Discovery of Mitochondrial Complex I Inhibitors as Anticancer and Radiosensitizer Drugs Based on Compensatory Stimulation of Lactate Release.

ABSTRACT: Cancer cells may stimulate glycolytic flux when O₂ becomes insufficient. Increase in L-lactate release therefore appears as an escape mechanism to drugs targeting mitochondrial respiration but also represents a response that may be exploited to screen for compounds blocking either mitochondrial carriers of oxidizable substrates or the electron transport chain. Here, we developed a screening procedure based on the capacity of cancer cells to release L-lactate to gain insights on the development of mitochondrial complex I inhibitors. For this purpose, we synthesized derivatives of carboxyamidotriazole, a compound previously described as a potential OXPHOS inhibitor. Two series of derivatives were generated by cycloaddition between benzylazide and either cyanoacetamides or alkynes.

SUBMITTER: Lan J 

PROVIDER: S-EPMC9658316 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature