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; M H Tomasson; A Pandiella; JF San Miguel; M Garayoa; K N Weilbaecher

doi:10.1038/leu.2012.183

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

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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, …

Leukemia, Vol.27(2), pp.430-440

02/2013

DOI: 10.1038/leu.2012.183

PMCID: PMC3771507

PMID: 22763387

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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, carfilzomib, 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 number 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 oprozomib 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, carfilzomib and oprozomib effectively shift the bone microenvironment from a catabolic to an anabolic state and, similar to bortezomib, may decrease skeletal complications of MM.

proteasome inhibitors

multiple myeloma

osteoblast

osteoclast

bone lesions

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Title: Subtitle: The epoxyketone-based proteasome inhibitors carfilzomib and orally bioavailable oprozomib have anti-resorptive and bone-anabolic activity in addition to anti-myeloma effects
Creators: M A Hurchla - Department of Medicine, Division of Oncology, Washington University School of Medicine, St Louis, MO, USA
A Garcia-Gomez - Centro de Investigación del Cáncer, IBMCC (Universidad de Salamanca-CSIC), Salamanca, Spain
M C Hornick - Department of Medicine, Division of Oncology, Washington University School of Medicine, St Louis, MO, USA
E M Ocio - Centro de Investigación del Cáncer, IBMCC (Universidad de Salamanca-CSIC), Salamanca, Spain
A Li - Department of Medicine, Division of Oncology, Washington University School of Medicine, St Louis, MO, USA
J F Blanco - Hospital Universitario de Salamanca-IBSAL, Salamanca, Spain
L Collins - Washington University in St. Louis School of Medicine
C J Kirk - ONYX Pharmaceuticals, South San Francisco, CA, USA
D Piwnica-Worms - BRIGHT Institute and Molecular Imaging Center, Mallinkrodt Institute of Radiology, Washington University School of Medicine, St Louis, MO, USA
R Vij - Department of Medicine, Division of Oncology, Washington University School of Medicine, St Louis, MO, USA
M H Tomasson - Department of Medicine, Division of Oncology, Washington University School of Medicine, St Louis, MO, USA
A Pandiella - Centro de Investigación del Cáncer, IBMCC (Universidad de Salamanca-CSIC), Salamanca, Spain
JF San Miguel - Centro de Investigación del Cáncer, IBMCC (Universidad de Salamanca-CSIC), Salamanca, Spain
M Garayoa - Centro de Investigación del Cáncer, IBMCC (Universidad de Salamanca-CSIC), Salamanca, Spain
K N Weilbaecher - Department of Medicine, Division of Oncology, Washington University School of Medicine, St Louis, MO, USA
Resource Type: Journal article
Publication Details: Leukemia, Vol.27(2), pp.430-440
DOI: 10.1038/leu.2012.183
PMID: 22763387
PMCID: PMC3771507
ISSN: 0887-6924
eISSN: 1476-5551
Grant note: R01 CA097250 || CA / National Cancer Institute : NCI P01 CA100730 || CA / National Cancer Institute : NCI
Language: English
Date published: 02/2013
Academic Unit: Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
Record Identifier: 9984094216902771

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