Arizona Health Sciences

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

TitleDisease modification of breast cancer-induced bone remodeling by cannabinoid 2 receptor agonists.
Publication TypeJournal Article
Year of Publication2013
AuthorsLozano-Ondoua AN, Hanlon KE, Symons-Liguori AM, Largent-Milnes TM, Havelin JJ, Ferland HL, Chandramouli A, Owusu-Ankomah M, Nikolich-Zugich T, Bloom AP, Jimenez-Andrade JMiguel, King T, Porreca F, Nelson MA, Mantyh PW, Vanderah TW
JournalJ Bone Miner Res
Volume28
Issue1
Pagination92-107
Date Published2013 Jan
ISSN1523-4681
KeywordsAnimals, Body Weight, Bone Remodeling, Bone Resorption, Cannabinoid Receptor Agonists, Cannabinoids, Cell Line, Tumor, Cell Proliferation, Enzyme-Linked Immunosorbent Assay, Female, Femur, Fractures, Bone, Indoles, Mammary Neoplasms, Animal, Mice, Mice, Inbred BALB C, Pain, Receptor, Cannabinoid, CB2, Survival Analysis
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.

DOI10.1002/jbmr.1732
Alternate JournalJ. Bone Miner. Res.
PubMed ID22903605
Grant ListR01 CA142115 / CA / NCI NIH HHS / United States
R01 CA142115-01 / CA / NCI NIH HHS / United States
Faculty Member Reference: 
Patrick W Mantyh
Tally Largent-Milnes, Ph.D.
Frank Porreca, PhD
Todd Vanderah, PhD