The mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) plays an important and hitherto unknown role in blocking a form of cell death called ferroptosis, according to a new study published today in Nature by researchers at the University of Texas MD Anderson Cancer Center. Preclinical findings suggest that targeting DHODH can restore ferroptosis-induced cell death, indicating novel therapeutic strategies that can be used to induce ferroptosis and inhibit tumor growth.
“By understanding ferroptosis and how cells defend themselves against it, we can develop therapeutic strategies to block these defense mechanisms and trigger cell death,” said lead author Boyi Gan, Ph.D., associate professor at experimental radiation oncology. “We have discovered that DHODH plays a key role in the defense against ferroptosis and shown that we can exploit this vulnerability with clinically tested therapies.”
Ferroptosis is a recently identified form of controlled cell death triggered by the toxic accumulation of lipid peroxides in the cell. Because lipid peroxides are generated by normal metabolic activities, cells also have mechanisms in place to defend themselves against ferroptosis. Glutathione peroxidase 4 (GPX4) is one of the main defense mechanisms identified to date.
In this study, the researchers used inhibitors of GPX4 to block its activity and identify new defense mechanisms. Metabolic analyzes directed them to DHODH, a mitochondrial enzyme that is normally involved in the pyrimidine biosynthetic pathway.
In cells with low expression of GPX4, loss of DHODH activity led to accumulation of lipid peroxides in mitochondria and activation of ferroptosis. In contrast, cells with high GPX4 expression were able to continue to block ferroptosis activity in the absence of DHODH. The results suggest that DHODH and GPX4 function as redundant defense mechanisms in the mitochondria to prevent ferroptosis.
The researchers further clarified the role of DHODH in the regulation of ferroptosis and then investigated the therapeutic potential of targeting this enzyme in cancer cells. Using extended preclinical models, they evaluated the DHODH inhibitor brequinar, which has been tested in several clinical trials for other indications.
In cancers with low GPX4, brequinar effectively induced ferroptosis and suppressed tumor growth, but the effects were not seen in cancers with high GPX4 content. However, the combination of brequinar and sulfasalazine, an FDA approved inducer of ferroptosis, resulted in a synergistic effect in overcoming the high expression of GPX4 and in blocking tumor growth.
“We were able to leverage our understanding of a novel defense mechanism for ferroptosis in a novel therapeutic strategy that shows promise in preclinical studies,” said Gan. “Because ferroptosis is active in all types of cancer, we believe it could have broad implications, particularly in cancers with low GPX4 expression.”
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