Abstract

This proposal is aimed at evaluating the hypothesis that bcl-2 inhibition of apoptosis is mediated by increased levels of glutathione (GSH). The LY-as lymphoma cell line, which readily undergoes apoptosis in response to chemotherapeutic agents and ionizing radiation, will be transfected with bcl-2 under control of the inducible lac promoter. Antisense phosphorothioate oligonucleotides will be used to reduce bcl-2 expression in the LY-ar cell line which expresses high levels of bcl-2 and is resistant to induction of apoptosis. The relationship between GSH levels and apoptosis will be characterized in both systems. The mechanisms responsible for higher levels of GSH in cells resistant to apoptosis will be delineated and the role of reactive oxygen species (ROS) as mediators of apoptosis and GSH scavenging will be further defined. Animal models using the LY-as and LY-ar cell lines will be used to evaluate strategies with buthionine sulfoximine (BSO) to lower GSH to increase sensitivity to apoptosis.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA069003-03
Application #
2712755
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Johnson, George S
Project Start
1996-06-01
Project End
1999-06-30
Budget Start
1998-06-01
Budget End
1999-06-30
Support Year
3
Fiscal Year
1998
Total Cost
Indirect Cost

  Institution

Name
University of Texas MD Anderson Cancer Center
Department
Radiation-Diagnostic/Oncology
Type
Other Domestic Higher Education
DUNS #
001910777
City
Houston
State
TX
Country
United States
Zip Code
77030

  Publications

Howard, Adrienne N; Bridges, Kathleen A; Meyn, Raymond E et al. (2009) ABT-737, a BH3 mimetic, induces glutathione depletion and oxidative stress. Cancer Chemother Pharmacol 65:41-54
Munshi, Anupama; Tanaka, Toshimitsu; Hobbs, Marvette L et al. (2006) Vorinostat, a histone deacetylase inhibitor, enhances the response of human tumor cells to ionizing radiation through prolongation of gamma-H2AX foci. Mol Cancer Ther 5:1967-74
Sah, Nand K; Munshi, Anupama; Hobbs, Marvette et al. (2006) Effect of downregulation of survivin expression on radiosensitivity of human epidermoid carcinoma cells. Int J Radiat Oncol Biol Phys 66:852-9
Spurgers, Kevin B; Gold, David L; Coombes, Kevin R et al. (2006) Identification of cell cycle regulatory genes as principal targets of p53-mediated transcriptional repression. J Biol Chem 281:25134-42
Munshi, Anupama; Kurland, John F; Nishikawa, Takashi et al. (2005) Histone deacetylase inhibitors radiosensitize human melanoma cells by suppressing DNA repair activity. Clin Cancer Res 11:4912-22
Honda, Tsuyoshi; Coppola, Simona; Ghibelli, Lina et al. (2004) GSH depletion enhances adenoviral bax-induced apoptosis in lung cancer cells. Cancer Gene Ther 11:249-55
Sah, Nand K; Munshi, Anupama; Kurland, John F et al. (2003) Translation inhibitors sensitize prostate cancer cells to apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) by activating c-Jun N-terminal kinase. J Biol Chem 278:20593-602
Kurland, John F; Voehringer, David W; Meyn, Raymond E (2003) The MEK/ERK pathway acts upstream of NF kappa B1 (p50) homodimer activity and Bcl-2 expression in a murine B-cell lymphoma cell line. MEK inhibition restores radiation-induced apoptosis. J Biol Chem 278:32465-70
Honda, Tsuyoshi; Kagawa, Shunsuke; Spurgers, Kevin B et al. (2002) A recombinant adenovirus expressing wild-type Bax induces apoptosis in prostate cancer cells independently of their Bcl-2 status and androgen sensitivity. Cancer Biol Ther 1:163-7
Munshi, A; McDonnell, T J; Meyn, R E (2002) Chemotherapeutic agents enhance TRAIL-induced apoptosis in prostate cancer cells. Cancer Chemother Pharmacol 50:46-52

Showing the most recent 10 out of 26 publications