Bioreductive chemotherapy is based on reductive activation of drugs by enzymes including cytosolic NAD(P)H:quinone oxidoreductases (NQO1 and NQO2) and microsomal NADPH:cytochrome P450 reductase, identification of tumors rich in those enzymes, and differences in oxygen and pH between normal and tumor tissues. Recently, we have identified and cloned the cytosolic glucose regulatory protein (GRP58) that also plays significant role in activation of drugs. GRP58 catalyzed activation of mitomycin C that led to DNA cross-linking. GRP58 was found overexpressed in many tumors including breast, uterus, lung and stomach. However, the mechanism of the role of GRP58 in mitomyein C-induced DNA cross-linking remains unknown. GRP58-null mouse has not been generated and the in vivo role of GRP58 remains largely unknown. Recent studies have shown that significant percentage of human individuals with chemotherapy-induced secondary leukemia carry both mutant NQO1 P187S alleles and are deficient in NQO 1 protein and activity. However, it is unknown if the absence of NQO1 contributed to chemotherapy- induced leukemia. NQO 1-null mice deficient in NQO 1 protein and activity were generated in our laboratory. The three specific aims of this competing renewal are as follows. 1). Determine the mechanism of the role of GRP58 in mitomycin C-induced DNA cross-linking. This will be achieved by testing the hypothesis that two thioredoxin domains in GRP58 in combination with thioredoxin reductase and/or phosphorylation of GRP58 and/or glycosylation of GRP58 play significant role in activation of mitomycin C or transport of mitomycin C to the nucleus leading to DNA cross-linking. We plan to use site-directed mutagenesis, transfection and other assays to achieve goals of this aim. 2). Generate GRP58-null mouse deficient in GRP58 and study the in vivo role of GRP58 in mouse development and mitomycin C toxicity. Embryonic stem cells and homologous recombination will be used to generate GRP58-null mice that will be exposed to mitomycin C and other anti-tumor drugs and analyzed for their sensitivity to DNA and membrane damage. 3). Investigate the in vivo role of NQO 1 in chemotherapy related leukemia, NQO 1-null mice will be exposed to alkylating agents or TOPOII inhibitors alone or with radiation and the mice analyzed for CBCs, bone marrow, lymph nodes, spleen and thymus for symptoms of myeloid and lymphoid leukemia and chromosomal aberrations. These studies are expected to provide mechanism of the role of GRP58 in mitomycin C-induced DNA cross-linking, in vivo role of GRP58 in mouse development and mitomycin C and other drugs toxicity and in vivo role ofNQO 1 in chemotherapy related leukemia.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Drug Discovery and Molecular Pharmacology Study Section (DMP)
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Forry, Suzanne L
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University of Maryland Baltimore
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Iskander, Karim; Barrios, Roberto J; Jaiswal, Anil K (2009) NRH:quinone oxidoreductase 2-deficient mice are highly susceptible to radiation-induced B-cell lymphomas. Clin Cancer Res 15:1534-42
Adikesavan, Anbu Karani; Unni, Emmanual; Jaiswal, Anil K (2008) Overlapping signal sequences control nuclear localization and endoplasmic reticulum retention of GRP58. Biochem Biophys Res Commun 377:407-12
Iskander, Karim; Barrios, Roberto J; Jaiswal, Anil K (2008) Disruption of NAD(P)H:quinone oxidoreductase 1 gene in mice leads to radiation-induced myeloproliferative disease. Cancer Res 68:7915-22
Gong, Xing; Gutala, Ramana; Jaiswal, Anil K (2008) Quinone oxidoreductases and vitamin K metabolism. Vitam Horm 78:85-101
Wang, Wei; Le, Wei-Dong; Pan, Tianhong et al. (2008) Association of NRH:quinone oxidoreductase 2 gene promoter polymorphism with higher gene expression and increased susceptibility to Parkinson's disease. J Gerontol A Biol Sci Med Sci 63:127-34
Adikesavan, Anbu Karani; Jaiswal, Anil K (2007) Thioredoxin-like domains required for glucose regulatory protein 58 mediated reductive activation of mitomycin C leading to DNA cross-linking. Mol Cancer Ther 6:2719-27
Adikesavan, Anbu Karani; Barrios, Roberto; Jaiswal, Anil K (2007) In vivo role of NAD(P)H:quinone oxidoreductase 1 in metabolic activation of mitomycin C and bone marrow cytotoxicity. Cancer Res 67:7966-71
Su, Shibing; Adikesavan, Anbu Karani; Jaiswal, Anil K (2006) Si RNA inhibition of GRP58 associated with decrease in mitomycin C-induced DNA cross-linking and cytotoxicity. Chem Biol Interact 162:81-7
Celli, Claudia M; Tran, Namphuong; Knox, Richard et al. (2006) NRH:quinone oxidoreductase 2 (NQO2) catalyzes metabolic activation of quinones and anti-tumor drugs. Biochem Pharmacol 72:366-76
Iskander, Karim; Jaiswal, Anil K (2005) Quinone oxidoreductases in protection against myelogenous hyperplasia and benzene toxicity. Chem Biol Interact 153-154:147-57

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