Disease modification of breast cancer-induced bone remodeling by cannabinoid 2 receptor agonists.

Abstract

Most commonly originating from breast malignancies, metastatic bone cancer causes bone destruction and severe pain. Although novel chemotherapeutic agents have increased life expectancy, patients are experiencing higher incidences of fracture, pain, and drug-induced side effects; furthermore, recent findings suggest that patients are severely undertreated for their cancer pain. Strong analgesics, namely opiates, are first-line therapy in alleviating cancer-related pain despite the severe side effects, including enhanced bone destruction with sustained administration. Bone resorption is primarily treated with bisphosphonates, which are associated with highly undesirable side effects, including nephrotoxicity and osteonecrosis of the jaw. In contrast, cannabinoid receptor 2 (CB(2) ) receptor-specific agonists have been shown to reduce bone loss and stimulate bone formation in a model of osteoporosis. CB(2) agonists produce analgesia in both inflammatory and neuropathic pain models. Notably, mixed CB(1) /CB(2) agonists also demonstrate a reduction in ErbB2-driven breast cancer progression. Here we demonstrate for the first time that CB(2) agonists reduce breast cancer-induced bone pain, bone loss, and breast cancer proliferation via cytokine/chemokine suppression. Studies used the spontaneously-occurring murine mammary cell line (66.1) implanted into the femur intramedullary space; measurements of spontaneous pain, bone loss, and cancer proliferation were made. The systemic administration of a CB(2) agonist, JWH015, for 7 days significantly attenuated bone remodeling, assuaged spontaneous pain, and decreased primary tumor burden. CB(2) -mediated effects in vivo were reversed by concurrent treatment with a CB(2) antagonist/inverse agonist but not with a CB(1) antagonist/inverse agonist. In vitro, JWH015 reduced cancer cell proliferation and inflammatory mediators that have been shown to promote pain, bone loss, and proliferation. Taken together, these results suggest CB(2) agonists as a novel treatment for breast cancer-induced bone pain, in which disease modifications include a reduction in bone loss, suppression of cancer growth, attenuation of severe bone pain, and increased survival without the major side effects of current therapeutic options.

• Authors: Alysia N Lozano-Ondoua, Katherine E Hanlon, Ashley M Symons-Liguori, Tally M Largent-Milnes, Josh J Havelin, Henry L Ferland 3rd, Anupama Chandramouli, Mabel Owusu-Ankomah, Tijana Nikolich-Zugich, Aaron P Bloom, Juan Miguel Jimenez-Andrade, Tamara King, Frank Porreca, Mark A Nelson, Patrick W Mantyh, Todd W Vanderah
• Journal: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research (J Bone Miner Res) Vol. 28 Issue 1 Pg. 92-107 (Jan 2013) ISSN: 1523-4681 [Electronic] United States
• PMID: 22903605 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 American Society for Bone and Mineral Research.

Chemical References

• AM 1241
• Cannabinoid Receptor Agonists
• Cannabinoids
• Indoles
• Receptor, Cannabinoid, CB2
• JHW 015

Topics

• Animals
• Body Weight (drug effects)
• Bone Remodeling (drug effects)
• Bone Resorption (drug therapy, etiology, pathology, physiopathology)
• Cannabinoid Receptor Agonists (administration & dosage, pharmacology, therapeutic use)
• Cannabinoids (administration & dosage, pharmacology, therapeutic use)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Enzyme-Linked Immunosorbent Assay
• Female
• Femur (diagnostic imaging, drug effects, pathology, physiopathology)
• Fractures, Bone (drug therapy, etiology, pathology, physiopathology)
• Indoles (administration & dosage, pharmacology, therapeutic use)
• Mammary Neoplasms, Animal (complications, pathology, physiopathology)
• Mice
• Mice, Inbred BALB C
• Pain (drug therapy, etiology, physiopathology)
• Radiography
• Receptor, Cannabinoid, CB2 (agonists, metabolism)
• Survival Analysis