Enhanced resistance of HeLa cells to cisplatin by overexpression of γ-glutamyltransferase

Daubeuf, Sandrine; Leroy, Pierre; Paolicchi, Aldo; Pompella, Alfonso; Wellman, Maria; Galteau, Marie‐Madeleine; Visvikis, Athanase

doi:10.1016/s0006-2952(02)01118-8

Cited by 44 publications

(31 citation statements)

References 25 publications

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“…Indeed, a low level of GSTp has been correlated to an overall survival rate of 82% with cisplatin in head and neck cancer patients, whereas a high level of the enzyme was associated with a twofold reduction in survival (Shiga et al, 1999). Overexpression of g-glutamyltransferase (g-GT) in cisplatin resistance is also observed, and this may further exacerbate inactivation of cisplatin (Daubeuf et al, 2002). g-GT is a key player in GSH homeostasis, and generates cysteinylglycine during GSH catabolism (Figure 2).…”

Section: Increased Inactivation By Thiol-containing Moleculesmentioning

confidence: 99%

Cisplatin: mode of cytotoxic action and molecular basis of resistance

2003

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Cisplatin is one of the most potent antitumor agents known, displaying clinical activity against a wide variety of solid tumors. Its cytotoxic mode of action is mediated by its interaction with DNA to form DNA adducts, primarily intrastrand crosslink adducts, which activate several signal transduction pathways, including those involving ATR, p53, p73, and MAPK, and culminate in the activation of apoptosis. DNA damage-mediated apoptotic signals, however, can be attenuated, and the resistance that ensues is a major limitation of cisplatinbased chemotherapy. The mechanisms responsible for cisplatin resistance are several, and contribute to the multifactorial nature of the problem. Resistance mechanisms that limit the extent of DNA damage include reduced drug uptake, increased drug inactivation, and increased DNA adduct repair. Origins of these pharmacologicbased mechanisms, however, are at the molecular level. Mechanisms that inhibit propagation of the DNA damage signal to the apoptotic machinery include loss of damage recognition, overexpression of HER-2/neu, activation of the PI3-K/Akt (also known as PI3-K/PKB) pathway, loss of p53 function, overexpression of antiapoptotic bcl-2, and interference in caspase activation. The molecular signature defining the resistant phenotype varies between tumors, and the number of resistance mechanisms activated in response to selection pressures dictates the overall extent of cisplatin resistance.

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Section: Increased Inactivation By Thiol-containing Moleculesmentioning

confidence: 99%

Cisplatin: mode of cytotoxic action and molecular basis of resistance

2003

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“…A recent paper showed that GGT was able to mediate extracellular detoxification of cisplatin . It turns out that cysteinylglycine, the product of GGT-mediated hydrolysis of GSH (see Figure 4), reacts with cisplatin about 5-fold faster than GSH (Daubeuf et al, 2002), leading to decreased cellular accumulation of cisplatin . Even more intriguing is the notion that GGT-mediated hydrolysis of GSH can create a low level of ROS, due to generation of the more reactive thiol cysteinylglycine, which can reduce ferric iron to ferrous iron and trigger an iron redox cycling with production of ROS .…”

Section: 13mentioning

confidence: 99%

Regulation of glutathione synthesis

Lu¹

2009

Molecular Aspects of Medicine

1,648

765

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Glutathione (GSH) is a ubiquitous intracellular peptide with diverse functions that include detoxification, antioxidant defense, maintenance of thiol status, and modulation of cell proliferation. GSH is synthesized in the cytosol of all mammalian cells in a tightly regulated manner. The major determinants of GSH synthesis are the availability of cysteine, the sulfur amino acid precursor, and the activity of the rate-limiting enzyme, glutamate cysteine ligase (GCL). GCL is composed for a catalytic (GCLC) and modifier (GCLM) subunit and they are regulated at multiple levels and at times differentially. The second enzyme of GSH synthesis, GSH synthase (GS) is also regulated in a coordinated manner as GCL subunits and its up-regulation can further enhance the capacity of the cell to synthesize GSH. Oxidative stress is well known to induce the expression of GSH synthetic enzymes. Key transcription factors identified thus far include Nrf2/Nrf1 via the antioxidant response element (ARE), activator protein-1 (AP-1) and nuclear factor κ B (NFκB). Dysregulation of GSH synthesis is increasingly being recognized as contributing to the pathogenesis of many pathological conditions. These include diabetes mellitus, pulmonary fibrosis, cholestatic liver injury, endotoxemia and drug-resistant tumor cells. Manipulation of the GSH synthetic capacity is an important target in the treatment of many of these disorders.

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“…Biochemical, cellular, and molecular approaches have been used to identify the molecular basis of resistance to cisplatin. Development of resistance to cisplatin in vivo and in cell lines is multifactorial, including changes in DNA repair proficiency (Fink et al, 1998;Branch et al, 2000;Fojo, 2001), proteins and enzymes involved in detoxicifications of cisplatin, such as metallothionein and glutathione-related enzymes (Kelly et al, 1988;Godwin et al, 1992;Daubeuf et al, 2002), chaperones (Yamamoto et al, 2001), signal transduction pathways (Basu et al, 1996), and cell cycle regulators . Alterations in the expression of proto-oncogenes, apoptosis-related genes, and cancer susceptibility genes have also been described in association with cisplatin resistance (Lowe et al, 1993;Husain et al, 1998;Slupianek et al, 2001).…”

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Reduced expression of small GTPases and hypermethylation of the folate binding protein gene in cisplatin-resistant cells

Liang

et al. 2004

Br J Cancer

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Reduced accumulation of cisplatin is the most consistent feature seen in cisplatin-resistant (CP-r) cells that are cross-resistant to other cytotoxic compounds, such as methotrexate. In this report, defective uptake of a broad range of compounds, including As 5 þ and 73 As 3 þ , was detected in CP-r human hepatoma and epidermal carcinoma cells that we have previously shown are defective in fluidphase endocytosis. Downregulation of several small GTPases, such as rab5, rac1, and rhoA, which regulate endocytosis, was found in CP-r cells. However, expression of an early endosomal protein and clathrin heavy chain was not changed, suggesting that the defective endocytic pathway is clathrin independent. Reduced expression of the cell surface protein, folate-binding protein (FBP), which is a carrier for the uptake of MTX, was also observed in the CP-r cells by confocal immunofluorescence microscopy and RealTime PCR. Reactivation of the silenced FBP gene in the CP-r cells by a DNA demethylation agent, 2-deoxy-5-aza-cytidine (DAC) demonstrates that hypermethylation occurred in the CP-r cells. The uptake of [

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Enhanced resistance of HeLa cells to cisplatin by overexpression of γ-glutamyltransferase

Cited by 44 publications

References 25 publications

Cisplatin: mode of cytotoxic action and molecular basis of resistance

Cisplatin: mode of cytotoxic action and molecular basis of resistance

Regulation of glutathione synthesis

Reduced expression of small GTPases and hypermethylation of the folate binding protein gene in cisplatin-resistant cells

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