PUBLICATION
Pyrazinib (P3), [(E)-2-(2-Pyrazin-2-yl-vinyl)-phenol], a small molecule pyrazine compound enhances radiosensitivity in oesophageal adenocarcinoma
- Authors
- Buckley, A.M., Dunne, M.R., Lynam-Lennon, N., Kennedy, S.A., Cannon, A., Reynolds, A.L., Maher, S.G., Reynolds, J.V., Kennedy, B.N., O'Sullivan, J.
- ID
- ZDB-PUB-190122-14
- Date
- 2019
- Source
- Cancer letters 447: 115-129 (Journal)
- Registered Authors
- Kennedy, Breandan N.
- Keywords
- Angiogenesis, Inflammation, Metabolism, Oesophageal cancer, Radiation
- 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
- PubMed
- 30664962 Full text @ Cancer Lett.
Citation
Buckley, A.M., Dunne, M.R., Lynam-Lennon, N., Kennedy, S.A., Cannon, A., Reynolds, A.L., Maher, S.G., Reynolds, J.V., Kennedy, B.N., O'Sullivan, J. (2019) Pyrazinib (P3), [(E)-2-(2-Pyrazin-2-yl-vinyl)-phenol], a small molecule pyrazine compound enhances radiosensitivity in oesophageal adenocarcinoma. Cancer letters. 447:115-129.
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 chemo-radiation 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 than 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping