title: Inflammasome Modulation by Chemotherapeutics in Malignant Mesothelioma.
abstract: Malignant mesothelioma (MM) is a fatal disease in dire need of therapy. The role of inflammasomes in cancer is not very well studied, however, literature supports both pro-and anti-tumorigenic effects of inflammasomes on cancer depending upon the type of cancer. Asbestos is a causative agent for MM and we have shown before that it causes inflammasome priming and activation in mesothelial cells. MM tumor cells/tissues showed decreased levels of inflammasome components like NLRP3 and caspase-1 as compared to human mesothelial cells or normal tissue counterpart of tumor. Based on our preliminary findings we hypothesized that treatment of MMs with chemotherapeutic drugs may elevate the levels of NLRP3 and caspase-1 resulting in increased cell death by pyroptosis while increasing the levels of IL-1β and other pro-inflammatory molecules. Therefore, a combined strategy of chemotherapeutic drug and IL-1R antagonist may play a beneficial role in MM therapy. To test our hypothesis we used two human MM tumor cell lines (Hmeso, H2373) and two chemotherapeutic drugs (doxorubicin, cisplatin). Through a series of experiments we showed that both chemotherapeutic drugs caused increases in NLRP3 levels, caspase-1 activation, pyroptosis and pro-inflammatory molecules released from MM cells. In vivo studies using SCID mice and Hmeso cells showed that tumors were smaller in combined treatment group of cisplatin and IL-1R antagonist (Anakinra) as compared to cisplatin alone or untreated control groups. Taken together our study suggests that chemotherapeutic drugs in combination with IL-1R antagonist may have a beneficial role in MM treatment.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Burlington, VT, United States of America.
authors.forename: Catherine
authors.initials: C
authors.lastname: Westbom
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Burlington, VT, United States of America.
authors.forename: Joyce K
authors.initials: JK
authors.lastname: Thompson
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Burlington, VT, United States of America.
authors.forename: Alan
authors.initials: A
authors.lastname: Leggett
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Burlington, VT, United States of America.
authors.forename: Maximilian
authors.initials: M
authors.lastname: MacPherson
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Burlington, VT, United States of America.
authors.forename: Stacie
authors.initials: S
authors.lastname: Beuschel
authors.affiliation: Department of Cardiothoracic Surgery, New York University School of Medicine, New York, New York, United States of America.
authors.forename: Harvey
authors.initials: H
authors.lastname: Pass
authors.affiliation: Department of Medical Biostatistics, University of Vermont College of Medicine, Burlington, VT, United States of America.
authors.forename: Pamela
authors.initials: P
authors.lastname: Vacek
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Burlington, VT, United States of America.
authors.forename: Arti
authors.initials: A
authors.lastname: Shukla
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D020170:Caspase 1 / Q000378:metabolism; D045744:Cell Line, Tumor / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D025461:Feedback, Physiological / Q000187:drug effects; D006801:Humans; D058847:Inflammasomes / Q000187:drug effects* / Q000378:metabolism; D053590:Interleukin 1 Receptor Antagonist Protein / Q000008:administration & dosage / Q000494:pharmacology; D020382:Interleukin-18 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008654:Mesothelioma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000086002:Mesothelioma, Malignant; D016513:Mice, SCID; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D002352:Carrier Proteins; C000589760:IL18 protein, human; D058847:Inflammasomes; D053590:Interleukin 1 Receptor Antagonist Protein; D020382:Interleukin-18; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D017472:Receptors, Interleukin-1; D004317:Doxorubicin; D020170:Caspase 1; D002945:Cisplatin