The Mitochondrial Disruptor Devimistat (CPI-613) Synergizes with Genotoxic Anticancer Drugs in Colorectal Cancer Therapy in a Bim-Dependent Manner

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.

Bioenergetic alteration in gastrointestinal cancers: The good, the bad and the ugly

“…Various agents have been tested for their anti-cancer efficacy, including AGI-5195, AG-221, AG-881, and CPI-613[ 286 ]. Among these compounds, CPI-613 is the only PDH and alpha-ketoglutarate dehydrogenase complex (KGDHC) dual targeting agent that has shown promising anti-cancer properties in GI cancer models both in vitro and in vivo [ 287 - 291 ]. The tolerability and safety of CPI-613, alone or in combination with other agents, has been evaluated or is currently being studied in patients with HCC, CCA, and CRC (NCT01766219, NCT05070104 and NCT02232152).…”

p53 triggers mitochondrial apoptosis following DNA damage-dependent replication stress by the hepatotoxin methyleugenol

“…Cell death induction was measured using Annexin V/PI staining and flow cytometry as described earlier [57]. Following treatment, attached and detached cells were harvested and washed with PBS.…”

Targeting cellular metabolism in head and neck cancer precision medicine era: A promising strategy to overcome therapy resistance

“…Indoximod (Hou et al, 2007; Metz et al, 2012), Epacadostat (Koblish et al, 2010; Liu et al, 2010) and Pf‐06840003 (Crosignani et al, 2017) are small molecule compound in the stage of clinical research. In addition, by blocking the enzyme activity of pyruvate dehydrogenase and α‐ketoglutarate dehydrogenase, CPI‐613 inhibits the tricarboxylic acid cycle (Arnold et al, 2022; Reddy et al, 2022). α‐ketoglutarate dehydrogenase, which upregulates GLS1 and ultimately promotes the compensatory role of glutaminolysis in cancer cell survival.…”