Cisplatin combined with zidovudine enhances cytotoxicity and oxidative stress in human head and neck cancer cells via a thiol-dependent mechanism

Mattson, David; Ahmad, Iman M.; Dayal, Disha; Parsons, Arlene D.; Aykin-Burns, Nūkhet; Li, Ling; Orcutt, Kevin P.; Spitz, Douglas R.; Dornfeld, Kenneth J.; Simons, Andrean L.

doi:10.1016/j.freeradbiomed.2008.10.023

Cited by 49 publications

(33 citation statements)

References 37 publications

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“…Administration of BSO leads to decreased GSH levels in virtually all tissues including developing embryos, and a marked GSH depletion is associated with tissue damage [44][45][46]. Additionally, pretreatment with BSO enhances the toxicity of radiation and drugs [32,34,45,47]. In the current study, BSO significantly increased the cytotoxicity induced by 2DG and DOX on T47D ( Figure 6A).…”

Section: Discussionsupporting

confidence: 56%

2DG enhances the susceptibility of breast cancer cells to doxorubicin

Ahmad

Mustafa

et al. 2010

Open Life Sciences

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2DG causes cytotoxicity in cancer cells by disrupting thiol metabolism while Doxorubicin (DOX) induces cytotoxicity in tumor cells by generating reactive oxygen species (ROS). Here we examined the combined cytotoxic action of 2DG and DOX in rapidly dividing T47D breast cancer cells vs. slowly growing MCF-7 breast cancer cells. T47D cells exposed to the combination of 2DG/DOX significantly decreased cell survival compared to controls, while 2DG/DOX had no effect on MCF-7 cells. 2DG/DOX also disrupted the oxidant status of T47D treated cells, decreased intracellular total glutathione and increased glutathione disulfide (%GSSG) compared to MCF-7 cells. Lipid peroxidation increased in T47D cells treated with 2DG and/or DOX, but not in MCF-7 cells. T47D cells were significantly protected by NAC, indicating that the combined treatment exerts its action by increasing ROS production and disrupting antioxidant stores. When we inhibited glutathione synthesis with BSO, T47D cells became more sensitive to 2DG/DOX-induced cytotoxicity, but NAC significantly reversed this cytotoxic effect. Finally, 2DG/DOX, and BSO significantly increased the %GSSG in T47D cells, an effect which was also reversed by NAC. Our results suggest that exposure of rapidly dividing breast cancer cells to 2DG/DOX enhances cytotoxicity via oxidative stress and via disruptions to thiol metabolism.

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Section: Discussionsupporting

confidence: 56%

2DG enhances the susceptibility of breast cancer cells to doxorubicin

Ahmad

Mustafa

et al. 2010

Open Life Sciences

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“…Mitochondrial dysfunction increases the oxidative stress [28]. It has been reported that cisplatin treatment of the cancer cells showed increase in oxidative stress [29,30]. Cisplatin exerts its cytotoxic activity through the formations of ROS and cross-links in DNA [31].…”

Section: Discussionmentioning

confidence: 99%

Protective Effects of Acetyl-l-Carnitine on Cisplatin Cytotoxicity and Oxidative Stress in Neuroblastoma

et al. 2009

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The most widely used platinum-derived drug is cisplatin in neuroblastoma (NB) chemotherapy, which is severely neurotoxic. Acetyl-L-Carnitine (ALC) is a natural occurring compound with a neuroprotective activity in several experimental paradigms. The aim of this study was to determine the effects of ALC on cisplatin induced cytotoxicity and oxidative stress in NB cells. SH-SY5Y (N-Myc negative) and KELLY (N-Myc positive) human NB cell lines were used. Cisplatin induced apoptosis was assessed by using a Cell Death Detection ELISA(PLUS) kit. Lipid peroxidation levels were determined by HPLC analysis. Glutathione levels were determined spectrophotometrically. ALC was used prophylactic or after cisplatin application. The level of cisplatin doses were determined in both type of NB cells at which 50% cell death occurred along with synchronized apoptosis induced. Prophylactic 10 and 50 micromol of ALC concentrations were decreased cisplatin induced lipid peroxidation compared to controls that normally exhibited apoptosis especially in SH-SY5Y cells. Cisplatin caused oxidative stress through decreasing glutathione levels in both cell types. ALC were effectively inhibited the increase in cisplatin induced oxidized glutathione and lipid peroxidation formation in NB cells. We suggested that prophylactic ALC would be a useful agent for cisplatin induced toxicity in NB cells.

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“…Indeed, during the apoptosis induced by cytotoxic agents, which by themselves induce oxidative stress such as pro-oxidants, xenobiotics, mitochondrial toxins, chemotherapeutics, and metals, GSH depletion is mediated by its oxidation to GSSG by ROS/RNS (61, 104, 169,199,237) (Table 1 and Fig. 2).…”

Section: Gsh Depletion During Cell Death: Where Does It Go?mentioning

confidence: 99%

Glutathione Efflux and Cell Death

Franco

Cidlowski

2012

Antioxidants & Redox Signaling

200

128

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Significance: Glutathione (GSH) depletion is a central signaling event that regulates the activation of cell death pathways. GSH depletion is often taken as a marker of oxidative stress and thus, as a consequence of its antioxidant properties scavenging reactive species of both oxygen and nitrogen (ROS/RNS). Recent Advances: There is increasing evidence demonstrating that GSH loss is an active phenomenon regulating the redox signaling events modulating cell death activation and progression. Critical Issues: In this work, we review the role of GSH depletion by its efflux, as an important event regulating alterations in the cellular redox balance during cell death independent from oxidative stress and ROS/RNS formation. We discuss the mechanisms involved in GSH efflux during cell death progression and the redox signaling events by which GSH depletion regulates the activation of the cell death machinery. Future Directions: The evidence summarized here clearly places GSH transport as a central mechanism mediating redox signaling during cell death progression. Future studies should be directed toward identifying the molecular identity of GSH transporters mediating GSH extrusion during cell death, and addressing the lack of sensitive approaches to quantify GSH efflux.

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Cisplatin combined with zidovudine enhances cytotoxicity and oxidative stress in human head and neck cancer cells via a thiol-dependent mechanism

Cited by 49 publications

References 37 publications

2DG enhances the susceptibility of breast cancer cells to doxorubicin

2DG enhances the susceptibility of breast cancer cells to doxorubicin

Protective Effects of Acetyl-l-Carnitine on Cisplatin Cytotoxicity and Oxidative Stress in Neuroblastoma

Glutathione Efflux and Cell Death

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