title: Cisplatin in combination with Phenethyl Isothiocyanate (PEITC), a potential new therapeutic strategy for malignant pleural mesothelioma.
abstract: Malignant pleural mesothelioma (MPM) is a very aggressive form of cancer with a poor diagnosis and prognosis. The first line treatment for MPM is a combination of cisplatin and Pemetrexed, which displayed limited efficacy and severe side effects. The naturally occurring compound phenethyl isothiocyanate (PEITC) previously showed interesting anti-tumor properties on several cancer cell lines. We thus aim at evaluating PEITC used alone or in combination with cisplatin in order to improve MPM treatment. Nine MPM cell lines and primary mesothelial cells (PMC), co-cultured or not with M2 macrophages present in MPM microenvironment, were used to assess PEITC and cisplatin anti-tumor properties. Compounds were used alone or in combination. Both PEITC and cisplatin were cytotoxic on MPM cells in a dose dependent manner. We herein showed that PEITC-induced cytotoxicity was due to the generation of reactive oxygen species. Moreover, we showed that cisplatin-PEITC combination allowed the potentialization of both compounds' cytotoxic effects and prevented the emergence of resistant MPM cells. Interestingly, PMC were not sensitive to the combination. Finally, we showed that M2 macrophages did not alter the anti-tumor properties of the combination. Cisplatin-PEITC combination thus represents a promising strategy to induce a selective toxicity towards malignant cells.
authors.affiliation: Inserm, UMR892, Nantes, F-44000, France. CNRS, UMR6299, Nantes, F-44000, France. Université Nantes, Nantes, F-44000, France.
authors.forename: Iza
authors.initials: I
authors.lastname: Denis
authors.affiliation: Inserm, UMR892, Nantes, F-44000, France. CNRS, UMR6299, Nantes, F-44000, France. Université Nantes, Nantes, F-44000, France. Service d'Oncologie Médicale Thoracique et Digestive, Hôpital Laënnec, CHU de Nantes, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Cellerin
authors.affiliation: Inserm, UMR892, Nantes, F-44000, France. CNRS, UMR6299, Nantes, F-44000, France. Université Nantes, Nantes, F-44000, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Gregoire
authors.affiliation: Inserm, UMR892, Nantes, F-44000, France. CNRS, UMR6299, Nantes, F-44000, France. Université Nantes, Nantes, F-44000, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Blanquart
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017209:Apoptosis; D045744:Cell Line, Tumor / Q000187:drug effects; D002470:Cell Survival; D002945:Cisplatin / Q000737:chemistry*; D018920:Coculture Techniques; D004249:DNA Damage; D019008:Drug Resistance, Neoplasm; D006801:Humans; D006861:Hydrogen Peroxide / Q000737:chemistry; D020128:Inhibitory Concentration 50; D017879:Isothiocyanates / Q000737:chemistry*; D008264:Macrophages / Q000187:drug effects; D008654:Mesothelioma / Q000188:drug therapy / Q000378:metabolism*; D010766:Phosphorylation; D010997:Pleural Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D011379:Prognosis; D017382:Reactive Oxygen Species / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D017879:Isothiocyanates; D017382:Reactive Oxygen Species; C058305:phenethyl isothiocyanate; D006861:Hydrogen Peroxide; D002945:Cisplatin