title: Aspirin delays mesothelioma growth by inhibiting HMGB1-mediated tumor progression.
abstract: High-mobility group box 1 (HMGB1) is an inflammatory molecule that has a critical role in the initiation and progression of malignant mesothelioma (MM). Aspirin (acetylsalicylic acid, ASA) is the most widely used nonsteroidal anti-inflammatory drug that reduces the incidence, metastatic potential and mortality of many inflammation-induced cancers. We hypothesized that ASA may exert anticancer properties in MM by abrogating the carcinogenic effects of HMGB1. Using HMGB1-secreting and -non-secreting human MM cell lines, we determined whether aspirin inhibited the hallmarks of HMGB1-induced MM cell growth in vitro and in vivo. Our data demonstrated that ASA and its metabolite, salicylic acid (SA), inhibit motility, migration, invasion and anchorage-independent colony formation of MM cells via a novel HMGB1-mediated mechanism. ASA/SA, at serum concentrations comparable to those achieved in humans taking therapeutic doses of aspirin, and BoxA, a specific inhibitor of HMGB1, markedly reduced MM growth in xenograft mice and significantly improved survival of treated animals. The effects of ASA and BoxA were cyclooxygenase-2 independent and were not additive, consistent with both acting via inhibition of HMGB1 activity. Our findings provide a rationale for the well documented, yet poorly understood antitumorigenic activity of aspirin, which we show proceeds via HMGB1 inhibition. Moreover, the use of BoxA appears to allow a more efficient HMGB1 targeting while eluding the known gastrointestinal side effects of ASA. Our findings are directly relevant to MM. Given the emerging importance of HMGB1 and its tumor-promoting functions in many cancer types, and of aspirin in cancer prevention and therapy, our investigation is poised to provide broadly applicable information.
authors.affiliation: University of Hawaii Cancer Center, University of Hawaii, Honolulu, HI 96813, USA.
authors.forename: H
authors.initials: H
authors.lastname: Yang
authors.affiliation: University of Hawaii Cancer Center, University of Hawaii, Honolulu, HI 96813, USA.
authors.forename: L
authors.initials: L
authors.lastname: Pellegrini
authors.affiliation: 1] University of Hawaii Cancer Center, University of Hawaii, Honolulu, HI 96813, USA [2] Department of Molecular Biosciences and Bioengineering, University of Hawaii, Honolulu, HI 96813, USA.
authors.forename: A
authors.initials: A
authors.lastname: Napolitano
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara 44121, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Giorgi
authors.affiliation: University of Hawaii Cancer Center, University of Hawaii, Honolulu, HI 96813, USA.
authors.forename: S
authors.initials: S
authors.lastname: Jube
authors.affiliation: San Raffaele University and Scientific Institute, Milan 20132, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Preti
authors.affiliation: University of Hawaii Cancer Center, University of Hawaii, Honolulu, HI 96813, USA.
authors.forename: C J
authors.initials: CJ
authors.lastname: Jennings
authors.affiliation: San Raffaele University and Scientific Institute, Milan 20132, Italy.
authors.forename: F
authors.initials: F
authors.lastname: De Marchis
authors.affiliation: University of Hawaii Cancer Center, University of Hawaii, Honolulu, HI 96813, USA.
authors.forename: E G
authors.initials: EG
authors.lastname: Flores
authors.affiliation: University of Hawaii Cancer Center, University of Hawaii, Honolulu, HI 96813, USA.
authors.forename: D
authors.initials: D
authors.lastname: Larson
authors.affiliation: University of Hawaii Cancer Center, University of Hawaii, Honolulu, HI 96813, USA.
authors.forename: I
authors.identifier: 0000000262480113
authors.initials: I
authors.lastname: Pagano
authors.affiliation: University of Hawaii Cancer Center, University of Hawaii, Honolulu, HI 96813, USA.
authors.forename: M
authors.initials: M
authors.lastname: Tanji
authors.affiliation: University of Hawaii Cancer Center, University of Hawaii, Honolulu, HI 96813, USA.
authors.forename: A
authors.initials: A
authors.lastname: Powers
authors.affiliation: Samuel Oschin Comprehensive Cancer Institute and Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: S
authors.initials: S
authors.lastname: Kanodia
authors.affiliation: University of Hawaii Cancer Center, University of Hawaii, Honolulu, HI 96813, USA.
authors.forename: G
authors.initials: G
authors.lastname: Gaudino
authors.affiliation: University of Hawaii Cancer Center, University of Hawaii, Honolulu, HI 96813, USA.
authors.forename: S
authors.initials: S
authors.lastname: Pastorino
authors.affiliation: Department of Cardiothoracic Surgery, New York Langone Medical Center, New York, NY 10016, USA.
authors.forename: H I
authors.initials: HI
authors.lastname: Pass
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara 44121, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Pinton
authors.affiliation: San Raffaele University and Scientific Institute, Milan 20132, Italy.
authors.forename: M E
authors.initials: ME
authors.lastname: Bianchi
authors.affiliation: University of Hawaii Cancer Center, University of Hawaii, Honolulu, HI 96813, USA.
authors.forename: M
authors.initials: M
authors.lastname: Carbone
mesh_terms: D016475:3T3 Cells; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001241:Aspirin / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005260:Female; D024243:HMGB1 Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D008654:Mesothelioma / Q000188:drug therapy* / Q000378:metabolism; D000086002:Mesothelioma, Malignant; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D009361:Neoplasm Invasiveness / Q000473:pathology; D020156:Salicylic Acid / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D020156:Salicylic Acid; D001241:Aspirin