| Author |
Yang, H. Pellegrini, L. Napolitano, A. Giorgi, C. Jube, S. Preti, A. Jennings, C. J. De Marchis, F. Flores, E. G. Larson, D. Pagano, I. Tanji, M. Powers, A. Kanodia, S. Gaudino, G. Pastorino, S. Pass, H. I. Pinton, P. Bianchi, M. E. Carbone, M. |
| Description |
Country affiliation: United States Author Affiliation: Yang H ( University of Hawaii Cancer Center, University of Hawaii, Honolulu, HI 96813, USA.); Pellegrini L ( University of Hawaii Cancer Center, University of Hawaii, Honolulu, HI 96813, USA.); Napolitano A ( 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.); Giorgi C ( Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara 44121, Italy.); Jube S ( University of Hawaii Cancer Center, University of Hawaii, Honolulu, HI 96813, USA.); Preti A ( San Raffaele University and Scientific Institute, Milan 20132, Italy.); Jennings CJ ( University of Hawaii Cancer Center, University of Hawaii, Honolulu, HI 96813, USA.); De Marchis F ( San Raffaele University and Scientific Institute, Milan 20132, Italy.); Flores EG ( University of Hawaii Cancer Center, University of Hawaii, Honolulu, HI 96813, USA.); Larson D ( University of Hawaii Cancer Center, University of Hawaii, Honolulu, HI 96813, USA.); Pagano I ( University of Hawaii Cancer Center, University of Hawaii, Honolulu, HI 96813, USA.); Tanji M ( University of Hawaii Cancer Center, University of Hawaii, Honolulu, HI 96813, USA.); Powers A ( University of Hawaii Cancer Center, University of Hawaii, Honolulu, HI 96813, USA.); Kanodia S ( Samuel Oschin Comprehensive Cancer Institute and Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.); Gaudino G ( University of Hawaii Cancer Center, University of Hawaii, Honolulu, HI 96813, USA.); Pastorino S ( University of Hawaii Cancer Center, University of Hawaii, Honolulu, HI 96813, USA.); Pass HI ( Department of Cardiothoracic Surgery, New York Langone Medical Center, New York, NY 10016, USA.); Pinton P ( Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara 44121, Italy.); Bianchi ME ( San Raffaele University and Scientific Institute, Milan 20132, Italy.); Carbone M ( University of Hawaii Cancer Center, University of Hawaii, Honolulu, HI 96813, USA.) |
| 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. |
