This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bradbury, C. M. Articles by Gius, D. Search for Related Content PubMed PubMed Citation Articles by Bradbury, C. M. Articles by Gius, D.

Increased Activator Protein 1 Activity as Well as Resistance to Heat-induced Radiosensitization, Hydrogen Peroxide, and Cisplatin Are Inhibited by Indomethacin in Oxidative Stress-resistant Cells¹

Section of Cancer Biology, Radiation Oncology Center, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri 63108 [C. M. B., J. E. L., S. J. W., L. M. R., S. K., D. G.], and Free Radical and Radiation Biology Program, Department of Radiology, B180 Medical Laboratories, University of Iowa, Iowa City, Iowa 52242 [D. R. S.]

It has been established that tumor cells develop resistance to a variety of therapeutic agents after multiple exposures to these agents/drugs. Many of these therapeutic agents also appear to increase the activity of transcription factors, such as activator protein 1 (AP-1), believed to be involved in cellular responses to oxidative stress. Therefore, we hypothesized that cellular resistance to cancer therapeutic agents may involve the increased activity of transcription factors that govern resistance to oxidative stress, such as AP-1. To investigate this hypothesis, a previously characterized cisplatin, hyperthermia, and oxidative stress-resistant Chinese hamster fibroblast cell line, OC-14, was compared to the parental HA-1 cell line. Electrophoretic mobility shift and Western blot assays performed on extracts isolated from OC-14 cells demonstrated a 10-fold increase in constitutive AP-1 DNA-binding activity as well as increased constitutive c-Fos and c-Jun immunoreactive protein relative to HA-1 cells. Treatment of OC-14 cells with indomethacin inhibited constitutive increases in AP-1 DNA-binding activity and c-Fos/c-Jun-immunoreactive protein levels. Clonogenic survival assays demonstrated that pretreatment with indomethacin, at concentrations that inhibited AP-1 activity, significantly reduced the resistance of OC-14 cells to heat-induced radiosensitization, hydrogen peroxide, and cisplatin. These results demonstrate a relationship between increases in AP-1 DNA-binding activity and increased cellular resistance to cancer therapeutic agents and oxidative stress that is inhibited by indomethacin. These results support the hypothesis that inhibition of AP-1 activity with nonsteroidal anti-inflammatory drugs, such as indomethacin, may represent a useful adjuvant to cancer therapy.

This article has been cited by other articles:

				M. V. Mishra, K. S. Bisht, L. Sun, K. Muldoon-Jacobs, R. Awwad, A. Kaushal, P. Nguyen, L. Huang, J. D. Pennington, S. Markovina, et al. DNMT1 as a Molecular Target in a Multimodality-Resistant Phenotype in Tumor Cells Mol. Cancer Res., February 1, 2008; 6(2): 243 - 249. [Abstract] [Full Text] [PDF]

				D. K. Smart, K. L. Ortiz, D. Mattson, C. M. Bradbury, K. S. Bisht, L. K. Sieck, M. W. Brechbiel, and D. Gius Thioredoxin Reductase as a Potential Molecular Target for Anticancer Agents That Induce Oxidative Stress Cancer Res., September 15, 2004; 64(18): 6716 - 6724. [Abstract] [Full Text] [PDF]

				K. S. Bisht, C. M. Bradbury, D. Mattson, A. Kaushal, A. Sowers, S. Markovina, K. L. Ortiz, L. K. Sieck, J. S. Isaacs, M. W. Brechbiel, et al. Geldanamycin and 17-Allylamino-17-demethoxygeldanamycin Potentiate the in Vitro and in Vivo Radiation Response of Cervical Tumor Cells via the Heat Shock Protein 90-Mediated Intracellular Signaling and Cytotoxicity Cancer Res., December 15, 2003; 63(24): 8984 - 8995. [Abstract] [Full Text] [PDF]

				X. Lin, F. Zhang, C. M. Bradbury, A. Kaushal, L. Li, D. R. Spitz, R. L. Aft, and D. Gius 2-Deoxy-D-Glucose-induced Cytotoxicity and Radiosensitization in Tumor Cells Is Mediated via Disruptions in Thiol Metabolism Cancer Res., June 15, 2003; 63(12): 3413 - 3417. [Abstract] [Full Text] [PDF]

				C. M. Bradbury, S. Markovina, S. J. Wei, L. M. Rene, I. Zoberi, N. Horikoshi, and D. Gius Indomethacin-induced Radiosensitization and Inhibition of Ionizing Radiation-induced NF-{kappa}B Activation in HeLa Cells Occur via a Mechanism Involving p38 MAP Kinase Cancer Res., October 1, 2001; 61(20): 7689 - 7696. [Abstract] [Full Text] [PDF]