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Disease modification of breast cancer–induced bone remodeling by cannabinoid 2 receptor agonists
Author(s) -
LozanoOndoua Alysia N,
Hanlon Katherine E,
SymonsLiguori Ashley M,
LargentMilnes Tally M,
Havelin Josh J,
Ferland Henry L,
Chandramouli Anupama,
OwusuAnkomah Mabel,
NikolichZugich Tijana,
Bloom Aaron P,
JimenezAndrade Juan Miguel,
King Tamara,
Porreca Frank,
Nelson Mark A,
Mantyh Patrick W,
Vanderah Todd W
Publication year - 2013
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1002/jbmr.1732
Subject(s) - medicine , breast cancer , bone pain , bone resorption , bone metastasis , osteoporosis , bone disease , bone remodeling , cancer , bisphosphonate , agonist , endocrinology , pharmacology , receptor
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. © 2013 American Society for Bone and Mineral Research