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Osteolysis and pain due to experimental bone metastases are improved by treatment with rapamycin

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Abstract

In advanced breast cancer, bone metastases occur in 70 % of patients. Managing the devastating pain associated with the disease is difficult. Rapamycin is an immunomodulatory drug that targets the mammalian target of rapamycin pathway. Rapamycin has been shown to decrease osteolysis associated with metastatic breast cancer in pre-clinical models and to reduce pain in inflammatory and neuropathic models. The aim of this study was to evaluate the effectiveness of rapamycin in reducing pain associated with experimental osteolytic metastases. Bone cancer was induced by intra-tibial injections of murine mammary carcinoma cells (4T1) in immunocompetent BALB/c mice and treated intraperitoneally for up to 5 weeks with vehicle, rapamycin or pamidronate (a bisphosphonate currently used to reduce bone loss in bone cancer patients). The control group received intra-tibial injection with saline (sham) and was treated with vehicle intraperitoneally. Cancer-induced osteolysis was observed histologically and radiographically 2–3 weeks following cancer inoculation and gradually increased with time. Measures of evoked nociceptive behaviors including sensitivity to mechanical, thermal, and cold stimuli and spontaneous nociceptive behaviors (limping, guarding) were evaluated. Significant hypersensitivity to sensory stimuli developed in cancer-bearing mice compared to sham 3 weeks following inoculation. Rapamycin decreased or delayed the development of cancer-induced mechanical, heat, and cold hypersensitivity, while pamidronate reduced heat and cold hypersensitivity. Both rapamycin and pamidronate had a partial protective effect on the spontaneous nociceptive behaviors, limping and guarding. Our data suggest that rapamycin may have efficacy in the management of pain associated with metastatic breast cancer.

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Acknowledgments

We thank Dr. Peter Siegel for providing the 4T1 cells, Drs. Magali Millecamps and Osama Hussein for teaching and supporting the pilot experiment, Drs. Monzur Murshed and Frank Rauch for advice on histomorphometric analysis and McGill University undergraduate students Anita Ramachandran, Jingwen Chen, Katia Fox, and Robert Samberg for helping with experiments. This study was supported by the Cancer Research Society/Quebec Breast Cancer Foundation grant to LSS and SVK. DMA is supported by the Ministry of Higher Education, Egypt. SVK holds Canada Research Chair in Osteoclast Biology.

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Authors and Affiliations

  1. Faculty of Dentistry, McGill University, Montreal, QC, Canada

    Dareen M. Abdelaziz, Laura S. Stone & Svetlana V. Komarova

  2. Alan Edwards Centre for Research on Pain, Montreal, QC, Canada

    Dareen M. Abdelaziz & Laura S. Stone

  3. Department of Anesthesiology, Faculty of Medicine, McGill University, Montreal, QC, Canada

    Laura S. Stone

  4. Department of Pharmacology & Therapeutics, Faculty of Medicine, McGill University, Montreal, QC, Canada

    Laura S. Stone

  5. Department of Neurology & Neurosurgery, Faculty of Medicine, McGill University, Montreal, QC, Canada

    Laura S. Stone

  6. Shriners Hospital for Children-Canada, 1529 Cedar Avenue, Room 300, Montreal, QC, H3G IA6, Canada

    Svetlana V. Komarova

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  1. Dareen M. Abdelaziz
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  2. Laura S. Stone
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Correspondence to Svetlana V. Komarova.

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Abdelaziz, D.M., Stone, L.S. & Komarova, S.V. Osteolysis and pain due to experimental bone metastases are improved by treatment with rapamycin. Breast Cancer Res Treat 143, 227–237 (2014). https://doi.org/10.1007/s10549-013-2799-0

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  • DOI: https://doi.org/10.1007/s10549-013-2799-0

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