Recent studies have demonstrated that the multidrug resistance-associated protein encoded by the MRP is involved in the transport of substrates containing glutathione (GSH) conjugates. These findings suggest that intracellular GSH levels and activities of gamma- glutamylcysteine synthetase (gamma-GCS), the rate-limiting enzyme for de novo biosynthesis of GSH, are important in MRP-mediated drug resistance. Indeed, the applicant has demonstrated coordinated expression of MRP and gamma-GCS in many independently established human drug-resistant tumor cell lines, in cultured cells transiently exposed to cytotoxic agents (heavy metals, alkylating agents, phenolic prooxidants and nitric oxide), and in human colorectal tumor biopsies. Because many of these agents are known to generate oxidative stress and his preliminary findings showed that overexpression of antioxidant GSH downregulates MRP, the central theme of this application is that oxidative stress is the underlying mechanism that controls the expression of MRP and gamma-GCS. To test this hypothesis, the applicant proposes in this application: (i) to determine the roles of antioxidant GSH in the coordinated regulation of these genes using inducible expression system to up-regulate the GSH levels and depletors to down-regulate the levels, (ii) to identify and characterize DNA sequences and transcription factors that are involved in the up- and down-regulation of MRP by prooxidants and antioxidants, (iii) to investigate regulation of MRP expression in colon cancer cells under nitrosative stress generated by nitric oxide signaling, and (iv) to establish animal models for the expression of MRP and gamma-GCS in colorectal cancers, because association of oxidative stress with colorectal carcinogenesis has been implicated. The applicant anticipates from these studies to learn the molecular mechanisms that control multidrug resistance gene expression in cancer cells, and thus to improve the efficacy of cancer chemotherapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA079085-03
Application #
6376909
Study Section
Special Emphasis Panel (ZRG2-ET-2 (01))
Program Officer
Forry, Suzanne L
Project Start
1999-08-01
Project End
2004-07-31
Budget Start
2001-09-19
Budget End
2004-07-31
Support Year
3
Fiscal Year
2001
Total Cost
$214,698
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Pathology
Type
Other Domestic Higher Education
DUNS #
001910777
City
Houston
State
TX
Country
United States
Zip Code
77030
Kuo, Macus Tien; Savaraj, Niramol; Feun, Lynn G (2010) Targeted cellular metabolism for cancer chemotherapy with recombinant arginine-degrading enzymes. Oncotarget 1:246-51
Tsai, Wen-Bin; Aiba, Isamu; Lee, Soo-yong et al. (2009) Resistance to arginine deiminase treatment in melanoma cells is associated with induced argininosuccinate synthetase expression involving c-Myc/HIF-1alpha/Sp4. Mol Cancer Ther 8:3223-33
Kuo, Macus Tien (2009) Redox regulation of multidrug resistance in cancer chemotherapy: molecular mechanisms and therapeutic opportunities. Antioxid Redox Signal 11:99-133
Liang, Zheng D; Stockton, David; Savaraj, Niramol et al. (2009) Mechanistic comparison of human high-affinity copper transporter 1-mediated transport between copper ion and cisplatin. Mol Pharmacol 76:843-53
Wangpaichitr, Medhi; Wu, Chunjing; You, Min et al. (2008) Inhibition of mTOR restores cisplatin sensitivity through down-regulation of growth and anti-apoptotic proteins. Eur J Pharmacol 591:124-7
Song, Im-Sook; Chen, Helen H W; Aiba, Isamu et al. (2008) Transcription factor Sp1 plays an important role in the regulation of copper homeostasis in mammalian cells. Mol Pharmacol 74:705-13
Aiba, Isamu; Hossain, Anwar; Kuo, Macus Tien (2008) Elevated GSH level increases cadmium resistance through down-regulation of Sp1-dependent expression of the cadmium transporter ZIP8. Mol Pharmacol 74:823-33
Chen, Helen H W; Song, Im-Sook; Hossain, Anwar et al. (2008) Elevated glutathione levels confer cellular sensitization to cisplatin toxicity by up-regulation of copper transporter hCtr1. Mol Pharmacol 74:697-704
Kuo, Macus Tien; Chen, Helen H W; Song, Im-Sook et al. (2007) The roles of copper transporters in cisplatin resistance. Cancer Metastasis Rev 26:71-83
Kuo, M Tien (2007) Roles of multidrug resistance genes in breast cancer chemoresistance. Adv Exp Med Biol 608:23-30

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