Osteoporosis 1-4

The epoxyketone-based proteasome inhibitors carfilzomib and orally bioavailable oprozomib have anti-resorptive and bone-anabolic activity in addition to anti-myeloma effects

M. A. Hurchla, A. Garcia-Gomez, M. C. Hornick, E. M. Ocio, A. Li, J. F. Blanco, L. Collins, C. J. Kirk, D. Piwnica-Worms, R. Vij, et al.

Leukemia. 2013 Feb;27(2):430-440.

Abstract: Proteasome inhibitors (Pis), namely bortezomib, have become a cornerstone therapy for multiple myeloma (MM), potently reducing tumor burden and inhibiting pathologic bone destruction. In clinical trials, carfilzonnib, a next generation epoxyketone-based irreversible PI, has exhibited potent anti-myeloma efficacy and decreased side effects compared with bortezomib. Carfilzomib and its orally bioavailable analog oprozomib, effectively decreased MM cell viability following continual or transient treatment mimicking in vivo pharmacokinetics. Interactions between myeloma cells and the bone marrow (BM) microenvironment augment the nunnber and activity of bone-resorbing osteoclasts (OCs) while inhibiting bone-forming osteoblasts (OBs), resulting in increased tumor growth and osteolytic lesions. At clinically relevant concentrations, carfilzomib and oprozomib directly inhibited OC formation and bone resorption in vitro, while enhancing osteogenic differentiation and matrix mineralization. Accordingly, carfilzomib and oprozonnib increased trabecular bone volume, decreased bone resorption and enhanced bone formation in non-tumor bearing mice. Finally, in mouse models of disseminated MM, the epoxyketone-based PIs decreased murine 5TGM1 and human RPMI-8226 tumor burden and prevented bone loss. These data demonstrate that, in addition to anti-myeloma properties, carfilzonnib and oprozomib effectively shift the bone microenvironment from a catabolic to an anabolic state and, similar to bortezomib, may decrease skeletal complications of MM. Leukemia (2013) 27, 430-440; doi:10.1038/leu.2012.183

*Times cited: 2

Keywords: proteasome inhibitors, multiple myeloma, osteoblast, osteoclast, bone, lesions, unfolded protein response, multiple-myeloma, osteoblast differentiation, in-vivo, irreversible inhibitor, osteoclast function, murine model, tgf-beta, bortezomib, cells

Link: http://www.ncbi.nlm.nih.gov/pubmed/22763387

Multiselect Ultimate Query Plugin by InoPlugs Web Design Vienna | Webdesign Wien and Juwelier SchönmannMultiselect Ultimate Query Plugin by InoPlugs Web Design Vienna | Webdesign Wien and Juwelier Schönmann