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Synthesis, Enzyme Localization, and Regulation of Neurosteroids
Published in Sheryl S. Smith, Neurosteroid Effects in the Central Nervous System, 2003
dehydrogenases) and the aldo-keto reductase (AKR) family (reviewed in Penning et al.92). Mammalian 3a HSDs are members of the AKR1 family of the AKR superfamily. A systematic nomenclature for the AKR superfamily originally was adopted in 1996 and was updated in September 2000.93 This nomenclature is recognized by the Human Genome Project (HUGO), and genomic information, including chromosomal localization, gene boundaries, human ESTs and SNPs, etc., can also be found on the website: http://www.med.upenn.edu/akr.
T-cell acute lymphoblastic leukemia: promising experimental drugs in clinical development
Published in Expert Opinion on Investigational Drugs, 2023
Novel drugs are currently emerging from promising preclinical studies. Inhibition of GLI1, a Hedgehog pathway transcription factor, resulted in improved survival in T-ALL preclinical models [98]. Selinexor (KPT-330), a selective inhibitor of nuclear export compound and an exportin-1 XPO1 antagonist, has shown preclinical efficacy in T-ALL [99], and is currently under investigation in relapsed pediatric ALL (NCT02091245). Eltanexor (KPT-8602), a second-generation XPO1 inhibitor, enhances the efficacy of dexamethasone therapy [100]. TYK2 pathway, chaperoned by heat shock proteins, acts to upregulate BCL2 and its inhibition by the drug Luminespib triggers apoptosis in vitro in T-ALL [101,102]. The aurora kinase-A inhibitor alisertib (MLN8237) and the aurora kinase-B inhibitor barasertib (AZD1152) have demonstrated promising results in ALL [103,104]. Alisertib is currently under investigation in combination with vorinostat in R/R T-ALL (NCT01567709). AZD1152 has shown synergy with vincristine [105]. Bortezomib, a proteasome inhibitor, has also shown encouraging data in relapsed T-ALL with 68% of CR when combined with chemotherapy [106] and is currently under clinical investigation in trials including T-ALL (NCT03117751, NCT01769209, NCT02518750, and NCT02112916). Preclinical models using the Nedd8-activating enzyme pevonedistat (MLN4924) has demonstrated cell-cycle arrest and apoptosis [107]. OBI-3424 has shown cytotoxic activity in preclinical models in T-ALL that express the Aldo-Keto Reductase 1 C3 (AKR1C3) enzyme [108].
Deoxynivalenol and its modified forms: key enzymes, inter-individual and interspecies differences in metabolism
Published in Drug Metabolism Reviews, 2022
Yating Wang, Jiefeng Li, Xu Wang, Wenda Wu, Eugenie Nepovimova, Qinghua Wu, Kamil Kuca
DON can be transformed into a variety of modified forms, including DON-3G produced by plants, DOM-1, 3-epi-DON, and 3-keto-DON by bacteria. 3-Ac-DON and 15-Ac-DON are produced by fungi and can be converted to DON. Enzymes and microorganisms promote DON detoxification via de-epoxidation, hydroxylation, and glucuronidation. UDP-glucuronosyltransferases are related to the production of DON-GlcA in animals, whereas UDP-glucosyltransferase is responsible for the glycosylation of DON to DON-3G in plants. In a two-step catalytic reaction mediated by dehydrogenase and aldo-keto reductase, (1) DON is oxidized by DepA to form 3-keto-DON in the presence of the coenzyme NADP+ and (2) DepB-catalyzed 3-keto-DON is reduced to 3-epi-DON, an NADPH-dependent dehydrogenase. Moreover, the TRI101/TRI201 genes encoding 3-O-acetyltransferase could catalyze DON to 3-Ac-DON in an acetyl-CoA-dependent manner. GST catalyzes DON to form DON-GSH (Table 1).
Proteomics-inspired precision medicine for treating and understanding multiple myeloma
Published in Expert Review of Precision Medicine and Drug Development, 2020
Matthew Ho, Giada Bianchi, Kenneth C. Anderson
Phosphoproteomic profiling in the multidrug resistant MM cell line RPMI-8226.R5 (resistant to melphalan, doxorubicin, bortezomib, etoposide, tunicamycin, and staurosporin) revealed that R5 cells had differential expression of 22 out of 46 kinases when compared to RPMI-8226 (sensitive isogenic counterpart) [179]. Amongst these, cMET and phospho-cMET expression were found to be elevated in R5 cells which resulted in the constitutive activation of downstream signaling pathways such as the MAPK pathway [179]. Importantly, the selective cMET inhibitor SU11274 induces apoptosis in R5 cells and restores sensitivity to bortezomib, melphalan, and doxorubicin [179]. Melphalan resistance, on the other hand, was found to be associated with a metabolic switch to glycolysis (Warburg effect), activation of oxidative stress response through VEGF/IL-8 signaling, and upregulation of aldo-keto reductase family 1 (AKR1) enzymes [180]. Ge et al. used MALDI-TOF/TOF to study the mechanisms of resistance to arsenic trioxide (ATO) [181]. The group reported reduced expression of 14-3-3ζ and increased expression of HSP90 as mediators of ATO resistance in MM [181]. Metabolomic profiling showed that resistance to the EGFR inhibitor Gefitinib in KRAS/NRAS/BRAF WT MM (but not KRAS/NRAS/BRAF mutants) was associated with an adaptive metabolic shift to the pentose phosphate pathway [182].