Abstract C187: Salicylates suppress tumor growth via inhibition of HMGB1.

Abstract

Abstract High-Mobility Group Box 1 (HMGB1) is a chromatin-associated protein critically involved in nucleosome assembly. During cell necrosis, HMGB1 is first translocated from the nucleus to the cytoplasm, and then passively released to the extracellular space, where it initiates and propagates the inflammatory response. Immune cells (e.g. macrophages) and cancer cells are also able to actively secrete HMGB1. Extracellular HMGB1 is therefore considered a crucial molecule for both chronic inflammation and cancer development, and a promising therapeutic target. In this study, using a malignant mesothelioma (MM) model, we tested the hypothesis that the known anti-cancer effects of aspirin (acetyl salicylic acid), the most widely used anti-inflammatory drug, and salicylic acid, its major metabolite, could be due to HMGB1 inhibition. In vitro, we analyzed the effects of salicylates on HMGB1-induced MM cell proliferation, wound healing, migration, invasion and anchorage-independent colony formation. Moreover, using a MM xenograft model, we tested whether in vivo suppression of HMGB1 signaling by salicylates or BoxA, a specific HMGB1 inhibitor, resulted in reduced MM growth and increased survival. Our results demonstrated that salicylates, at doses normally used in clinical practice (≤1 mM), significantly suppress HMGB1-induced in vitro pro-tumorigenic effects on MM cells and inhibits in vivo MM growth, significantly extending mice survival. Our findings are critically relevant to the understanding of the poorly known anti-cancer effects of salicylates. From this perspective, they apply to more than 50 million people in the USA alone currently taking aspirin. Finally, these preclinical results could be translated to improve the current treatment of the usually lethal MM, and of other HMGB1-related malignancies as well. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C187. Citation Format: Andrea Napolitano, Laura Pellegrini, Sandro Jube, Cormac J. Jennings, Erin G. Flores, David Larson, Vishal S. Negi, Ian Pagano, Mika Tanji, Amy Powers, Sandra Pastorino, Harvey I. Pass, Marco E. Bianchi, Michele Carbone, Haining Yang. Salicylates suppress tumor growth via inhibition of HMGB1. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C187.