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

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

doi:10.1016/j.freeradbiomed.2008.10.023

Back

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

Journal article

Open access

Peer reviewed

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

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

Free radical biology & medicine, Vol.46(2), pp.232-237

2009

DOI: 10.1016/j.freeradbiomed.2008.10.023

PMCID: PMC2659778

PMID: 18983911

Files and links (1)

url

http://doi.org/10.1016/j.freeradbiomed.2008.10.023View

Open Access

Abstract

Oxidative stress and mitochondrial dysfunction in cancer cells represent features that may be exploited therapeutically. We determined whether agents that induce mitochondrial dysfunction, such as zidovudine (AZT) and cisplatin (CIS), could enhance killing of human head and neck cancer cells via oxidative stress. AZT- and/or CIS-induced cytotoxicity was determined using clonogenic survival, mitochondrial membrane potential was analyzed to investigate mitochondrial function, and glutathione was measured to determine thiol metabolism perturbations. AZT + CIS significantly increased toxicity and reduced mitochondrial membrane potential in FaDu, Cal-27, and SQ20B head and neck cancer cells while increasing the percentage of glutathione disulfide (%GSSG). Treatment with the thiol antioxidant N-acetylcysteine (NAC) reversed the loss of mitochondrial membrane potential and the increase in %GSSG and partially protected FaDu and Cal-27 cells from AZT + CIS. Finally, an inhibitor of glutathione synthesis, l-buthionine-[ S,R]-sulfoximine, sensitized the cells to AZT + CIS-induced cytotoxicity, which was partially reversed by NAC. These results suggest that exposure of cancer cells to agents that induce mitochondrial dysfunction, such as AZT, causes significant sensitization to CIS-induced toxicity via disruptions in thiol metabolism and oxidative stress. These findings provide a biochemical rationale for evaluating agents that induce mitochondrial dysfunction in combination with chemotherapy and inhibitors of glutathione metabolism in head and neck cancer.

Oxidative stress

NAC

Azidothymidine

Free radicals

Cisplatin

Cancer

Mitochondrial membrane potential

BSO

Details

Title: Subtitle: Cisplatin combined with zidovudine enhances cytotoxicity and oxidative stress in human head and neck cancer cells via a thiol-dependent mechanism
Creators: David M Mattson - Department of Radiation Medicine, Roswell Park Cancer Institute, Buffalo, NY 14263, USA
Iman M Ahmad - Department of Radiography, Allied Health Sciences Faculty, The Hashemite University, Al-Zarqa’, Jordan
Disha Dayal - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA
Arlene D Parsons - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA
Nukhet Aykin-Burns - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA
Ling Li - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA
Kevin P Orcutt - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA
Douglas R Spitz - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA
Kenneth J Dornfeld - Department of Biochemistry and Molecular Biology, University of Minnesota, Duluth, MN 55812, USA
Andrean L Simons - Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA
Resource Type: Journal article
Publication Details: Free radical biology & medicine, Vol.46(2), pp.232-237
DOI: 10.1016/j.freeradbiomed.2008.10.023
PMID: 18983911
PMCID: PMC2659778
NLM abbreviation: Free Radic Biol Med
ISSN: 0891-5849
eISSN: 1873-4596
Publisher: Elsevier Inc
Language: English
Date published: 2009
Academic Unit: Oral Pathology, Radiology and Medicine; Pathology; Pharmaceutical Sciences and Experimental Therapeutics; Radiation Oncology
Record Identifier: 9984047743802771

Metrics

10 Record Views

46 Times Cited - Web of Science