The proteasome inhibitor CEP-18770 enhances the anti-myeloma activity of bortezomib and melphalan.
The anti-multiple myeloma (MM) efficacy of bortezomib has led to the development of other proteasome inhibitors (PI), including CEP-18770 which has shown anti-MM effects in preclinical studies. However, the efficacy of orally (PO) or intravenously (IV) administered CEP-18770 in multiple MM models and in combination with conventional anti-MM therapies has not been evaluated. Herein, we show that CEP-18770 combined with melphalan or bortezomib induces synergistic inhibition of MM cell viability in vitro. In MM xenograft models, the addition of CEP-18770 IV to melphalan completely prevented the growth of both melphalan-sensitive and melphalan-resistant tumours. The combination of CEP-18770 IV and bortezomib induced complete regression of bortezomib-sensitive tumours and markedly delayed progression of bortezomib-resistant tumours compared to treatment with either agent alone. Single agent CEP-18770 PO also showed marked anti-MM effects in these xenograft models. These studies provide strong preclinical rationale for further development of this novel PI in the treatment of MM as a monotherapy as well as combined with either melphalan or bortezomib.
Sanchez
Eric
E
Institute for Myeloma & Bone Cancer Research, 9201 W. Sunset Boulevard, West Hollywood, CA 90069, USA.
Li
Mingjie
M
Steinberg
Jeffrey A
JA
Wang
Cathy
C
Shen
Jing
J
Bonavida
Benjamin
B
Li
Zhi-Wei
ZW
Chen
Haiming
H
Berenson
James R
JR
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D000069286:Bortezomib; D016923:Cell Death / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004357:Drug Synergism; D008297:Male; D008558:Melphalan / Q000008:administration & dosage / Q000494:pharmacology; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000008:administration & dosage / Q000494:pharmacology; D013912:Threonine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D001897:Boronic Acids; D061988:Proteasome Inhibitors; D011719:Pyrazines; D013912:Threonine; D000069286:Bortezomib; C527966:delanzomib; D008558:Melphalan