NPI-0052 enhances tumoricidal response to conventional cancer therapy in a colon cancer model.
OBJECTIVE
In the current study, we examine the effects of a novel proteasome inhibitor, NPI-0052 (salinosporamide A), on proteasome function and nuclear factor-kappaB activation and evaluate its ability to enhance treatment response in colon cancer xenografts when administered orally.


METHODS
The effects of treatment on nuclear factor-kappaB activation, cell cycle regulation, and apoptosis were determined. The pharmacodynamic effect of NPI-0052 on 20S proteasome function was assayed in vivo following oral and i.v. drug administration and compared with treatment with bortezomib. The effect of combined treatment with chemotherapy was determined in a colon cancer xenograft model.


RESULTS
We found that NPI-0052 is a potent, well-tolerated proteasome inhibitor that has pharmacodynamic properties distinct from bortezomib in that it achieves significantly higher and more sustained levels of proteasome inhibition. When combined with chemotherapy, NPI-0052 increases apoptosis and shifts cells toward G2 cell cycle arrest. When added to chemotherapy in vivo [using combinations of 5-fluorouracil (5-FU), CPT-11, Avastin (bevacizumab), leucovorin, and oxaliplatin], NPI-0052 significantly improved the tumoricidal response and resulted in a 1.8-fold increased response to CPT-11, 5-FU, and leucovorin triple-drug combination (P=0.0002, t test), a 1.5-fold increased response to the oxaliplatin, 5-FU, and leucovorin triple-drug combination (P=0.013, t test), and a 2.3-fold greater response to the CPT-11, 5-FU, leucovorin, and Avastin regimen (P=0.00057).


CONCLUSIONS
The high level of proteasome inhibition achieved by NPI-0052 is well tolerated and significantly improves the tumoricidal response to multidrug treatment in a colon cancer xenograft model. Further evaluation of this novel proteasome inhibitor in clinical trials is indicated.
Cusack
James C
JC
Division of Surgical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston 02114, USA. jcusack@partners.org
Liu
Rong
R
Xia
Lijun
L
Chao
Ta-Hsiang
TH
Pien
Christine
C
Niu
Wei
W
Palombella
Vito J
VJ
Neuteboom
Saskia T C
ST
Palladino
Michael A
MA
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D002453:Cell Cycle / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D004333:Drug Administration Routes; D004357:Drug Synergism; D005260:Female; D006801:Humans; D007783:Lactones / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects; D011719:Pyrazines / Q000494:pharmacology; D011758:Pyrroles / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D001897:Boronic Acids; D007783:Lactones; D016328:NF-kappa B; D011719:Pyrazines; D011758:Pyrroles; D014409:Tumor Necrosis Factor-alpha; D000069286:Bortezomib; C475865:marizomib; D046988:Proteasome Endopeptidase Complex