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Development and Maintenance of a Preclinical Patient Derived Tumor Xenograft Model for the Investigation of Novel Anti-Cancer Therapies
Published on: September 30, 2016
The Mitochondrial Disruptor Devimistat (CPI-613) Synergizes with Genotoxic Anticancer Drugs in Colorectal Cancer
Carina Arnold1,2,3, Philipp Demuth1, Nina Seiwert1,2,3
1Division of Food Chemistry and Toxicology, Department of Chemistry, Technical University of Kaiserslautern, Kaiserslautern, Germany.
Abstract:
Colorectal cancer is one of the most frequent tumor entities, with an increasing incidence and mortality in younger adults in Europe and the United States. Five-year survival rates for advanced colorectal cancer are still low, highlighting the need for novel targets in colorectal cancer therapy. Here, we investigated the therapeutic potential of the compound devimistat (CPI-613) that targets altered mitochondrial cancer cell metabolism and its synergism with the antineoplastic drugs 5-fluorouracil (5-FU) and irinotecan (IT) in colorectal cancer. Devimistat exerted a comparable cytotoxicity in a panel of established colorectal cancer cell lines and patient-derived short-term cultures independent of their genetic and epigenetic status, whereas human colonic epithelial cells were more resistant, indicating tumor selectivity. These findings were corroborated in intestinal organoid and tumoroid models. Mechanistically, devimistat disrupted mitochondrial membrane potential and severely impaired mitochondrial respiration, resulting in colorectal cancer cell death induction independent of p53. Combination treatment of devimistat with 5-FU or IT demonstrated synergistic cell killing in colorectal cancer cells as shown by Combenefit modeling and Chou-Talalay analysis. Increased cell death induction was revealed as a major mechanism involving downregulation of antiapoptotic genes and accumulation of proapoptotic Bim, which was confirmed by its genetic knockdown. In human colorectal cancer xenograft mouse models, devimistat showed antitumor activity and synergized with IT, resulting in prolonged survival and enhanced therapeutic efficacy. In human tumor xenografts, devimistat prevented IT-triggered p53 stabilization and caused synergistic Bim induction. Taken together, our study revealed devimistat as a promising candidate in colorectal cancer therapy by synergizing with established antineoplastic drugs in vitro and in vivo.
Insights
Devimistat shows promise in colorectal cancer therapy by targeting cancer cell metabolism. It effectively synergizes with 5-fluorouracil and irinotecan, enhancing cell death and antitumor activity in preclinical models.
Area of Science:
- Oncology
- Cancer Metabolism
- Drug Discovery
Background:
- Colorectal cancer (CRC) incidence and mortality are rising, especially in younger adults.
- Advanced CRC has poor survival rates, necessitating new therapeutic targets.
- Altered mitochondrial metabolism is a hallmark of cancer cells.
Purpose of the Study:
- To investigate devimistat's therapeutic potential in colorectal cancer.
- To evaluate devimistat's synergism with 5-fluorouracil (5-FU) and irinotecan (IT).
- To explore devimistat's mechanism of action and tumor selectivity.
Main Methods:
- Cytotoxicity assays in CRC cell lines and patient-derived cultures.
- Organoid and tumoroid model assessments.
- Mitochondrial function, apoptosis, and gene expression analyses.
- In vivo studies using colorectal cancer xenograft mouse models.
Main Results:
- Devimistat exhibited tumor selectivity, with greater cytotoxicity in cancer cells than normal colon cells.
- Devimistat disrupted mitochondrial respiration and induced cell death independently of p53.
- Combination therapy with devimistat and 5-FU or IT showed synergistic cytotoxicity.
- Devimistat demonstrated antitumor activity in vivo and enhanced IT efficacy, prolonging survival.
Conclusions:
- Devimistat targets altered cancer cell metabolism, showing selective cytotoxicity against colorectal cancer.
- Devimistat synergizes with standard chemotherapeutics (5-FU, IT) to enhance cell death and therapeutic outcomes.
- Devimistat represents a promising therapeutic candidate for colorectal cancer, particularly in combination strategies.
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