Abstract

This project is based on the hypothesis that the oxidized fatty acid products formed as a result of lipid peroxidation contribute to the overall cytotoxic effect of certain anticancer therapies. The overall objectives are to identify the 'stable' lipid peroxidation products formed in intact neoplastic cells exposed to oxidative stress, investigate how these cells respond to the accumulation of polyunsaturated fatty acid (PUFA) peroxidation products, and determine whether retention of these products contributes to the cytotoxic effects of therapies that induce lipid peroxidation. The primary experimental model will be the U937 human monocytic leukemia cell line.
The first aim i s to identify the radical adduct formed by U937 cell enriched with PUFA. Next, we will determine whether lipid radical formation correlates with lipid peroxidation and cytotoxicity by investigating whether the presence of spin traps reduce the cytotoxic effects.
A third aim i s to identify radioactive oxidation products that remain associated with the U937 cells following exposure to oxidative stress.
A fourth aim i s to determine the extent to which radioactive PUFA oxidation products can be incorporated into U937 cells. Model compounds that are presently available in radioactive form will be tested; these include hydroxyeicosatetraenoic acids, hydroxyoctadecadienoic acids, and epoxyeicosatrienoic acids. The mechanism of any antiproliferative action will be explored, beginning with possible effects on calcium flux, eicosanoid formation, and cyclic nucleotide formation. In the fifth aim, the antitoxicant enzyme and alpha-tocopherol responses of U937 cells to accumulation of these PUFA oxidation products will be explored. Finally, to test the generality of the findings, potentially important observations made with the U937 cells will be explored in other tumor lines, including the MCF-7 breast carcinoma. This information will provide a better understanding of the role of lipid peroxidation in the cytotoxic effects of anticancer treatments that are associated with free radical generation.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA066081-04
Application #
6203297
Study Section
Project Start
1999-08-31
Project End
2001-06-30
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
4
Fiscal Year
1999
Total Cost
Indirect Cost

  Institution

Name
University of Iowa
Department
Type
DUNS #
041294109
City
Iowa City
State
IA
Country
United States
Zip Code
52242

  Publications

Khoo, Nicholas K H; Hebbar, Sachin; Zhao, Weiling et al. (2013) Differential activation of catalase expression and activity by PPAR agonists: implications for astrocyte protection in anti-glioma therapy. Redox Biol 1:70-9
Carr, Wanakee J; Oberley-Deegan, Rebecca E; Zhang, Yuping et al. (2011) Antioxidant proteins and reactive oxygen species are decreased in a murine epidermal side population with stem cell-like characteristics. Histochem Cell Biol 135:293-304
Du, J; Liu, J; Smith, B J et al. (2011) Role of Rac1-dependent NADPH oxidase in the growth of pancreatic cancer. Cancer Gene Ther 18:135-43
Sun, Wenqing G; Weydert, Christine J; Zhang, Yuping et al. (2010) Superoxide Enhances the Antitumor Combination of AdMnSOD Plus BCNU in Breast Cancer. Cancers (Basel) 2:68-87
Simons, Andrean L; Mattson, David M; Dornfeld, Ken et al. (2009) Glucose deprivation-induced metabolic oxidative stress and cancer therapy. J Cancer Res Ther 5 Suppl 1:S2-6
Aykin-Burns, Nùkhet; Ahmad, Iman M; Zhu, Yueming et al. (2009) Increased levels of superoxide and H2O2 mediate the differential susceptibility of cancer cells versus normal cells to glucose deprivation. Biochem J 418:29-37
Sun, Wenqing; Kalen, Amanda L; Smith, Brian J et al. (2009) Enhancing the antitumor activity of adriamycin and ionizing radiation. Cancer Res 69:4294-300
Du, Changbin; Gao, Zhen; Venkatesha, Venkatasubbaiah A et al. (2009) Mitochondrial ROS and radiation induced transformation in mouse embryonic fibroblasts. Cancer Biol Ther 8:1962-71
Jacobs, Kristi Muldoon; Pennington, J Daniel; Bisht, Kheem S et al. (2008) SIRT3 interacts with the daf-16 homolog FOXO3a in the mitochondria, as well as increases FOXO3a dependent gene expression. Int J Biol Sci 4:291-9
Weydert, Christine J; Zhang, Yuping; Sun, Wenqing et al. (2008) Increased oxidative stress created by adenoviral MnSOD or CuZnSOD plus BCNU (1,3-bis(2-chloroethyl)-1-nitrosourea) inhibits breast cancer cell growth. Free Radic Biol Med 44:856-67

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