title: Fingolimod potentiates the effects of sunitinib malate in a rat breast cancer model.
abstract: Most of the antiangiogenic strategies used in oncology principally target endothelial cells through the vascular endothelial growth factor (VEGF) pathway. Multiple kinase inhibitors can secondarily reduce mural cell stabilization of the vessels by blocking platelet-derived growth factor receptor (PDGFR) activity. However, sphingosine-1-phosphate (S1P), which is also implicated in mural cell recruitment, has yet to be targeted in clinical practice. We therefore investigated the potential of a simultaneous blockade of the PDGF and S1P pathways on the chemotactic responses of vascular smooth muscle cells (VSMCs) and the resulting effects of this blockade on breast tumor growth. Due to crosstalk between the S1P and PDGF pathways, we used AG1296 and/or VPC-23019 to inhibit PDGFR-β and S1PR1/S1PR3 receptors, respectively. We showed that S1PR1 and S1PR3 are the principal receptors that mediate the S1P chemotactic signal on rat VSMCs and that they act synergistically with PDGFR-β during PDGF-B signaling. We also showed that simultaneous blockade of the PDGFR-β and S1PR1/S1PR3 signals had a synergistic effect, decreasing VSMC migration velocity toward endothelial cell and breast carcinoma cell-secreted cytokines by 65-90%. This blockade also strongly decreased the ability of VSMCs to form a three-dimensional cell network. Similar results were obtained with the combination of sunitinib malate (a VEGFR/PDGFR kinase inhibitor) and fingolimod (an S1P analog). Sunitinib malate is a clinically approved cancer treatment, whereas fingolimod is currently indicated only for treatment of multiple sclerosis. Orally administered, the combination of these drugs greatly decreased rat breast tumor growth in a syngeneic cancer model (Walker 256). This bi-therapy did not exert cumulative toxicity and histological analysis of the tumors revealed normalization of the tumor vasculature. The simultaneous blockade of these signaling pathways with sunitinib malate and fingolimod may provide an effective means of reducing tumor angiogenesis, and may improve the delivery of other chemotherapies.
authors.affiliation: Department of Biochemistry and Molecular Genetics, School of Medicine, University of Limoges, Limoges, France.
authors.forename: Yoanne
authors.initials: Y
authors.lastname: Mousseau
authors.forename: Séverine
authors.initials: S
authors.lastname: Mollard
authors.forename: Karine
authors.initials: K
authors.lastname: Faucher-Durand
authors.forename: Laurence
authors.initials: L
authors.lastname: Richard
authors.forename: Angélique
authors.initials: A
authors.lastname: Nizou
authors.forename: Jeanne
authors.initials: J
authors.lastname: Cook-Moreau
authors.forename: Yasser
authors.initials: Y
authors.lastname: Baaj
authors.forename: Hao
authors.initials: H
authors.lastname: Qiu
authors.forename: Xavier
authors.initials: X
authors.lastname: Plainard
authors.forename: Laurent
authors.initials: L
authors.lastname: Fourcade
authors.forename: Benoit
authors.initials: B
authors.lastname: Funalot
authors.forename: Franck G
authors.initials: FG
authors.lastname: Sturtz
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D001013:Aorta, Thoracic / Q000473:pathology; D002279:Carcinoma 256, Walker / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D002465:Cell Movement; D002478:Cells, Cultured; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005260:Female; D000068876:Fingolimod Hydrochloride; D007211:Indoles / Q000008:administration & dosage; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D009368:Neoplasm Transplantation; D011409:Propylene Glycols / Q000008:administration & dosage; D020574:Proto-Oncogene Proteins c-sis / Q000494:pharmacology / Q000502:physiology; D011758:Pyrroles / Q000008:administration & dosage; D051381:Rats; D017207:Rats, Sprague-Dawley; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000378:metabolism / Q000502:physiology; D013110:Sphingosine / Q000008:administration & dosage / Q000031:analogs & derivatives; D000081025:Sphingosine-1-Phosphate Receptors; D018709:Statistics, Nonparametric; D000077210:Sunitinib; D047368:Tumor Burden / Q000187:drug effects; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: D007211:Indoles; D011409:Propylene Glycols; D020574:Proto-Oncogene Proteins c-sis; D011758:Pyrroles; D049349:Receptors, Lysosphingolipid; C578617:S1PR3 protein, rat; D000081025:Sphingosine-1-Phosphate Receptors; D020032:Tyrphostins; C106250:6,7-dimethoxy-3-phenylquinoxaline; D020797:Receptor, Platelet-Derived Growth Factor beta; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine; D000077210:Sunitinib