Oxaliplatin induces prostaglandin E2 release in vascular endothelial cells

• Published in: Cancer chemotherapy and pharmacology 2019-08, Vol.84 (2), p.345-350
• Main Authors: Matsunuma, Satoru, Handa, Satoko, Kamei, Daisuke, Yamamoto, Hitomi, Okuyama, Kiyoshi, Kato, Yasuhisa
• Format: Article
• Language: English
• Subjects: Anti-inflammatory agents; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Arachidonic acid; Cancer Research; Cell culture; Cell Culture Techniques; Cisplatin; Cyclooxygenase-1; Dinoprostone - metabolism; Endothelial cells; Endothelial Cells - drug effects; Enzyme-linked immunosorbent assay; Flurbiprofen; Humans; Inflammation; Intravenous administration; Medicine; Medicine & Public Health; Metabolism; Nonsteroidal anti-inflammatory drugs; Oncology; Original Article; Oxaliplatin; Oxaliplatin - pharmacology; Oxaliplatin - therapeutic use; Pain; Pain perception; Pharmacology/Toxicology; Platinum; Prostaglandin E2; Secretion; Umbilical cord
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-019-03901-7

Purpose Oxaliplatin (L-OHP) is known to induce adverse reactions at the injection site, including vascular pain, but the underlying mechanisms have not been clarified. Vascular pain during intravenous L-OHP administration can be inhibited by taking non-steroidal anti-inflammatory drugs (NSAIDs). In this study, we investigated the involvement of the arachidonic acid cascade and prostaglandin (PG) E 2 and 15d-PGJ 2 in vascular pain sensation during intravenous delivery of L-OHP. Methods Cultured normal human umbilical cord vein endothelial cells (HUVECs) were treated with L-OHP or L-OHP + NSAID flurbiprofen for 2 h and analyzed for the release of PGE 2 and 15d-PGJ 2 into culture supernatant by ELISA. Results The results showed that L-OHP significantly and dose-dependently increased PGE 2 secretion by HUVECs; however, flurbiprofen effectively prevented PGE 2 increase. On the other hand, cisplatin, another platinum anticancer drug, did not stimulate PGE 2 production. Other PGs, including 15d-PGJ 2 , 6-keto PGF 1α , PGF 2α , and PGD 2 were not increased by L-OHP or cisplatin. Protein expression analysis revealed that cyclooxygenase 1 and cytoplasmic PGE synthase involved in constitutive PG metabolism were expressed in HUVECs but not affected by L-OHP exposure. Conclusions This study indicates that L-OHP treatment specifically upregulated PGE 2 secretion by vascular endothelial cells, which may contribute to vascular pain, and that NSAIDs can be used to inhibit PGE 2 release and attenuate L-OHP-induced hyperalgesia.