Induction of hemangiosarcoma in mice after chronic treatment with S1P-modulator siponimod and its lack of relevance to rat and human

• DOI: 10.1007/s00204-018-2189-9
• Publication Date: 2018-03-19T10:40:32Z
• Authors: Francois Pognan; J. Andreas Mahl; Maria Papoutsi; David Ledieu; Marc Raccuglia; Diethilde Theil; Sarah B. Voytek; Patrick J. Devine; Katie Kubek-Luck; Natalie Claudio; Andre Cordier; Annabelle Heier; Carine Kolly; Andreas Hartmann; Salah-Dine Chibout; Page Bouchard; Christian Trendel...
• Keywords: Male; 0301 basic medicine; 0303 health sciences; Hemangiosarcoma; Administration, Oral; Endothelial Cells; Mice, Inbred Strains; Genotoxicity and Carcinogenicity; Toxicokinetics; 12. Responsible consumption; 3. Good health; Rats, Sprague-Dawley; Receptors, Lysosphingolipid; 03 medical and health sciences; Species Specificity; Benzyl Compounds; Animals; Azetidines; Humans; Endothelium, Vascular; Rats, Wistar; Toxicity Tests, Chronic; Transcriptome; Cells, Cultured; Placenta Growth Factor

A high incidence of hemangiosarcoma (HSA) was observed in mice treated for 2 years with siponimod, a sphingosine-1-phosphate receptor 1 (S1P1) functional antagonist, while no such tumors were rats under the same treatment conditions. In 3-month rat (90 mg/kg/day) and 9-month mouse (25 75 vivo mechanistic studies, vascular endothelial cell (VEC) activation both species, but VEC proliferation persistent increases circulating placental growth factor (PLGF2) only seen mouse. mice, these effects sustained over study duration, increased mitotic gene expression present at day 3 PLGF2 induced during first week treatment. mouse, activation, mitosis induction, stimulation likely led to neo-angiogenesis which life-long may result HSA formation. rats, despite transient stimuli did not formation HSA. vitro, primary cultures mirrored their respective findings release. Human VECs, like cells, unresponsive siponimod proliferative response release all tested concentrations. Hence, it is suggested that human cells also reproduce lack siponimod. conclusion, molecular mechanisms leading siponimod-induced are considered species specific irrelevant humans.