TY - JOUR
T1 - Disease modifying actions of interleukin-6 blockade in a rat model of bone cancer pain
AU - Remeniuk, Bethany
AU - King, Tamara
AU - Sukhtankar, Devki
AU - Nippert, Amy
AU - Li, Nancy
AU - Li, Fuying
AU - Cheng, Kejun
AU - Rice, Kenner C.
AU - Porreca, Frank
N1 - Funding Information:
This work was funded by NCI T32CA009213 (B.R.) and NIH R01 DA034975 (F.P.), and support from the University of Arizona Cancer Center grant NCI P30 CA023074. The micro-CT was performed and analyzed by Lucy Liaw, PhD and Terry Henderson at the Microcomputed Tomography Services at Maine Medical Center Research Institute. This core is supported by the Maine INBRE funded by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health. The H&E images were performed by Peter Caradona within the COBRE Histology and Imaging core at the University of New England that is supported by the National Institute of General Medical Sciences (NIGMS) (P20GM103643). Osteoblast images were analyzed by Naomi Goshima at the University of Arizona. A portion of this work was supported by the NIH Intramural Research Programs of the National Institute on Drug Abuse (NIDA) and the National Institute of Alcohol Abuse and Alcoholism (NIAAA) (K.C.R.).
Publisher Copyright:
© 2017 International Association for the Study of Pain.
PY - 2018/4/1
Y1 - 2018/4/1
N2 - Metastasis of cancer to the skeleton represents a debilitating turning point in the lives of patients. Skeletal metastasis leads to moderate to severe ongoing pain along with bone remodeling that can result in fracture, events that dramatically diminish quality of life. Interleukin-6 (IL-6) levels are elevated in patients with metastatic breast cancer and are associated with a lower survival rate. We therefore determined the consequences of inhibition of IL-6 signaling using a novel small molecule antagonist, TB-2-081, on bone integrity, tumor progression, and pain in a rodent model of breast cancer. Rat MAT B III mammary adenocarcinoma cells were injected and sealed within the tibia of female Fischer rats. Growth of these cells within the rat tibia elicited increased IL-6 levels both within the bone exudate and in the plasma, produced ongoing pain and evoked hypersensitivity, and bone fracture that was observed by approximately day 12. Systemic TB-2-081 delivered by subcutaneous osmotic minipumps starting at tumor implantation prevented tumor-induced ongoing bone pain and evoked hypersensitivity without altering tumor growth. Remarkably, TB-2-081 infusion significantly reduced osteolytic and osteoblastic bone remodeling and time to fracture likely by decreasing osteoclastogenesis and associated increase in bone resorption. These findings indicate that blockade of IL-6 signaling may represent a viable, disease-modifying strategy to prevent tumor-induced bone remodeling allowing for stabilization of bone and decreased fractures as well as diminished ongoing pain that may improve quality of life of patients with skeletal metastases. Notably, anti-IL-6 antibodies are clinically available allowing for rapid testing of these possibilities in humans.
AB - Metastasis of cancer to the skeleton represents a debilitating turning point in the lives of patients. Skeletal metastasis leads to moderate to severe ongoing pain along with bone remodeling that can result in fracture, events that dramatically diminish quality of life. Interleukin-6 (IL-6) levels are elevated in patients with metastatic breast cancer and are associated with a lower survival rate. We therefore determined the consequences of inhibition of IL-6 signaling using a novel small molecule antagonist, TB-2-081, on bone integrity, tumor progression, and pain in a rodent model of breast cancer. Rat MAT B III mammary adenocarcinoma cells were injected and sealed within the tibia of female Fischer rats. Growth of these cells within the rat tibia elicited increased IL-6 levels both within the bone exudate and in the plasma, produced ongoing pain and evoked hypersensitivity, and bone fracture that was observed by approximately day 12. Systemic TB-2-081 delivered by subcutaneous osmotic minipumps starting at tumor implantation prevented tumor-induced ongoing bone pain and evoked hypersensitivity without altering tumor growth. Remarkably, TB-2-081 infusion significantly reduced osteolytic and osteoblastic bone remodeling and time to fracture likely by decreasing osteoclastogenesis and associated increase in bone resorption. These findings indicate that blockade of IL-6 signaling may represent a viable, disease-modifying strategy to prevent tumor-induced bone remodeling allowing for stabilization of bone and decreased fractures as well as diminished ongoing pain that may improve quality of life of patients with skeletal metastases. Notably, anti-IL-6 antibodies are clinically available allowing for rapid testing of these possibilities in humans.
KW - Bone remodeling
KW - Cancer pain
KW - Cancer-induced bone pain
KW - IL-6
KW - IL-6 antagonist
UR - http://www.scopus.com/inward/record.url?scp=85053891374&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85053891374&partnerID=8YFLogxK
U2 - 10.1097/j.pain.0000000000001139
DO - 10.1097/j.pain.0000000000001139
M3 - Article
C2 - 29300279
AN - SCOPUS:85053891374
VL - 159
SP - 684
EP - 698
JO - Pain
JF - Pain
SN - 0304-3959
IS - 4
ER -