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Beyond Brooding on Oncometabolic Havoc in IDH-Mutant Gliomas and AML: Current and Future Therapeutic Strategies

1
Department of Biomedical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA
2
Surgical Oncology, Brandon Regional Hospital, Brandon, FL 33511, USA
3
Department of Medicine, Rutgers Robert Wood Johnson Medical School and Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA
*
Author to whom correspondence should be addressed.
Cancers 2018, 10(2), 49; https://doi.org/10.3390/cancers10020049
Received: 30 December 2017 / Revised: 3 February 2018 / Accepted: 6 February 2018 / Published: 11 February 2018
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. View Full-Text
Keywords: IDH mutations; D-2 hydroxyglutarate; epigenetic effects; hydroxy-methyl cytosine; histone methylations; glioblastoma; hematopoietic cancers; α-KG-dependent dioxygenases IDH mutations; D-2 hydroxyglutarate; epigenetic effects; hydroxy-methyl cytosine; histone methylations; glioblastoma; hematopoietic cancers; α-KG-dependent dioxygenases
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MDPI and ACS Style

Madala, H.R.; Punganuru, S.R.; Arutla, V.; Misra, S.; Thomas, T.J.; Srivenugopal, K.S. Beyond Brooding on Oncometabolic Havoc in IDH-Mutant Gliomas and AML: Current and Future Therapeutic Strategies. Cancers 2018, 10, 49. https://doi.org/10.3390/cancers10020049

AMA Style

Madala HR, Punganuru SR, Arutla V, Misra S, Thomas TJ, Srivenugopal KS. Beyond Brooding on Oncometabolic Havoc in IDH-Mutant Gliomas and AML: Current and Future Therapeutic Strategies. Cancers. 2018; 10(2):49. https://doi.org/10.3390/cancers10020049

Chicago/Turabian Style

Madala, Hanumantha R.; Punganuru, Surendra R.; Arutla, Viswanath; Misra, Subhasis; Thomas, T. J.; Srivenugopal, Kalkunte S. 2018. "Beyond Brooding on Oncometabolic Havoc in IDH-Mutant Gliomas and AML: Current and Future Therapeutic Strategies" Cancers 10, no. 2: 49. https://doi.org/10.3390/cancers10020049

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