Newer human inosine 5′-monophosphate dehydrogenase 2 (<i>h</i>IMPDH2) inhibitors as potential anticancer agents

Shah, Chetan; Kharkar, Prashant S.

doi:10.1080/14756366.2018.1474211

Cited by 19 publications

(11 citation statements)

References 37 publications

(36 reference statements)

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“…In addition, TYMP has been demonstrated to directly stimulate the expression of angiogenic factors such as VEGF, TNFα, and IL-8 [18] as well as promote angiogenesis [19,20]. Moreover, IMPDH2, which is synthesized by guanine nucleotide rate-limiting enzymes, provides guanine nucleotides for T cell proliferation [21,22] and is highly expressed in proliferating tumor tissues [23]. The function and roles of TYMP and IMPDH2 and other proteins participating in the drug metabolism pathway in the pathogenesis of PV are unknown and need to be further studied.…”

Section: Discussionmentioning

confidence: 99%

Quantitative analysis of differentially expressed proteins in psoriasis vulgaris using tandem mass tags and parallel reaction monitoring

et al. 2020

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Background: Psoriasis vulgaris (PV) is a chronic autoimmune inflammatory disease with epidermal hyperkeratosis and parakeratosis. Methods: The study was to elucidate the pathogenesis of PV by quantitative proteomic analysis of skin lesion biopsies of PV and healthy tissues with tandem mass tags (TMTs) coupled with liquid chromatography-mass spectrometry (LC-MS)/MS. Results: A total of 4562 differentially expressed proteins (DEPs) between PV lesional tissues (n = 11) and healthy tissues (n = 11) were identified, of which 299 were upregulated and 206 were downregulated using |fold change| > 1.3 as the cutoff threshold. The Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis revealed that the DEPs were mainly enriched in the activation of immune cells (drug metabolism pathway, NOD-like pathway, and IL-17 pathway), cell proliferation (ribosomal pathway, DNA replication pathway, and base replication pathway), metabolism-related pathways (fatty acid biosynthesis and metabolism, PPAR pathway, glycerophospholipid metabolism, and cortisol synthesis and breakdown), and glandular secretion (saliva secretion, gastric acid secretion, and pancreatic fluid secretion). Thirteen DEPs that were relatively highly expressed in the drug metabolism pathway were validated with parallel reaction monitoring (PRM), of which MPO, TYMP, IMPDH2, GSTM4, and ALDH3A1 were highly expressed in PV, whereas CES1, MAOB, MGST1, and GSTT1 were less expressed in PV. Conclusions: These findings confirmed that these proteins participate in the drug metabolism-other enzyme pathways and play crucial roles in the activation and proliferation of immune cells in the pathogenesis of PV.

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Section: Discussionmentioning

confidence: 99%

Quantitative analysis of differentially expressed proteins in psoriasis vulgaris using tandem mass tags and parallel reaction monitoring

et al. 2020

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“…In addition, TYMP has been demonstrated to directly stimulate the expression of angiogenic factors such as VEGF, TNFα, and IL-8 [18] as well as promote angiogenesis [19,20]. Moreover, IMPDH2, which is synthesized by guanine nucleotide ratelimiting enzymes, provides guanine nucleotides for T cell proliferation [21,22] and is highly expressed in proliferating tumor tissues [23]. The function and roles of TYMP and IMPDH2 and other proteins participating in the drug metabolism pathway in the pathogenesis of PV are unknown and need to be further studied.…”

Section: Discussionmentioning

confidence: 99%

Quantitative analysis of differentially expressed proteins in psoriasis vulgaris using tandem mass tags and parallel reaction monitoring

Liu

Lin

Wang

et al. 2020

Preprint

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BackgroundPsoriasis vulgaris (PV) is a chronic autoimmune inflammatory disease with epidermal hyperkeratosis and parakeratosis.MethodsThe study was to elucidate the pathogenesis of PV by quantitative proteomic analysis of skin lesion biopsies of PV and healthy tissues with tandem mass tags (TMTs) coupled with liquid chromatography–mass spectrometry (LC-MS)/MS.ResultsA total of 4562 differentially expressed proteins (DEPs) between PV lesional tissues (n = 11) and healthy tissues (n = 11) were identified, of which 299 were upregulated and 206 were downregulated using |fold change| > 1.3 as the cutoff threshold. The Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis revealed that the DEPs were mainly enriched in the activation of immune cells (drug metabolism pathway, NOD-like pathway, and IL-17 pathway), cell proliferation (ribosomal pathway, DNA replication pathway, and base replication pathway), metabolism-related pathways (fatty acid biosynthesis and metabolism, PPAR pathway, glycerophospholipid metabolism, and cortisol synthesis and breakdown), and glandular secretion (saliva secretion, gastric acid secretion, and pancreatic fluid secretion). Thirteen DEPs that were relatively highly expressed in the drug metabolism pathway were validated with parallel reaction monitoring (PRM), of which MPO, TYMP, IMPDH2, GSTM4, and ALDH3A1 were highly expressed in PV, whereas CES1, MAOB, MGST1, and GSTT1 were less expressed in PV.ConclusionsThese findings confirmed that these proteins participate in the drug metabolism-other enzyme pathways and play crucial roles in the activation and proliferation of immune cells in the pathogenesis of PV.

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“…Two isoforms of IMPDH have been identified: type 1 and type 2 [138]. Human IMPDH type 1 (hIMPDH1) is ubiquitously expressed and its activity is maintained at near constant level in normal and neoplastic cells, whereas the human IMPDH type 2 (hIMPDH2) isoform appears upregulated in proliferating cells [139]. The disproportionate increase of hIMPDH2 activity in neoplastic cells has made this isoform a key target for the development of anticancer drugs.…”

Section: Inosine 5′-monophosphate Dehydrogenasementioning

confidence: 99%

“…The underlying rationale for the increased activity of hIMPDH2 may be that, although guanylates can be salvaged from guanine by HPRT, the level of circulating guanine is low in dividing cells and this route is probably insufficient to satisfy the needs of guanylates. Indeed, both natural and synthetic inhibitors of IMPDH are used as anticancer [139], antiviral [140], immunosuppressive, and antimicrobial agents [141,142,143,144,145,146]. In Tuberous Sclerosis Complex 2 (TSC-2) deficient cell and tumour models with aberrantly elevated mammalian Target of Rapamycin Complex 1 (mTORC1) signalling and actively producing ribosomes, IMPDH inhibition, by limiting the nucleotide pool, leads to selective replication stress, DNA damage, and apoptosis [147].…”

Section: Inosine 5′-monophosphate Dehydrogenasementioning

confidence: 99%

Purine-Metabolising Enzymes and Apoptosis in Cancer

Camici¹,

Garcia‐Gil

Pesi³

et al. 2019

Cancers

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The enzymes of both de novo and salvage pathways for purine nucleotide synthesis are regulated to meet the demand of nucleic acid precursors during proliferation. Among them, the salvage pathway enzymes seem to play the key role in replenishing the purine pool in dividing and tumour cells that require a greater amount of nucleotides. An imbalance in the purine pools is fundamental not only for preventing cell proliferation, but also, in many cases, to promote apoptosis. It is known that tumour cells harbour several mutations that might lead to defective apoptosis-inducing pathways, and this is probably at the basis of the initial expansion of the population of neoplastic cells. Therefore, knowledge of the molecular mechanisms that lead to apoptosis of tumoural cells is key to predicting the possible success of a drug treatment and planning more effective and focused therapies. In this review, we describe how the modulation of enzymes involved in purine metabolism in tumour cells may affect the apoptotic programme. The enzymes discussed are: ectosolic and cytosolic 5′-nucleotidases, purine nucleoside phosphorylase, adenosine deaminase, hypoxanthine-guanine phosphoribosyltransferase, and inosine-5′-monophosphate dehydrogenase, as well as recently described enzymes particularly expressed in tumour cells, such as deoxynucleoside triphosphate triphosphohydrolase and 7,8-dihydro-8-oxoguanine triphosphatase.

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Newer human inosine 5′-monophosphate dehydrogenase 2 (hIMPDH2) inhibitors as potential anticancer agents

Cited by 19 publications

References 37 publications

Quantitative analysis of differentially expressed proteins in psoriasis vulgaris using tandem mass tags and parallel reaction monitoring

Quantitative analysis of differentially expressed proteins in psoriasis vulgaris using tandem mass tags and parallel reaction monitoring

Quantitative analysis of differentially expressed proteins in psoriasis vulgaris using tandem mass tags and parallel reaction monitoring

Purine-Metabolising Enzymes and Apoptosis in Cancer

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