Fingolimod potentiates the effects of sunitinib malate in a rat breast cancer model

• Published in: Breast cancer research and treatment Vol. 134; no. 1; pp. 31 - 40
• Main Authors: Mousseau, Yoanne, Mollard, Séverine, Faucher-Durand, Karine, Richard, Laurence, Nizou, Angélique, Cook-Moreau, Jeanne, Baaj, Yasser, Qiu, Hao, Plainard, Xavier, Fourcade, Laurent, Funalot, Benoit, Sturtz, Franck G.
• Format: Journal Article
• Language: English
• Published: Boston Springer US 01-07-2012; Springer; Springer Nature B.V; Springer Verlag
• Subjects: Angiogenesis; Angiogenesis inhibitors; Animals; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Aorta, Thoracic - pathology; Biochemistry, Molecular Biology; Biological and medical sciences; Breast cancer; Cancer; Cancer research; Cancer therapies; Carcinoma 256, Walker - blood supply; Carcinoma 256, Walker - drug therapy; Carcinoma 256, Walker - pathology; Cell Movement; Cells, Cultured; Chemotherapy; Drug Screening Assays, Antitumor; Drug Synergism; Drug therapy; Female; Fingolimod Hydrochloride; Genetics; Genomics; Gynecology. Andrology. Obstetrics; Human genetics; Indoles - administration & dosage; Life Sciences; Male; Mammary gland diseases; Mammary Neoplasms, Experimental - blood supply; Mammary Neoplasms, Experimental - drug therapy; Mammary Neoplasms, Experimental - pathology; Medical sciences; Medicine; Medicine & Public Health; Molecular biology; Myocytes, Smooth Muscle - drug effects; Myocytes, Smooth Muscle - metabolism; Myocytes, Smooth Muscle - physiology; Neoplasm Transplantation; Neurobiology; Neurons and Cognition; Oncology; Phosphates; Platelet-derived growth factor; Preclinical Study; Propylene Glycols - administration & dosage; Proto-Oncogene Proteins c-sis - pharmacology; Proto-Oncogene Proteins c-sis - physiology; Pyrroles - administration & dosage; Rats; Rats, Sprague-Dawley; Receptor, Platelet-Derived Growth Factor beta - antagonists & inhibitors; Receptor, Platelet-Derived Growth Factor beta - metabolism; Receptors, Lysosphingolipid - metabolism; Receptors, Lysosphingolipid - physiology; Rodents; Sphingosine; Sphingosine - administration & dosage; Sphingosine - analogs & derivatives; Statistics, Nonparametric; Tumor Burden - drug effects; Tumors; Tyrphostins - pharmacology; Vascular endothelial growth factor; Sunitinib malate; Angiogenesis; VSMC; Fingolimod; Chemotaxis; Breast tumor; Antineoplastic agent; Animal model; Breast disease; Rat; Sunitinib; Neovascularization; Antiangiogenic agent; Protein-tyrosine kinase; Enzyme; Tyrosine kinase inhibitor; Transferases; Rodentia; Enzyme inhibitor; Breast cancer; Malignant tumor; Mammary gland diseases; Vertebrata; Mammalia; Multikinase inhibitor; Cancer
• ISSN: 0167-6806; 1573-7217
• DOI: 10.1007/s10549-011-1903-6

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.