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Updated: Nov 3, 2025
Author Spotlight: Transmitochondrial Cybrid Generation Using Cancer Cell Lines
Published on: March 17, 2023
Targeting Mitochondrial Oncometabolites: A New Approach to Overcome Drug Resistance in Cancer
Martina Godel1, Giacomo Ortone1, Dario Pasquale Anobile1
1Department of Oncology, University of Torino, via Santena 5/bis, 10126 Torino, Italy.
Abstract:
Drug resistance is the main obstacle for a successful cancer therapy. There are many mechanisms by which cancers avoid drug-mediated death, including alterations in cellular metabolism and apoptotic programs. Mitochondria represent the cell's powerhouse and the connection between carbohydrate, lipid and proteins metabolism, as well as crucial controllers of apoptosis, playing an important role not only in tumor growth and progression, but also in drug response. Alterations in tricarboxylic acid cycle (TCA) caused by mutations in three TCA enzymes-isocitrate dehydrogenase, succinate dehydrogenase and fumarate hydratase-lead to the accumulation of 2-hydroxyglutarate, succinate and fumarate respectively, collectively known as oncometabolites. Oncometabolites have pleiotropic effects on cancer biology. For instance, they generate a pseudohypoxic phenotype and induce epigenetic changes, two factors that may promote cancer drug resistance leading to disease progression and poor therapy outcome. This review sums up the most recent findings about the role of TCA-derived oncometabolites in cancer aggressiveness and drug resistance, highlighting possible pharmacological strategies targeting oncometabolites production in order to improve the efficacy of cancer treatment.
Insights
Cancer drug resistance is a major hurdle. Mutations in tricarboxylic acid cycle (TCA) enzymes cause oncometabolite buildup, promoting resistance and poor outcomes.
Area of Science:
- Biochemistry
- Cancer Biology
- Metabolic Oncology
Background:
- Drug resistance remains a significant challenge in cancer therapy.
- Mitochondria are central to cellular metabolism and apoptosis, influencing tumor progression and drug response.
- Alterations in cancer cell metabolism and apoptotic pathways contribute to therapeutic failure.
Purpose of the Study:
- To review recent findings on the role of tricarboxylic acid cycle (TCA)-derived oncometabolites in cancer.
- To explore how these oncometabolites influence cancer aggressiveness and drug resistance.
- To highlight potential therapeutic strategies targeting oncometabolite production.
Main Methods:
- Literature review of recent scientific findings.
- Analysis of the biochemical pathways involving TCA enzymes and oncometabolites.
- Synthesis of information on the biological effects of oncometabolites in cancer.
Main Results:
- Mutations in TCA enzymes lead to the accumulation of oncometabolites (2-hydroxyglutarate, succinate, fumarate).
- Oncometabolites induce a pseudohypoxic state and epigenetic modifications.
- These effects contribute to cancer drug resistance, disease progression, and reduced treatment efficacy.
Conclusions:
- TCA-derived oncometabolites play a critical role in cancer aggressiveness and drug resistance.
- Targeting oncometabolite production presents a promising avenue for improving cancer therapy efficacy.
- Further research into these metabolic pathways could lead to novel anti-cancer strategies.
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