Potential for selective modulation of glutathione in cancer chemotherapy1Presented at the International Conference on Glutathione and Glutathione-Linked Enzymes in Human Cancer and Other Diseases, Hilton Head, SC, USA, November 1996.1

Chen, Xiang; Carystinos, George D.; Batist, Gerald

doi:10.1016/s0009-2797(97)00166-x

Cited by 52 publications

(5 citation statements)

References 20 publications

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“…The levels of glutathione were depleted with BSO, a selective inhibitor of γ-glutamylcysteine synthase, a key enzyme in the glutathione biosynthetic pathway. 58,62 Upon exposure of the cells to BSO for 20-28 h, levels of glutathione in COLO-316 cells have been shown to decrease to ∼13% of the initial value. 63,64 In COLO-316, depletion of glutathione did not have a major effect on the cytotoxicity of cisplatin, 63 although increase in cisplatin cytotoxicity has been observed in other cell lines.…”

Section: Resultsmentioning

confidence: 99%

Live Cell Cytotoxicity Studies: Documentation of the Interactions of Antitumor Active Dirhodium Compounds with Nuclear DNA

et al. 2009

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The promising antitumor activity of dirhodium complexes has been known for over 30 years. There remains, however, a general lack of understanding of their activity in cellulo. In this study, we report the DNA interactions and activity in living cells of six monosubstituted dirhodium(II,II) complexes of general formula [Rh(2)(mu-O(2)CCH(3))(2)(eta(1)-O(2)CCH(3))(L)(CH(3)OH)](+), where L = bpy (2,2'-bipyridine) (1), phen (1,10-phenanthroline) (2), dpq (dipyrido[3,2-f:2',3'-h]quinoxaline) (3), dppz (dipyrido[3,2-a:2',3'-c]phenazine) (4), dppn (benzo[i]dipyrido[3,2-a:2',3'-c]phenazine) (5), and dap (4,7-dihydrodibenzo[de,gh][1,10]phenanthroline) (6). DNA interactions were investigated by UV/visible spectroscopy, relative viscosity measurements, and electrophoretic mobility shift assay. These measurements indicate that compound 5 exhibits the strongest interaction with DNA. Compound 5 also causes the most damage to DNA after cellular internalization, as evaluated by the alkaline comet assay. Compound 5, however, is not the most effective at inhibiting cell viability of the human cancer cells HeLa and COLO-316. The greater hydrophobicity of 5 as compared to that of 4, which is the most effective compound in the series, hinders its ability to reach its cellular target(s). Data from modulation studies of glutathione using N-acetylcysteine and L-buthionine-sulfoximine indicate that changes in glutathione levels do not affect the activity of these particular dirhodium complexes. These results suggest that glutathione is not the only agent involved in the deactivation of these dirhodium complexes.

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Section: Resultsmentioning

confidence: 99%

Live Cell Cytotoxicity Studies: Documentation of the Interactions of Antitumor Active Dirhodium Compounds with Nuclear DNA

et al. 2009

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“…Increasing evidence now demonstrates that the redox status of cells is an important factor in determining whether tumor cells can withstand chemotherapy [26]. Although there are multiple potential detoxification mechanisms that affect the efficacy of chemotherapeutic drugs and confer drug resistance to targeted cells, GSH has a prominent role in resistance to chemotherapy [27]. GSH and its associated enzymes play a critical role in the cell susceptibility to the cytotoxic effect of alkylating agents, doxorubicin, cisplatin and nitrosoureas [28].…”

Section: Discussionmentioning

confidence: 99%

Role of oxidative stress and intracellular glutathione in the sensitivity to apoptosis induced by proteasome inhibitor in thyroid cancer cells

Zhang

Meng

et al. 2009

BMC Cancer

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BackgroundThe proteasome inhibitor bortezomib has shown impressive clinical activity alone and in combination with conventional and other novel agents for the treatment of multiple myeloma (MM) and some solid cancers. Although bortezomib is known to be a selective proteasome inhibitor, the downstream mechanisms of cytotoxicity and drug resistance are poorly understood.MethodsProteasome activity, intracellular glutathione (GSH) and ROS levels, as well as activities of GSH synthesis enzymes were measured using spectrophotometric methods. Cell death was analyzed using flow cytometry and caspase activity assay. The expression level of GSH synthesis enzymes were measured using real-time RT-PCR.ResultsAt concentrations that effectively inhibited proteasome activity, bortezomib induced apoptosis in FRO cells, but not in ARO cells. Bortezomib elevated the amount of glutathione (GSH) and the treatment with bortezomib increased the level of mRNA for GCL, a rate-limiting enzyme in glutathione synthesis. Furthermore, depletion of GSH increases apoptosis induced by bortezomib, in contrast, repletion of GSH decreases bortezomib-mediated cell death.ConclusionGSH protects cells from proteasome inhibition-induced oxidative stress and glutathione-dependent redox system might play an important role in the sensitivity to proteasome inhibition-induced apoptosis.

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“…Despite these promising phase I results, no follow-up data are available about phase II trials with BSO. In a preliminary report presenting data from a trial of melphalan combined with BSO in melanoma patients, a stronger GSH depletion was observed in tumor vs normal cells (Chen et al 1998 ). Recent molecular studies indicated that alternative pathways may compensate for the inhibition of GSH synthesis by BSO, such as the deubiquitinases and thioredoxin antioxidant pathways (Harris et al 2019 , 2015 ).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of the glutamate-cysteine ligase catalytic subunit with buthionine sulfoximine enhances the cytotoxic effect of doxorubicin and cyclophosphamide in Burkitt lymphoma cells

Kazimierska,

Leśniewska,

Bakker

et al. 2023

J Appl Genetics

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Burkitt lymphoma (BL) is a highly aggressive lymphoma that mainly affects children and young adults. Chemotherapy is effective in young BL patients but the outcome in adults is less satisfactory. Therefore, there is a need to enhance the cytotoxic effect of drugs used in BL treatment. Glutathione (GSH) is an important antioxidant involved in processes such as regulation of oxidative stress and drug detoxification. Elevated GSH levels have been observed in many cancers and were associated with chemoresistance. We previously identified GCLC, encoding an enzyme involved in GSH biosynthesis, as an essential gene in BL. We now confirm that knockout of GCLC decreases viability of BL cells and that the GCLC protein is overexpressed in BL tissues. Moreover, we demonstrate that buthionine sulfoximine (BSO), a known inhibitor of GCLC, decreases growth of BL cells but does not affect control B cells. Furthermore, we show for the first time that BSO enhances the cytotoxicity of compounds commonly used in BL treatment, doxorubicin, and cyclophosphamide. Given the fact that BSO itself was not toxic to control cells and well-tolerated in clinical trials, combination of chemotherapy with BSO may allow reduction of the doses of cytotoxic drugs required to obtain effective responses in BL patients.

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Potential for selective modulation of glutathione in cancer chemotherapy1Presented at the International Conference on Glutathione and Glutathione-Linked Enzymes in Human Cancer and Other Diseases, Hilton Head, SC, USA, November 1996.1

Cited by 52 publications

References 20 publications

Live Cell Cytotoxicity Studies: Documentation of the Interactions of Antitumor Active Dirhodium Compounds with Nuclear DNA

Live Cell Cytotoxicity Studies: Documentation of the Interactions of Antitumor Active Dirhodium Compounds with Nuclear DNA

Role of oxidative stress and intracellular glutathione in the sensitivity to apoptosis induced by proteasome inhibitor in thyroid cancer cells

Inhibition of the glutamate-cysteine ligase catalytic subunit with buthionine sulfoximine enhances the cytotoxic effect of doxorubicin and cyclophosphamide in Burkitt lymphoma cells

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