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

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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.

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Acknowledgments

We thank Marc Pignot producing the glass templates used in the agarose assay. This research project was supported by Fondation pour la Recherche Médicale (Comité Limousin).

Conflict of interest

The authors declare that they do not have financial relationships with any of the organizations that sponsored the research, and they do not have any other real or apparent conflict(s) of interest that may have a direct bearing on the subject matter of the article.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Genetics, School of Medicine, University of Limoges, Limoges, France

    Yoanne Mousseau, Séverine Mollard, Karine Faucher-Durand, Laurence Richard, Angélique Nizou, Jeanne Cook-Moreau, Yasser Baaj, Hao Qiu, Xavier Plainard, Laurent Fourcade, Benoit Funalot & Franck G. Sturtz

  2. Laboratory of Biochemistry, School of Medicine, University of Limoges, 2, Rue du Dr. Raymond Marcland, 87025, Limoges, France

    Franck G. Sturtz

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  1. Yoanne Mousseau
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  2. Séverine Mollard
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Correspondence to Franck G. Sturtz.

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Mousseau, Y., Mollard, S., Faucher-Durand, K. et al. Fingolimod potentiates the effects of sunitinib malate in a rat breast cancer model. Breast Cancer Res Treat 134, 31–40 (2012). https://doi.org/10.1007/s10549-011-1903-6

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  • DOI: https://doi.org/10.1007/s10549-011-1903-6

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