NPI-0052 Enhances Tumoricidal Response to Conventional Cancer Therapy in a Colon Cancer Model
| Autor: | Ta-Hsiang Chao, Lijun Xia, Saskia T. C. Neuteboom, Vito J. Palombella, James C. Cusack, Wei Niu, Michael A. Palladino, Rong Liu, Christine S. Pien |
|---|---|
| Rok vydání: | 2006 |
| Předmět: |
Proteasome Endopeptidase Complex
Cancer Research Bevacizumab Colorectal cancer medicine.medical_treatment Mice Nude Antineoplastic Agents Apoptosis Adenocarcinoma Pharmacology Bortezomib Lactones Mice chemistry.chemical_compound In vivo Antineoplastic Combined Chemotherapy Protocols Tumor Cells Cultured medicine Animals Humans Pyrroles Chemotherapy Tumor Necrosis Factor-alpha business.industry Drug Administration Routes Cell Cycle NF-kappa B Drug Synergism medicine.disease Boronic Acids Xenograft Model Antitumor Assays digestive system diseases Oxaliplatin Oncology chemistry Pyrazines Colonic Neoplasms Immunology Proteasome inhibitor Female business Salinosporamide A medicine.drug |
| Zdroj: | Clinical Cancer Research. 12:6758-6764 |
| ISSN: | 1557-3265 1078-0432 |
| Popis: | Purpose: In the current study, we examine the effects of a novel proteasome inhibitor, NPI-0052 (salinosporamide A), on proteasome function and nuclear factor-κB activation and evaluate its ability to enhance treatment response in colon cancer xenografts when administered orally. Experimental Design: The effects of treatment on nuclear factor-κB 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|