Abstract
Isocitrate dehydrogenases 1 and 2 (IDH1,2), the key Krebs cycle enzymes that generate NADPH reducing equivalents, undergo heterozygous mutations in >70% of low- to mid-grade gliomas and ~20% of acute myeloid leukemias (AMLs) and gain an unusual new activity of reducing the α-ketoglutarate (α-KG) to D-2 hydroxyglutarate (D-2HG) in a NADPH-consuming reaction. The oncometabolite D-2HG, which accumulates >35 mM, is widely accepted to drive a progressive oncogenesis besides exacerbating the already increased oxidative stress in these cancers. More importantly, D-2HG competes with α-KG and inhibits a large number of α-KG-dependent dioxygenases such as TET (Ten-eleven translocation), JmjC domain-containing KDMs (histone lysine demethylases), and the ALKBH DNA repair proteins that ultimately lead to hypermethylation of the CpG islands in the genome. The resulting CpG Island Methylator Phenotype (CIMP) accounts for major gene expression changes including the silencing of the MGMT (O6-methylguanine DNA methyltransferase) repair protein in gliomas. Glioma patients with IDH1 mutations also show better therapeutic responses and longer survival, the reasons for which are yet unclear. There has been a great surge in drug discovery for curtailing the mutant IDH activities, and arresting tumor proliferation; however, given the unique and chronic metabolic effects of D-2HG, the promise of these compounds for glioma treatment is uncertain. This comprehensive review discusses the biology, current drug design and opportunities for improved therapies through exploitable synthetic lethality pathways, and an intriguing oncometabolite-inspired strategy for primary glioblastoma.
Highlights
To compensate for an increased demand for energy, biosynthetic precursors, and increased macromolecular synthesis, cancer cells enforce a metabolic switching from oxidative phosphorylation to aerobic glycolysis
This review summarizes the biochemical and molecular changes associated with Isocitrate Dehydrogenases (IDHs) mutations, how they contribute to the initiation and progression of cancer, and opportunities for molecular targeting
IDHs play a crucial role in cellular protection against oxidative stress by generating more than half of reducing equivalent NADPH in cells [4], which is essential for recycling GSH and other redox functions [6]
Summary
To compensate for an increased demand for energy, biosynthetic precursors, and increased macromolecular synthesis, cancer cells enforce a metabolic switching from oxidative phosphorylation to aerobic glycolysis. Many oncogenes such as the c-myc, Ras and PI3K-mTOR, facilitate a deranged cancer metabolism through a metabolic stress and glutamine addiction [1]. IDHs play a crucial role in cellular protection against oxidative stress by generating more than half of reducing equivalent NADPH in cells [4], which is essential for recycling GSH and other redox functions [6]. IDH2 is localized in mitochondria [8] and shares almost 97% sequence homology with IDH1 It regulates Krebs cycle and serves as one of the major sources of mitochondrial NADPH. In contrast to IDH1 and IDH2, the heterotetrameric IDH3 is not subjected to cancer mutations (Figure 1)
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