Glutathione transferases: substrates, inihibitors and pro-drugs in cancer and neurodegenerative diseases

Allocati, Nerino; Masulli, Michele; Ilio, Carmine Di; Federici, L.

doi:10.1038/s41389-017-0025-3

Cited by 421 publications

(339 citation statements)

References 126 publications

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“…On the other hand, "frequent negatively correlated genes" are associated with small molecule metabolism (xenobiotic metabolic processes, P-value < 3.2 x 10 -3 ). In this group, we found, among others, the cytochrome CYP2J2, and the GSTK1 and MGST glutathione transferases, which are highly expressed in cancers and known to confer drug resistance through their conjugating activity [47][48][49][50]. Following other studies that reported similar results [9], we checked for the presence of multidrug transporters (MDTs).…”

Section: Resultsmentioning

confidence: 83%

Encircling the regions of the pharmacogenomic landscape that determine drug response

Fernández‐Torras

Duran‐Frigola

Aloy

2018

Preprint

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The integration of large-scale drug sensitivity screens and genome-wide experiments is changing the field of pharmacogenomics, revealing molecular determinants of drug response without the need for a priori, hypothesis-driven assumptions about drug action. In particular, transcriptomic signatures of drug sensitivity may guide drug repositioning, the discovery of synergistic drug combinations and suggest new therapeutic biomarkers. However, the inherent complexity of transcriptomic signatures, with thousands of genes differentially expressed, makes them hard to interpret, giving poor mechanistic insights and hampering translation to the clinics. Here we show how network biology can help simplify transcriptomic drug signatures, filtering out irrelevant genes, accounting for tissue-specific biases and ultimately yielding functionally-coherent, less noisy drug modules. We successfully analyzed 170 drugs tested in 637 cancer cell lines, proving a broad applicability of our approach and evincing an intimate relationship between modules' gene expression levels and drugs' mechanisms of action. Further, we have characterized multiple aspects of our transcriptomic modules. As a result, the drugs included in this study are now annotated well beyond the reductionist (targetcentered) view.

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Section: Resultsmentioning

confidence: 83%

Encircling the regions of the pharmacogenomic landscape that determine drug response

Fernández‐Torras

Duran‐Frigola

Aloy

2018

Preprint

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“…Indeed, our finding that the direct inhibition of 2-Cys PRDX with conoidin A and the specific inhibition of GSTP1, enzyme necessary for the re-activation of PRDX6 peroxidase activity, with ezatiostat [28][29][30][31] induce rapid and extensive cell death in PND3 gonocytes implies that high levels of ROS are formed in these cells in physiological conditions. This further suggests that PRDXs play an essential role in maintaining ROS at levels required for physiological functions, but not high enough to induce cell damage.…”

Section: Discussionmentioning

confidence: 96%

Protective Role of Peroxiredoxins against Reactive Oxygen Species in Neonatal Rat Testicular Gonocytes

et al. 2019

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Peroxiredoxins (PRDXs) are antioxidant enzymes that protect cells from oxidative stress and play a role in reactive oxygen species (ROS)-mediated signaling. We reported that PRDXs are critical for human fertility by maintaining sperm viability and regulating ROS levels during capacitation. Moreover, studies on Prdx6 −/− mice revealed the essential role of PRDX6 in the viability, motility, and fertility competence of spermatozoa. Although PRDXs are abundant in the testis and spermatozoa, their potential role at different phases of spermatogenesis and in perinatal germ cells is unknown. Here, we examined the expression and role of PRDXs in isolated rat neonatal gonocytes, the precursors of spermatogonia, including spermatogonial stem cells. Gene array, qPCR analyses showed that PRDX1, 2, 3, 5, and 6 transcripts are among the most abundant antioxidant genes in postnatal day (PND) 3 gonocytes, while immunofluorescence confirmed the expression of PRDX1, 2, and 6 proteins. The role of PRDXs in gonocyte viability was examined using PRDX inhibitors, revealing that the 2-Cys PRDXs and PRDX6 peroxidases activities are critical for gonocytes viability in basal condition, likely preventing an excessive accumulation of endogenous ROS in the cells. In contrast to its crucial role in spermatozoa, PRDX6 independent phospholipase A 2 (iPLA 2 ) activity was not critical in gonocytes in basal conditions. However, under conditions of H 2 O 2 -induced oxidative stress, all these enzymatic activities were critical to maintain gonocyte viability. The inhibition of PRDXs promoted a two-fold increase in lipid peroxidation and prevented gonocyte differentiation. These results suggest that ROS are produced in neonatal gonocytes, where they are maintained by PRDXs at levels that are non-toxic and permissive for cell differentiation. These findings show that PRDXs play a major role in the antioxidant machinery of gonocytes, to maintain cell viability and allow for differentiation.PRDXs are classified depending on the cysteine residues (Cys) in their active site, that will react with peroxides. They comprise the 2-Cys PRDX1 to 4, the atypical 2-Cys PRDX5, and the 1-Cys PRDX6, which has the particularity of being bifunctional, with both peroxidase and calcium-independent phospholipase A 2 (iPLA 2 ) activities [4]. The 2-Cys PRDX1 to 4 are homodimers in which the thiol of a cysteine residue of one PRDX subunit gets oxidized, then further reacts with the thiol group of the catalytic cysteine of the other subunit, forming a disulfide bond between the two subunits. By contrast, in the atypical PRDX5, 2 Cys of the same chain react upon oxidation to form an intrasubunit disulfide bond. Inactive PRDXs are then reactivated by a reduction of the disulfide bonds by thioredoxin (TRX), itself further reactivated by TRX reductase (TRD), using NADPH as a reducing equivalent. In the case of PRDX6, since the enzyme has only one catalytic Cys, the oxidized thiol will be reduced by the glutathione-GSH-transferase P1 (GSTP1) system [4][5][6].Studies in PRDXs kno...

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“…At present, eight classes of the soluble cytoplasmic mammalian glutathione S‐transferases have been identified: alpha, kappa, mu, omega, pi, sigma, theta and zeta (https://www.genenames.org/cgi-bin/genefamilies/set/567). The GST genes are upregulated in response to oxidative stress and are overexpressed in many tumours, which are, by definition, maintaining a young state of the cells (Allocati et al ., ). The majority of these enzymes had already the high efficient form in our ancestors (Aarts et al ., ).…”

Section: The Taming Of Fire and Its Consequencesmentioning

confidence: 97%

Bacteria in the ageing gut: did the taming of fire promote a long human lifespan?

Danchin

2018

Environmental Microbiology

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Unique among animals as they evolved towards Homo sapiens, hominins progressively cooked their food on a routine basis. Cooked products are characterized by singular chemical compounds, derived from the pervasive Maillard reaction. This same reaction is omnipresent in normal metabolism involving carbonyls and amines, and its products accumulate with age. The gut microbiota acts as a first line of defence against the toxicity of cooked Maillard compounds, that also selectively shape the microbial flora, letting specific metabolites to reach the blood stream. Positive selection of metabolic functions allowed the body of hominins who tamed fire to use and dispose of these age-related compounds. I propose here that, as a hopeful accidental consequence, this resulted in extending human lifespan far beyond that of our great ape cousins. The limited data exploring the role of taming fire on the human genetic setup and on its microbiota is discussed in relation with ageing.

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Glutathione transferases: substrates, inihibitors and pro-drugs in cancer and neurodegenerative diseases

Cited by 421 publications

References 126 publications

Encircling the regions of the pharmacogenomic landscape that determine drug response

Encircling the regions of the pharmacogenomic landscape that determine drug response

Protective Role of Peroxiredoxins against Reactive Oxygen Species in Neonatal Rat Testicular Gonocytes

Bacteria in the ageing gut: did the taming of fire promote a long human lifespan?

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