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. Epub 2019 Jan 19.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / drug therapy*
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Esophageal Neoplasms / drug therapy*
  • Humans
  • Neoadjuvant Therapy / methods
  • Phenols / pharmacology*
  • Pyrazines / pharmacology*
  • Radiation Tolerance / drug effects*
  • Radiation-Sensitizing Agents / pharmacology*
  • Small Molecule Libraries / pharmacology*
  • Zebrafish

Substances

  • Antineoplastic Agents
  • Phenols
  • Pyrazines
  • Radiation-Sensitizing Agents
  • Small Molecule Libraries

Supplementary concepts

  • Adenocarcinoma Of Esophagus