Itraconazole increases resolvin e3 concentration and 12/15-lipoxygenase inhibitor attenuates itraconazole cytotoxicity in cervical cancer cells

Abstract

Background/Aim: The anticancer mechanism of itraconazole remains unsolved; therefore, we studied itraconazole-induced alterations in specialized pro-resolving mediators (SPMs) in cancer cells.Materials and Methods: The human cervical squamous carcinoma cell line CaSki was cultured with or without 1 μM itraconazole.Liquid chromatography/mass spectrometry analysis was conducted to identify SPMs that were influenced by itraconazole.Cell growth experiments were conducted using itraconazole and inhibitors targeting the metabolic pathways of candidate SPMs.Results: Resolvin E3, resolvin E2, prostaglandin J2 (PGJ2), delta-12-PGJ2, and maresin 2 were identified as candidate SPMs.The 12/15-lipoxygenase inhibitor, which is involved in the conversion of 18-hydroxy-eicosapentaenoic acid to resolvin E3, attenuated the inhibitory effect of itraconazole.Inhibition of the PGJ2 metabolic pathway did not interfere with itraconazole treatment.Conclusion: The metabolic pathway of SPMs, including resolving E3, could be proposed as an anticancer target of itraconazole.Itraconazole, an antifungal agent, has shown anticancer activities in clinical and preclinical studies.The reversal effect of itraconazole on chemoresistance via inhibition of P-gp of cancer cells was reported in 1999 (1).Since 2008, itraconazole has been used in experimental studies to treat cancer patients in combination with chemotherapy.Patients.