title: The epoxyketone-based proteasome inhibitors carfilzomib and orally bioavailable oprozomib have anti-resorptive and bone-anabolic activity in addition to anti-myeloma effects.
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.
authors: Department of Medicine, Division of Oncology, Washington University School of Medicine, St Louis, MO, USA.
authors: M A
authors: MA
authors: Hurchla
authors: A
authors: A
authors: Garcia-Gomez
authors: M C
authors: MC
authors: Hornick
authors: E M
authors: EM
authors: Ocio
authors: A
authors: A
authors: Li
authors: J F
authors: JF
authors: Blanco
authors: L
authors: L
authors: Collins
authors: C J
authors: CJ
authors: Kirk
authors: D
authors: D
authors: Piwnica-Worms
authors: R
authors: R
authors: Vij
authors: M H
authors: MH
authors: Tomasson
authors: A
authors: A
authors: Pandiella
authors: J F
authors: JF
authors: San Miguel
authors: M
authors: M
authors: Garayoa
authors: K N
authors: KN
authors: Weilbaecher
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D015153:Blotting, Western; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001862:Bone Resorption / Q000188:drug therapy* / Q000209:etiology; D001897:Boronic Acids / Q000008:administration & dosage; D000069286:Bortezomib; D002113:Calcification, Physiologic / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004852:Epoxy Compounds / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000150:complications / Q000188:drug therapy*; D009842:Oligopeptides / Q000008:administration & dosage; D010006:Osteoblasts / Q000187:drug effects / Q000473:pathology; D010010:Osteoclasts / Q000187:drug effects / Q000473:pathology; D010012:Osteogenesis / Q000187:drug effects*; D061988:Proteasome Inhibitors / Q000627:therapeutic use*; D011719:Pyrazines / Q000008:administration & dosage; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment / Q000187:drug effects
chemical_list: D001897:Boronic Acids; D004852:Epoxy Compounds; D009842:Oligopeptides; D061988:Proteasome Inhibitors; D011719:Pyrazines; D012333:RNA, Messenger; D000069286:Bortezomib; C524865:carfilzomib