl)-phenol], a small molecule pyrazine compound enhances radiosensitivity in oesophageal adenocarcinoma

  • Cancer Lett. 2019 Apr 10:447:115-129. doi: 10.1016/j.canlet.2019.01.009.
Amy M Buckley 1,  Margaret R Dunne 1,  Niamh Lynam-Lennon 1,  Susan A Kennedy 1,  Aoife Cannon 1,  Alison L Reynolds 2,  Stephen G Maher 1,  John V Reynolds 1,  Breandán N Kennedy 3,  Jacintha O'Sullivan 4
Affiliations

Affiliations

  • 1 Department of Surgery, Trinity Translational Medicine Institute, St. James's Hospital, Trinity College Dublin, Ireland.
  • 2 UCD School of Veterinary Medicine, Veterinary Sciences Centre, University College Dublin, Ireland; UCD Conway Institute & UCD School of Biomolecular and Biomedical Science, University College Dublin, Ireland.
  • 3 UCD Conway Institute & UCD School of Biomolecular and Biomedical Science, University College Dublin, Ireland.
  • 4 Department of Surgery, Trinity Translational Medicine Institute, St. James's Hospital, Trinity College Dublin, Ireland. Electronic address: OSULLIJ4@tcd.ie.
PMID: 30664962 DOI: 10.1016/j.canlet.2019.01.009
Abstract

Oesophageal adenocarcinoma (OAC) is an aggressive disease with 5-year survival rates of <20%. Only 20-30% OAC patients show a beneficial response to neoadjuvant therapy. Altered mitochondrial function is linked with radioresistance in OAC. We identified pyrazinib (P3), a pyrazine phenol small molecule drug with anti-angiogenic and anti-metabolic activity in-vivo in zebrafish and in-vitro isogenic models of OAC radioresistance. Pyrazinib (P3) significantly inhibited blood vessel development in zebrafish (p < 0.001). In-vivo in zebrafish and in-vitro in an isogenic model of OAC radioresistance, pyrazinib (P3) significantly reduced measures of Oxidative Phosphorylation and glycolysis. Pyrazinib (P3) significantly reduced the surviving fraction in OE33P; radiation-sensitive and OE33R; radiation-resistant cells following irradiation. Under hypoxic conditions pyrazinib (P3) significantly reduced OE33R cell survival following 4 Gy irradiation (p = 0.0216). Multiplex ELISA showed significantly higher secreted levels of 9 of 30 detected inflammatory and angiogenic factors in OE33R radioresistant cells compared to OE33P cells; IL-8, IL-4, IL-6, IL-2, IL-12p70, IL-10, MCP-1, IP-10, ICAM (p < 0.05). Pyrazinib (P3) significantly reduced the secretions of IL-6 (p = 0.0006), IL-8 (p = 0.0488), and IL-4 (p = 0.0111) in OE33R cells. Collectively, these findings support further development of pyrazinib (P3) as a novel therapeutic radiosensitiser in OAC.

Keywords

Angiogenesis; Inflammation; Metabolism; Oesophageal cancer; Radiation.

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