Ezatiostat hydrochloride for the treatment of myelodysplastic syndromes

Mahadevan, Daruka; Sutton, G.

doi:10.1517/13543784.2015.1021003

Cited by 31 publications

(22 citation statements)

References 35 publications

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“…Under cellular stress conditions where reactive oxygen stress is heightened, GSTP1 has been shown to dimerize into larger aggregates and preclude binding to JNK, enabling JNK activation. In the context of hematopoiesis, GSTP1 inhibition has been shown to play a cytoprotective role in both erythroid and lymphoid cells, and the GSTP1 inhibitor Ezatiostat has been shown to be clinically effective for myelodisplastic syndrome (Mahadevan and Sutton, 2015; Zhang et al, 2014). While we report here that GSTP1 inhibition does not activate JNK signaling in our TNBC cells, GSTP1 may still directly regulate other signaling pathways through protein interactions or glutathionylation-mediated pathways (Zhang et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

“…A highly potent GSTP1 inhibitor Ezatiostat developed by Telik, Inc. has passed Phase II clinical trials in human patients for treatment of myelodysplastic syndrome, indicating that GSTP1 inhibitors are likely to be well-tolerated in human patients (Mahadevan and Sutton, 2015). Beyond the many previously reported biochemical and therapeutic roles of GSTP1 (Grek et al, 2013; Tew and Townsend, 2011; Townsend and Tew, 2003), our study suggests that GSTP1 inhibitors may also be promising stand-alone therapeutics for TNBCs.…”

Section: Discussionmentioning

confidence: 99%

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GSTP1 Is a Driver of Triple-Negative Breast Cancer Cell Metabolism and Pathogenicity

Louie

Grossman

Crawford

et al. 2016

Cell Chemical Biology

127

142

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Breast cancers possess fundamentally altered metabolism that fuels their pathogenicity. While many metabolic drivers of breast cancers have been identified, the metabolic pathways that mediate breast cancer malignancy and poor prognosis are less well understood. Here, we used a reactivity-based chemoproteomic platform to profile metabolic enzymes that are enriched in breast cancer cell-types linked to poor prognosis, including triple-negative breast cancer (TNBC) cells and breast cancer cells that have undergone an epithelial-mesenchymal transition-like state of heightened malignancy. We identified glutathione-S-transferase Pi 1 (GSTP1) as a novel TNBC target that controls cancer pathogenicity by regulating glycolytic and lipid metabolism, energetics, and oncogenic signaling pathways through a protein interaction that activates glyceraldehyde-3-phosphate dehydrogenase activity. We show that genetic or pharmacological inactivation of GSTP1 impairs cell survival and tumorigenesis in TNBC cells. We put forth GSTP1 inhibitors as a novel therapeutic strategy for combatting TNBCs through impairing key cancer metabolism and signaling pathways.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

GSTP1 Is a Driver of Triple-Negative Breast Cancer Cell Metabolism and Pathogenicity

Louie

Grossman

Crawford

et al. 2016

Cell Chemical Biology

127

142

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“…5f ). Its interaction with the enzyme results in JNK activation and c-Jun phophorilation 106 . This compound was found efficaceous in the treatment of myelodisplastic syndrome and its investigation has so far moved up to phase I-IIa clinical trials.…”

Section: Gst Inhibitorsmentioning

confidence: 99%

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

et al. 2018

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Glutathione transferase classical GSH conjugation activity plays a critical role in cellular detoxification against xenobiotics and noxious compounds as well as against oxidative stress. However, this feature is also exploited by cancer cells to acquire drug resistance and improve their survival. As a result, various members of the family were found overexpressed in a number of different cancers. Moreover several GST polymorphisms, ranging from null phenotypes to point mutations, were detected in members of the family and found to correlate with the onset of neuro-degenerative diseases. In the last decades, a great deal of research aimed at clarifying the role played by GSTs in drug resistance, at developing inhibitors to counteract this activity but also at exploiting GSTs for prodrugs specific activation in cancer cells. Here we summarize some of the most important achievements reached in this lively area of research.

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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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Ezatiostat hydrochloride for the treatment of myelodysplastic syndromes

Cited by 31 publications

References 35 publications

GSTP1 Is a Driver of Triple-Negative Breast Cancer Cell Metabolism and Pathogenicity

GSTP1 Is a Driver of Triple-Negative Breast Cancer Cell Metabolism and Pathogenicity

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

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

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