Pognan, Francois, Mahl, Joerg Andreas, Papoutsi, Maria, Ledieu, David, Raccuglia, Marc, Theil, Diethilde, Voytek, Sarah, Devine, Pj, Cordier, Andre, Heier, Annabelle, Kolly, Carine, Hartmann, Andreas, Chibout, Salah-Dine and Trendelenburg, Christian (2018) Induction of hemangiosarcoma in mice after chronic treatment with S1P-modulator siponimod appears irrelevant to rat and human. Archives of toxicology. ISSN 1432-0738; 0340-5761

Abstract

A high incidence of hemangiosarcoma (HSA) was observed in mice treated for 2 years with Siponimod, a Sphingosine-1-phosphate Receptor 1 (S1P1) reverse agonist, while no such tumors were observed in rats under the same treatment conditions. In vivo mechanistic 9-month and 3-month mouse and rat studies respectively, showed vascular endothelial cell (VEC) activation in both species, but established marked differences in mitosis stimulation and in release of circulating placental growth factor 2 (PLGF2). In mice, these effects were sustained over the study duration, while in rats the mitotic expression was upregulated at day 3 only and PLGF2 was induced only during the first week of treatment. In the mouse, the persistent VEC activation, mitosis induction and PLGF2 stimulation likely led to sustained neo-angiogenesis which over life-long treatment may result in HSA formation. In rats, despite sustained VEC activation, the transient mitotic and PLGF2 stimuli did not result in the formation of HSA. In vitro, the mouse and rat endothelial primary cell cultures mirrored their respective in vivo behaviors for cell proliferation and PLGF2 release in vivo profile. Human VECs, like rat cells, were unresponsive to Siponimod treatment with no proliferative response and no release of PLGF2 at all tested concentrations. Hence it is suggested that the human cells also reproduce a lack of in vivo response to Siponimod. In conclusion, the new molecular mechanism described here leading to Siponimod-induced hemangiosarcoma in mice appears irrelevant to humans.

Item Type:	Article
Date Deposited:	16 May 2018 00:45
Last Modified:	16 May 2018 00:45
URI:	https://oak.novartis.com/id/eprint/34454