Inhibition of Calcitonin Gene-Related Peptide and Insulin-Like Growth Factor: A Potential New Therapeutic Strategy To Reduce Bone Pain in Bone Metastases of Breast Cancer.

Abstract Bone pain caused by bone metastases is one of the most common complications in patients with breast cancer. However, the precise molecular mechanism of bone pain is unknown. We have shown that the acid released upon bone resorption by osteoclasts and the transient receptor potential vanilloid receptor (TRPV1), an acid-sensing receptor on the algetic nerves terminating at the bone, are involved in the mechanism underlying this bone pain. In this study, we investigated the relationships among TRPV1, bone-derived insulin-like growth factor-1 (IGF-1) which is released from bone due to increased bone resorption during the progression of bone metastases, and neuropeptide calcitonin gene-related peptide (CGRP) and examined whether cancer-induced bone pain can be decreased by the inhibition of IGF-1 and CGRP. To study this in vitro, we established organ cultures of mouse dorsal root ganglions (DRGs), which are the primary sensory neurons innervating bone. Culture supernatants harvested from the mouse neonatal calvariae, which had abundant growth factor in bone, showed elevated TRPV1 and CGRP mRNA expressions in mouse DRGs. These up-regulated mRNA expressions were inhibited by the administration of a TRPV1 inhibitor (I-RTX); AG1024, a specific inhibitor of IGF receptor tyrosine kinase; or zoledronate. Taken together, these results suggest that CGRP and bone-derived IGF-1 may play a role in the induction of bone pain. To approach the role of CGRP and bone-derived IGF-1 in vivo, we established a mouse model of cancer-induced bone pain by inoculating the 4T1 mouse breast cancer cells into the marrow cavity of tibiae. Tumor-inoculated tibiae showed significantly increased pain behaviors compared with the non-tumor-bearing tibiae, indicating 4T1 cells induced bone pain. RT-PCR showed elevated mRNA expression of TRPV1 and CGRP in the ipsi-lateral tumor-bearing DRGs. The administration of a CGRP inhibitor (CGRP 8-37) in a continuous manner using an ALZET osmotic pump implanted under the mouse skin; the intraperitoneal administration of AG1024; and the administration of alendronate significantly reduced pain behaviors in tumor-bearing tibiae. In addition, mRNA expression of CGRP was decreased by CGRP 8-37, and mRNA expression of TRVP1 and CGRP was also decreased by AG1024 in the ipsi-lateral DRGs. Neither of these drugs showed a direct effect on the growth of the tumor in this study. In conclusion, our results suggest that TRPV1, CGRP, and the bone-derived IGF-1 are strongly related and might play a role in breast cancer-induced bone pain. The inhibition of the CGRP and bone-derived IGF-1 could be a potential therapeutic strategy to reduce bone pain; although further investigations are required in this direction. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1110.