Mechanism of the Anti-Cancer Drug Lonidamine

Cover for Journal of Biological Chemistry
1 January, 2016
Volume 291, Issue 1

View the cover and the story 
on JBC website

JBC-Lili

One of the projects for Lili’s postdoc research is the mechanisms of anti-cancer drugs, especially those targeting cancer cell metabolism. Cancer cell metabolism is very different from normal cell metabolism. These special metabolisms are normally featured with high demand of nutrients in order to provide energy to support the rapid growth and proliferation of cancer cells. Therefore, cancer cell metabolic pathways can be potentially targeted for anti-cancer treatment. The recent research on preclinical and clinical research has further shed light on its future clinical application. Lonidamine (1-(2,4-dichlorobenzyl)-1H-indazole-3-carboxylic acid) is an anti-cancer drug known for its ability to inhibit cancer cell metabolism. It has been used in many clinical trials and can effectively improve the efficacy of other anti-cancer agents. However, the mechanism by which that Lonidamine induces cancer cell death was unclear. For this project, I discovered that Lonidamine targets respiratory complex II, an essential enzyme complex in mitochondria where the biochemical process of respiration and energy production occur. I further defined the exact targeting site of Lonidamine on complex II. The inhibition of complex II by Lonidamine markedly altered several essential metabolic pathways in cancer cells. It also led to production of large amount of reactive oxygen species (ROS) through complex II. The high levels of ROS induced by Lonidamine are toxic to cancer cells, which significantly contributes to its cancer-cell killing activity.

The cover image shows the antitumor agent lonidamine (yellow) inhibits the succinate-ubiquinone reductase activity of complex II (orange) on the mitochondria membrane. . Lonidamine induces ROS generation through complex II and alters glutamine metabolism. The blue and green molecules are mitochondrial complex I and III.



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