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Molecular and cellular mechanisms underlying the failure of mitochondrial metabolism drugs in cancer clinical trials
Karthik Vasan, Navdeep S. Chandel
Karthik Vasan, Navdeep S. Chandel
Published February 1, 2024
Citation Information: J Clin Invest. 2024;134(3):e176736. https://doi.org/10.1172/JCI176736.
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Molecular and cellular mechanisms underlying the failure of mitochondrial metabolism drugs in cancer clinical trials

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Abstract

Authors

Karthik Vasan, Navdeep S. Chandel

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Figure 1

Drugs that target the mitochondrial electron transport chain in cancer cells have antineoplastic properties.

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Drugs that target the mitochondrial electron transport chain in cancer c...
Mitochondrial electron transport chain (ETC) is necessary to sustain metabolites required for cancer cell growth. Metformin’s primary anticancer mechanism involves the inhibition of mitochondrial ETC complex I. The drug’s safety and efficacy are associated with organic cation transporters (OCTs), which have varying presence across regular tissues and cancers. Metformin relies on OCTs for cell entry, and variability in OCT expression levels along with the ability of cancer cells to metabolically adjust to the tumor microenvironment might account for inconsistent results in clinical trials. New drugs on the horizon targeting the ETC include the antimalaria drug atovaquone, an inhibitor of mitochondrial complex III, and ONC201, an activator of mitochondrial protease caseinolytic protease P (CLPP) that degrades ETC proteins. The molecular determinants that would make these drugs effective and their specific therapeutic window need to be addressed.

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