Combination treatment of resveratrol and capsaicin radiosensitizes pancreatic tumor cells by unbalancing DNA repair response to radiotherapy towards cell death

• Published in: Cancer letters 2019-06, Vol.451, p.1-10
• Main Authors: Vendrely, Véronique, Amintas, Samuel, Noel, Cécile, Moranvillier, Isabelle, Lamrissi, Isabelle, Rousseau, Benoit, Coulibaly, Soulé, Bedel, Aurélie, Moreau-Gaudry, François, Buscail, Etienne, Chiche, Laurence, Belleannée, Geneviève, Dupin, Charles, Dabernat, Sandrine
• Format: Article
• Language: English
• Subjects: Adenocarcinoma; Animals; Apoptosis; Cancer therapies; Capsaicin; Capsaicin - administration & dosage; Capsaicin - therapeutic use; Cell cycle; Cell death; Cell Death - drug effects; Cellular precipitates; Chemoradiotherapy; Chemotherapy; Data collection; Deoxyribonucleic acid; DNA; DNA damage; DNA repair; DNA Repair - drug effects; Double-strand break repair; Drug Therapy, Combination; Humans; Life Sciences; Medical prognosis; Mice; Mutation; Pancreas; Pancreatic cancer; Pancreatic ductal adenocarcinoma; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - therapy; Phosphorylation; Radiation therapy; Radiation-Sensitizing Agents - administration & dosage; Radiation-Sensitizing Agents - therapeutic use; Radiolysis; Radiosensitizers; Radiotherapy; Reactive oxygen species; Resveratrol; Resveratrol - administration & dosage; Resveratrol - therapeutic use; Toxicity; Tumor cells; Tumors; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2019.02.038

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers because it is highly resistant to every available therapeutic strategy, in particular conventional chemotherapy or radiotherapy (RT). Sensitizing tumor cells to existing treatments remains a good option to obtain fast and applicable results. Considering that ionizing radiations induce radiolysis-derived reactive oxygen species (ROS), we hypothesized that ROS-inducing bioactive food components (BFCs) could exacerbate ROS-related cell damages, including DNA double stranded breaks (DSBs), leaving the cellular ROS scavenging systems overwhelmed, and precipitating tumor cell death. Combination of resveratrol and capsaicin radiosensitized radiosensitive tumor cells, but RT did not increase BFC combination toxicity in radioresistant tumor cells. BFC addition to RT increased ROS production and led to significant tumor volume reduction in xenografted mouse preclinical model. Strikingly, BFCs inhibited RT-induced DNA damage molecular response by strongly limiting the first steps of DSB repair, and by keeping cells in cell cycle, provoking exacerbated intrinsic apoptosis. This study positions BFCs as potent radiosensitizers when combined, and identifies an actionable molecular pathway by resveratrol and capsaicin combination. •Resveratrol and capsaicin used in combination increase radiosensitivity of pancreatic tumor cells.•Combined Bioactive Food Components (BFCs) addition to radiotherapy increases radio-induced reactive oxygen species.•BFCs combination with radiotherapy was more potent to limit tumor progression than radiotherapy alone.•Resveratrol and capsaicin strongly inhibit DNA double stranded break repair induced by radiotherapy.•BFCs might be an option as nutrition complements to radiosensitize pancreatic adenocarcinoma.