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Targeting Glutathione Metabolism: Partner in Crime in Anticancer Therapy.

ABSTRACT: Glutathione (GSH) is the predominant low-molecular-weight antioxidant with a ubiquitous distribution inside the cell. The steady-state level of cellular GSH is dependent on the balance between synthesis, hydrolysis, recycling of glutathione disulphide (GSSG) as well as cellular extrusion of reduced, oxidized, or conjugated-forms. The augmented oxidative stress typical of cancer cells is accompanied by an increase of glutathione levels that confers them growth advantage and resistance to a number of chemotherapeutic agents. Targeting glutathione metabolism has been widely investigated for cancer treatment although GSH depletion as single therapeutic strategy has resulted largely ineffective if compared with combinatorial approaches. In this review, we circumstantiate the role of glutathione in tumour development and progression focusing on how interfering with different steps of glutathione metabolism can be exploited for therapeutic purposes. A dedicated section on synthetic lethal interactions with GSH modulators will highlight the promising option of harnessing glutathione metabolism for patient-directed therapy in cancer.

SUBMITTER: Desideri E

PROVIDER: S-EPMC6724225 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Targeting Glutathione Metabolism: Partner in Crime in Anticancer Therapy.

Desideri Enrico E Ciccarone Fabio F Ciriolo Maria Rosa MR

Nutrients 20190816 8

Glutathione (GSH) is the predominant low-molecular-weight antioxidant with a ubiquitous distribution inside the cell. The steady-state level of cellular GSH is dependent on the balance between synthesis, hydrolysis, recycling of glutathione disulphide (GSSG) as well as cellular extrusion of reduced, oxidized, or conjugated-forms. The augmented oxidative stress typical of cancer cells is accompanied by an increase of glutathione levels that confers them growth advantage and resistance to a number ...[more]

PMID: 31426306

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Project description:Distinctive patterns of chromatin modification control gene expression and define cellular identity during development and cell differentiation. Polycomb repressive complex 2 (PRC2), the sole mammalian enzymatic complex capable of establishing gene-repressive high-degree methylation of histone H3 at lysine 27 (H3K27), plays crucial roles in regulation of normal and malignant hematopoiesis. Recently, increasing evidence has indicated that recurrent gain-of-function mutation and overexpression of EZH2, the catalytic subunit of PRC2, drive and promote malignant transformation such as B-cell lymphomagenesis, providing a rationale for PRC2 inhibition as a novel anticancer strategy. Here, we summarize the recently developed strategies for inhibition of PRC2, which include a series of highly specific, highly potent, small-molecule inhibitors of EZH2 and EZH1, an EZH2-related methyltransferase. PRC2 establishes functional crosstalk with numerous epigenetic machineries during dynamic regulation of gene transcription. Perturbation of such functional crosstalk caused by genetic events observed in various hematologic cancers, such as inactivation of SNF5 and somatic mutation of UTX, confers PRC2 dependence, thus rendering an increased sensitivity to PRC2 inhibition. We discuss our current understanding of EZH2 somatic mutations frequently found in B-cell lymphomas and recurrent mutations in various other epigenetic regulators as novel molecular predictors and determinants of PRC2 sensitivity. As recent advances have indicated a critical developmental or tumor-suppressive role for PRC2 and EZH2 in various tissue types, we discuss concerns over potentially toxic or even adverse effects associated with EZH2/1 inhibition in certain biological contexts or on cancer genetic background. Collectively, inhibition of PRC2 catalytic activity has emerged as a promising therapeutic intervention for the precise treatment of a range of genetically defined hematologic malignancies and can be potentially applied to a broader spectrum of human cancers that bear similar genetic and epigenetic characteristics.

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Dataset Information

Targeting Glutathione Metabolism: Partner in Crime in Anticancer Therapy.

Publications

Targeting Glutathione Metabolism: Partner in Crime in Anticancer Therapy.

Similar Datasets

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