Oxaliplatin induces prostaglandin E2 release in vascular endothelial cells

PurposeOxaliplatin (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.MethodsCultured normal human umbilical cord vein endothelial cells (HUVECs) were treated with L-OHP or L-OHP+NSAID flurbiprofen for 2h and analyzed for the release of PGE(2) and 15d-PGJ(2) into culture supernatant by ELISA.ResultsThe 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(1 alpha), PGF(2 alpha), 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.ConclusionsThis 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.