DHODH and cancer: promising prospects to be explored

Zhou, Yue; Tao, Lei; Zhou, Xia; Zuo, Zeping; Gong, Jin; Liu, Xiaocong; Zhou, Yang; Liu, Chunqi; Sang, Na; Liu, Huan; Zou, Jiao; Gou, Kun; Yang, Xiaowei; Zhao, Yinglan

doi:10.1186/s40170-021-00250-z

Cited by 86 publications

(69 citation statements)

References 166 publications

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“…Pyrimidine participates in synthesizing not only nucleotides but also polysaccharides and phospholipids, which play an essential role in human metabolism. When cells become cancerous [ 23 ] or infected by pathogenic microorganisms [ 24 , 25 ], the overall metabolic activity and the demand for pyrimidines are increased compared with those in quiescent cells. Munger et al researched human cytomegalovirus (HCMV)-infected human fibroblasts using liquid chromatography–tandem mass spectrometry and identified 167 differentially abundant metabolites.…”

Section: The Pyrimidine Synthesis Pathway Is a Reliable Hta Targetmentioning

confidence: 99%

“…DHODH inhibitors (DHODHi) have been used to treat malignant tumors, autoimmune diseases, viral or bacterial infections, parasitic diseases, and other diseases [ 23 , 31 , 33 , 34 , 35 ]. DHODHi inhibit viral infection by three mechanisms: (1) inhibiting viral replication (pathway 1 in Figure 2 ), (2) promoting interferon-stimulated genes (ISGs) expression (pathway 2 in Figure 2 ), and (3) regulating inflammation (pathway 3 in Figure 2 ).…”

Section: The Essential Role Of Dhodh In the De Novo ...mentioning

confidence: 99%

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A Broad Antiviral Strategy: Inhibitors of Human DHODH Pave the Way for Host-Targeting Antivirals against Emerging and Re-Emerging Viruses

Song

et al. 2022

Viruses

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New strategies to rapidly develop broad-spectrum antiviral therapies are urgently required for emerging and re-emerging viruses. Host-targeting antivirals (HTAs) that target the universal host factors necessary for viral replication are the most promising approach, with broad-spectrum, foresighted function, and low resistance. We and others recently identified that host dihydroorotate dehydrogenase (DHODH) is one of the universal host factors essential for the replication of many acute-infectious viruses. DHODH is a rate-limiting enzyme catalyzing the fourth step in de novo pyrimidine synthesis. Therefore, it has also been developed as a therapeutic target for many diseases relying on cellular pyrimidine resources, such as cancers, autoimmune diseases, and viral or bacterial infections. Significantly, the successful use of DHODH inhibitors (DHODHi) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection further supports the application prospects. This review focuses on the advantages of HTAs and the antiviral effects of DHODHi with clinical applications. The multiple functions of DHODHi in inhibiting viral replication, stimulating ISGs expression, and suppressing cytokine storms make DHODHi a potent strategy against viral infection.

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Section: The Pyrimidine Synthesis Pathway Is a Reliable Hta Targetmentioning

confidence: 99%

Section: The Essential Role Of Dhodh In the De Novo ...mentioning

confidence: 99%

A Broad Antiviral Strategy: Inhibitors of Human DHODH Pave the Way for Host-Targeting Antivirals against Emerging and Re-Emerging Viruses

Song

et al. 2022

Viruses

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“…Glutamine plays a further role in promoting glutathione production and amino acid synthesis through glutamate cysteine ligase (GCL) and glutamic-oxaloacetic transaminase (GOT), respectively [ 98 , 99 ]. In cancer cells, CAD converts glutamate to dihydroorotate [ 100 ], which can be converted to orotate by the mitochondrial enzyme, dihydroorotate dehydrogenase (DHODH) under normoxic conditions [ 101 ]. Alternatively, under hypoxic conditions, when glutamine metabolism is elevated, dihydroorotate can be secreted by the cancer cells to alleviate the resulting intracellular nitrogen burden [ 102 ].…”

Section: Amino Acid Metabolismmentioning

confidence: 99%

Nuclear Receptor-Mediated Metabolic Reprogramming and the Impact on HR+ Breast Cancer

Hussein

Khanna

Yunus

et al. 2021

Cancers

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Metabolic reprogramming enables cancer cells to adapt to the changing microenvironment in order to maintain metabolic energy and to provide the necessary biological macromolecules required for cell growth and tumor progression. While changes in tumor metabolism have been long recognized as a hallmark of cancer, recent advances have begun to delineate the mechanisms that modulate metabolic pathways and the consequence of altered signaling on tumorigenesis. This is particularly evident in hormone receptor positive (HR+) breast cancers which account for approximately 70% of breast cancer cases. Emerging evidence indicates that HR+ breast tumors are dependent on multiple metabolic processes for tumor progression, metastasis, and therapeutic resistance and that changes in metabolic programs are driven, in part, by a number of key nuclear receptors including hormone-dependent signaling. In this review, we discuss the mechanisms and impact of hormone receptor mediated metabolic reprogramming on HR+ breast cancer genesis and progression as well as the therapeutic implications of these metabolic processes in this disease.

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“…It has been hypothesized that malignant cells have a higher requirement for pyrimidine nucleotides and a lower tolerance for pyrimidine nucleotide “starvation”, resulting in a greater dependence on DHODH than do healthy cells ( 15 ). Prolonged periods of pyrimidine starvation result in the inhibition of malignant cell proliferation, promotion of differentiation, or death without affecting resting healthy differentiated cells, thus providing a basis for selective activity and a high therapeutic window ( 16 ).…”

Section: Introductionmentioning

confidence: 99%

Emvododstat, a Potent Dihydroorotate Dehydrogenase Inhibitor, Is Effective in Preclinical Models of Acute Myeloid Leukemia

et al. 2022

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Blocking the pyrimidine nucleotide de novo synthesis pathway by inhibiting dihydroorotate dehydrogenase (DHODH) results in the cell cycle arrest and/or differentiation of rapidly proliferating cells including activated lymphocytes, cancer cells, or virally infected cells. Emvododstat (PTC299) is an orally bioavailable small molecule that inhibits DHODH. We evaluated the potential for emvododstat to inhibit the progression of acute myeloid leukemia (AML) using several in vitro and in vivo models of the disease. Broad potent activity was demonstrated against multiple AML cell lines, AML blasts cultured ex vivo from patient blood samples, and AML tumor models including patient-derived xenograft models. Emvododstat induced differentiation, cytotoxicity, or both in primary AML patient blasts cultured ex vivo with 8 of 10 samples showing sensitivity. AML cells with diverse driver mutations were sensitive, suggesting the potential of emvododstat for broad therapeutic application. AML cell lines that are not sensitive to emvododstat are likely to be more reliant on the salvage pathway than on de novo synthesis of pyrimidine nucleotides. Pharmacokinetic experiments in rhesus monkeys demonstrated that emvododstat levels rose rapidly after oral administration, peaking about 2 hours post-dosing. This was associated with an increase in the levels of dihydroorotate (DHO), the substrate for DHODH, within 2 hours of dosing indicating that DHODH inhibition is rapid. DHO levels declined as drug levels declined, consistent with the reversibility of DHODH inhibition by emvododstat. These preclinical findings provide a rationale for clinical evaluation of emvododstat in an ongoing Phase 1 study of patients with relapsed/refractory acute leukemias.

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DHODH and cancer: promising prospects to be explored

Cited by 86 publications

References 166 publications

A Broad Antiviral Strategy: Inhibitors of Human DHODH Pave the Way for Host-Targeting Antivirals against Emerging and Re-Emerging Viruses

A Broad Antiviral Strategy: Inhibitors of Human DHODH Pave the Way for Host-Targeting Antivirals against Emerging and Re-Emerging Viruses

Nuclear Receptor-Mediated Metabolic Reprogramming and the Impact on HR+ Breast Cancer

Emvododstat, a Potent Dihydroorotate Dehydrogenase Inhibitor, Is Effective in Preclinical Models of Acute Myeloid Leukemia

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