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Inhibition of Mitochondrial Complex II by the Anticancer Agent Lonidamine
Lili Guo1, Alexander A Shestov2, Andrew J Worth1
1From the Penn Superfund Research and Training Program Center, Center of Excellence in Environmental Toxicology, and Department of Systems Pharmacology and Translational Therapeutics and.
Abstract:
The antitumor agent lonidamine (LND; 1-(2,4-dichlorobenzyl)-1H-indazole-3-carboxylic acid) is known to interfere with energy-yielding processes in cancer cells. However, the effect of LND on central energy metabolism has never been fully characterized. In this study, we report that a significant amount of succinate is accumulated in LND-treated cells. LND inhibits the formation of fumarate and malate and suppresses succinate-induced respiration of isolated mitochondria. Utilizing biochemical assays, we determined that LND inhibits the succinate-ubiquinone reductase activity of respiratory complex II without fully blocking succinate dehydrogenase activity. LND also induces cellular reactive oxygen species through complex II, which reduced the viability of the DB-1 melanoma cell line. The ability of LND to promote cell death was potentiated by its suppression of the pentose phosphate pathway, which resulted in inhibition of NADPH and glutathione generation. Using stable isotope tracers in combination with isotopologue analysis, we showed that LND increased glutaminolysis but decreased reductive carboxylation of glutamine-derived α-ketoglutarate. Our findings on the previously uncharacterized effects of LND may provide potential combinational therapeutic approaches for targeting cancer metabolism.
Insights
Lonidamine (LND) disrupts cancer cell energy by accumulating succinate and inhibiting respiratory complex II. This antitumor agent also generates reactive oxygen species and impairs the pentose phosphate pathway, leading to cancer cell death.
Area of Science:
- Biochemistry
- Cancer Metabolism
- Cellular Respiration
Background:
- Lonidamine (LND) is an antitumor agent known to affect cancer cell energy production.
- Its precise impact on central energy metabolism remains incompletely understood.
Purpose of the Study:
- To fully characterize the effects of lonidamine on central energy metabolism in cancer cells.
- To investigate the mechanisms underlying LND-induced cancer cell death.
Main Methods:
- Biochemical assays to assess enzyme activity and metabolite levels.
- Mitochondrial respiration studies.
- Stable isotope tracing and isotopologue analysis.
- Cell viability assays.
Main Results:
- LND treatment led to significant succinate accumulation in cancer cells.
- LND inhibited respiratory complex II (succinate-ubiquinone reductase) activity and suppressed succinate-induced mitochondrial respiration.
- LND induced reactive oxygen species production and reduced cell viability.
- LND suppressed the pentose phosphate pathway, decreasing NADPH and glutathione levels.
- LND increased glutaminolysis while decreasing reductive carboxylation of glutamine-derived α-ketoglutarate.
Conclusions:
- Lonidamine uniquely affects cancer cell energy metabolism by targeting complex II and altering glutamine metabolism.
- LND's ability to induce oxidative stress and deplete protective metabolites contributes to its antitumor effects.
- These findings suggest potential therapeutic strategies combining LND with other metabolic inhibitors.
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