Increased Cisplatin Sensitivity of Human Fibroblasts from a Subject with Inherent Glutathione Deficiency

Hansson, Johan; Edgren, Margareta; Egyházi, Suzanne; Hao, Xiao-Yong; Mannervik, Bengt; Ringborg, Ulrik

doi:10.3109/02841869609083999

Cited by 12 publications

(6 citation statements)

References 23 publications

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“…Modulation of the GSH content (Meijer et al, 1992;Hansson et al, 1996) and GST activity (Awasthi et al, 1994) has been shown to affect cisplatin cytotoxicity in human tumor cells. Likewise, modulation of the GS-X pump also changed the sensitivity of tumor cells to other anticancer drugs, which are substrates of glutathione-related detoxification mechanisms (Wijnholds et al, 1997;Zhang and Wong, 1997).…”

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confidence: 97%

Modulation of Cisplatin Cytotoxicity and Cisplatin-Induced DNA Cross-Links in HepG2 Cells by Regulation of Glutathione-Related Mechanisms

et al. 2001

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Glutathione (GSH), glutathione S-transferase (GST), and glutathione conjugate export pump (GS-X pump) have been shown to participate collectively in the detoxification of many anticancer drugs, including cisplatin. Identification and regulation of the rate-limiting step in the overall system for cisplatin detoxification is of crucial importance for sensitization of human tumor cells to cisplatin. In this study, the GSH content, GST activity, and GS-X pump activity were regulated separately to examine effects of the regulation on cisplatin cytotoxicity and cisplatin-induced DNA interstrand cross-links (ICL) in HepG2 cells. Seventy-percent depletion of GSH by buthionine sulfoximine (BSO) and 50% increase of GSH by monoethyl GSH ester (GSHe) potentiated and decreased cisplatin cytotoxicity, respectively. This was reflected by a significant decrease and increase of their respective IC(50) values by 62 and 107%. Cisplatin-induced ICL was also potentiated by depletion of GSH by BSO and decreased by enrichment of GSH by GSHe, as shown by a 125% increase and a 34% decrease of cross-linked DNA compared with control samples exposed to cisplatin alone (p = 0.008 and 0.03, respectively). On the other hand, inhibition of GST and GS-X pump by ethacrynic acid, quercetin, tannic acid, and indomethacin at concentrations that inhibited activities of GST and GS-X pump by more than 50% had no significant effects on cisplatin cytotoxicity and cisplatin-induced DNA ICL in these cells. The results showed that of the parameters measured, intracellular GSH seems to be the rate-limiting factor, and its regulation would provide a more promising strategy for sensitization of human liver tumor cells to cisplatin.

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confidence: 97%

Modulation of Cisplatin Cytotoxicity and Cisplatin-Induced DNA Cross-Links in HepG2 Cells by Regulation of Glutathione-Related Mechanisms

et al. 2001

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“…GSTP1, the isoform predominantly expressed in human fibroblasts (Hansson et al, 1996), is polymorphic due to the substitution Ile105Val located close to the enzyme substrate-binding site (Zimniak et al, 1994). Under our experimental conditions, the activity of the homozygous wild-type GSTP1 was slightly higher than that of the homozygous mutant.…”

Section: Discussionmentioning

confidence: 64%

“…GSTP1 is the GST predominantly expressed in human fibroblasts (Hansson et al, 1996). This enzyme has been shown to be polymorphic in human populations (Eaton et al, 1999).…”

Section: Tegdma-induced Modulation Of Gst Activity In Fibroblasts Andmentioning

confidence: 99%

TEGDMA Modulates Glutathione Transferase P1 Activity in Gingival Fibroblasts

et al. 2004

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Dental resinous materials can contain large amounts (from 30 to 50%) of triethylene-glycol-dimethacrylate (TEGDMA). This compound leaches into aqueous media and is toxic to dental pulp, as well as to gingival fibroblasts in vitro. To elucidate the mechanism of TEGDMA toxicity, we investigated the effects on glutathione (GSH) level and glutathione transferase P1 (GSTP1) activity in cultured human gingival fibroblasts. TEGDMA cytotoxic concentrations (from 0.5 to 2 mM) induced a depletion of GSH without formation of oxidized GSH (GSSG). In fibroblasts expressing the wild-type GSTP1, TEGDMA both inhibited and potentiated GSTP1 activity at high (IC50 = 1.1 mM) and low concentrations, respectively. In contrast, cells expressing the GSTP1 *A/*B variant showed a weak inhibition of GST activity only, associated with greater sensitivity to drug toxicity. Biochemical analysis of GSTP1 inhibition revealed that TEGDMA is a non-competitive antagonist with respect to GSH and substrate. Thus, TEGDMA interference with GSH and GSTP1 activity may contribute to dental-resin-induced adverse effects.

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“…Disturbances within the GSH system, resulting in decreased cellular GSH, have been documented in many conditions including Alzheimer's (2, 3) and Parkinson's (4) diseases, schizophrenia (5–7), and AIDS (8). Conversely, increased tumor GSH can be associated with chemotherapy drug resistance (9–13). Some reports have shown that peripheral erythrocyte GSH levels and glutathione‐ S ‐transferase (GST) activity positively correlate with tumor levels and activity and chemotherapeutic response (14), while other reports have shown that increasing GSH levels via the administration of thiol compounds can help to diminish the level of GSH depletion associated with the use of some chemotherapeutic agents, thus offering a cytoprotective effect (15, 16).…”

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confidence: 99%

Novel use of the fluorescent dye 5‐(and‐6)‐chloromethyl SNARF‐1 acetate for the measurement of intracellular glutathione in leukemic cells and primary lymphocytes

et al. 2007

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Glutathione (GSH) plays an important role in protecting cells against injury, particularly during oxidative stress. Alterations in GSH metabolism are becoming the focus of attention in many diseases such as cancer, neurodegeneration, and AIDS. As such, a rapid assessment of GSH levels in a clinical setting is of increasing importance. We tested the efficacy of the thiol-labeling fluorescent dye CM-SNARF in its ability to measure variations in GSH concentration using a visible-light flow cytometer. GSH levels in I83, Jurkat, and primary lymphocytes were depleted with buthionine sulfoximine (BSO) or diamide, or increased with N-acetylcysteine (NAC). Following each treatment, cells were divided and either labeled with CM-SNARF followed by flow cytometry analysis, or assayed for GSH using a biochemical method. BSO treatment caused a maximal 87-90% decrease in GSH and 68-76% decrease in fluorescence units. Diamide depleted GSH 91-95%, corresponding to a fluorescence decrease of 85-88%. NAC treatment increased GSH levels 27% and fluorescence 12-19%. The overall correlation (R 2 ) between mean GSH concentration and mean fluorescence was 0.80-0.88. CM-SNARF can be used to semi-quantitatively and rapidly determine intracellular variations in GSH concentration in the range of 10-150 nmoles GSH/mg protein. ' 2007International Society for Analytical Cytology Key terms glutathione (GSH); flow cytometry; 5-(and-6)-chloromethyl SNARF-1 acetate; buthionine sulfoximine (BSO); diamide; primary lymphocytes; N-acetylcysteine GLUTATHIONE (GSH) is a major intracellular antioxidant and plays an important role in several cellular processes including the maintenance of redox potential, amino acid transport, and the protection of cells from damage by free radicals, peroxides, and toxins (1). Disturbances within the GSH system, resulting in decreased cellular GSH, have been documented in many conditions including Alzheimer's (2,3) and Parkinson's (4) diseases, schizophrenia (5-7), and AIDS (8). Conversely, increased tumor GSH can be associated with chemotherapy drug resistance (9-13). Some reports have shown that peripheral erythrocyte GSH levels and glutathione-S-transferase (GST) activity positively correlate with tumor levels and activity and chemotherapeutic response (14), while other reports have shown that increasing GSH levels via the administration of thiol compounds can help to diminish the level of GSH depletion associated with the use of some chemotherapeutic agents, thus offering a cytoprotective effect (15,16). Collectively, these reports suggest that the clinical measurement of GSH concentration should prove useful in disease diagnosis and monitoring, especially in terms of cancer management where patient GSH levels may influence the choice and dosing of chemotherapy regimens. As a result, the ability to rapidly measure GSH concentrations in clinical samples is of increasing importance.

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Increased Cisplatin Sensitivity of Human Fibroblasts from a Subject with Inherent Glutathione Deficiency

Cited by 12 publications

References 23 publications

Modulation of Cisplatin Cytotoxicity and Cisplatin-Induced DNA Cross-Links in HepG2 Cells by Regulation of Glutathione-Related Mechanisms

Modulation of Cisplatin Cytotoxicity and Cisplatin-Induced DNA Cross-Links in HepG2 Cells by Regulation of Glutathione-Related Mechanisms

TEGDMA Modulates Glutathione Transferase P1 Activity in Gingival Fibroblasts

Novel use of the fluorescent dye 5‐(and‐6)‐chloromethyl SNARF‐1 acetate for the measurement of intracellular glutathione in leukemic cells and primary lymphocytes

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