CPI-613 is a lipoate derivative that inhibits pyruvate dehydrogenase and α-ketoglutarate dehydrogenase (Anderson et al. 2018). These enzymes in the Krebs cycle allow for carbons from either glucose or glutamine to enter cellular respiration, thereby preventing oxidative phosphorylation. CPI-613 activates pyruvate dehydrogenase kinase, which phosphorylates and inactivates pyruvate dehydrogenase. CPI-613 activates a redox process through a burst of reactive oxygen species that blocks α-ketoglutarate dehydrogenase’s activity (Stuart et al. 2014). A maximum tolerated dose of 500 mg/m2 of CPI-613 in combination with the chemotherapy FOLFIRINOX approximately doubled the response rate of patients with metastatic pancreatic adenocarcinoma and showed promising effects for median survival rates (Alistar et al. 2017). The researchers imagine similar effects to be possible in combination with phenformin. By eliminating mitochondrial OXPHOS in PaCSCs, these cells will have no energy to survive and will undergo apoptosis. Since these PaCSCs are the main drivers of metastasis, eradicating them also exterminates their EMT, metastatic niche, chemoresistant, and plastic functions, resulting in an overall greater prognosis for the patient.
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