COX-2 inhibition reduces bone tumor growth in animal models: A role for celecoxib treatment in cAMP/protein kinase A-induced tumors.

Wednesday, October 10, 2012 — Poster Session II
Noon – 2:00 p.m	Natcher Conference Center, Building 45	NICHD	CLIN/TRANS-21

Authors

• E. Saloustros
• E. Mertz
• M. Nesterova
• M. Keil
• S.M De la Luz
• N Kiran
• A Horvath
• S Leikin
• C Stratakis

Abstract

Background: Carney Complex is a multiple neoplasia syndrome characterized by skin lesions and endocrine and other tumors. Mice with deletion of one prkar1a allele develop various CNC-like tumors and multiple tail lesions. Further deletion of a prkaca allele increases the number and severity of bone lesions. PKA activity is stimulated by inflammasome activation both in mouse and human cells. The released prostaglandin E2 (PGE2) further increases cAMP and activates PKA and Wnt signaling. These data led us to investigate COX-2 inhibiton in prkar1α+/-/prkacα+/- mice. Methods: Mice were exposed to celecoxib-containing diet (1,500 mg/kg) and standard NIH-31 diet for six weeks. Sixteen and seven days before sacrifice, mice were injected with calcein which labels bone forming surfaces. Results: Celecoxib reduced the rate of tumor growth by two-fold through apoptosis enhancement and proliferation decrease. Treatment reduced PKA enzymatic activity while the expression of all inflammasome-related genes (ets-1, caspase-1, il1b and cox2) was down-regulated by at least 70% in the bone tumors from treated animals. Conclusion: COX-2 inhibition reduces bone tumor growth in prkar1α+/-/prkacα+/- mice. Since local tumor control is clinically meaningful for patients with cAMP-induced tumors, celecoxib may merit consideration as the first molecularly targeted therapy in this setting.

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