The Importance of DT-Diaphorase in Mitomycin C Resistance in Human Colon Cancer Cell Lines

Lambert, Paul A.; Kang, Yuan; Greaves, Bridget; Perry, Roger R.

doi:10.1006/jsre.1998.5481

Cited by 11 publications

(2 citation statements)

References 16 publications

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“…A polymorphism of the gene encoding DT-diaphorase has been described (Traver et al 1997). This mutation (a C-to-T transition at base pair 609 coding for a proline to serine substitution) causes a loss of enzyme activity Siegel et al 1999) and resistance to anticancer agents that require reductive activation (Lambert et al 1998). Individuals homozygous for this change (T/T) have no detectable DT-diaphorase activity.…”

Section: Discussionmentioning

confidence: 99%

NAD(P)H:Quinone Oxidoreductase 1 Expression in Kidney Podocytes

Zappa

Ward

Pedrinis

et al. 2003

J Histochem Cytochem.

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(FZ,TW,JB,AM), and Institute of Pathology of Southern Switzerland, Locarno, Switzerland (EP) S U M M A R Y NAD(P)H:quinone oxidoreductase 1 (NQO1; DT-diaphorase; DTD) is a cytosolic two-electron reductase, and compounds of the quinone family such as mitomycin C are efficiently bioactivated by this enzyme. The observation that DT-diaphorase is highly expressed in many cancerous tissues compared to normal tissues has provided us with a potentially selective target that can be exploited in the design of novel anticancer agents. Because of the relative lack of information about the cell-specific expression of DT-diaphorase, the purpose of this study was to map the distribution of this enzyme in normal human tissues. Fifteen tissue samples from normal human kidney were analyzed for expression of DT-diaphorase by immunohistochemistry (two-step indirect method). We found a specific high expression of DT-diaphorase in glomerular visceral epithelial cells (podocytes). These results suggest that a high expression of DT-diaphorase in podocytes could play a major role in the pathogenesis of renal toxicity and mitomycin C-induced hemolytic uremic syndrome, in which injury to the glomerular filtration mechanism is the primary damage, leading to a cascade of deleterious events including microangiopathic hemolytic anemia and thrombocytopenia. This observation has potential therapeutic implications because the DT-diaphorase metabolic pathway is influenced by many agents, including drugs, diet, and environmental cell factors such as pH and oxygen tension.

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Section: Discussionmentioning

confidence: 99%

NAD(P)H:Quinone Oxidoreductase 1 Expression in Kidney Podocytes

Zappa

Ward

Pedrinis

et al. 2003

J Histochem Cytochem.

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“…In this way, the increment obtained in GST activity (1.84) was also similar to the activity increment obtained by the same author on ES-2R cells (2.6) (11). In addition, these results suggest that GSH and GST may play an important role in MDR cells that express high levels of P-gly, as in K-H300 leukemic cells (2) or on a panel of colon cancer cell lines selected by repeated mitomycin C exposure (10). In contrast, other authors (18) have selected an alkylating-resistant cell line derived from the MCF-7 human breast carcinoma that do not express the multidrug-resistant phenotype but a significant increase in the cellular content of glutathione has been measured, suggesting that other resistance mechanisms could be operative (18).…”

Section: Statistical Analysis>mentioning

confidence: 93%

P-glycoprotein, glutathione and glutathione S-transferase increase in a colon carcinoma

Ruiz-Gómez

Souviron

Martı́nez-Morillo

et al. 2000

J. Physiol. Biochem.

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The acquisition of resistance to anticancer agents used in chemotherapy is the main cause of treatment failure in malignant disorders, provoking tumours to become resistant during treatment, although they initially respond to it. The main multidrug resistance (MDR) mechanism in tumour cells is the expression of P-gly-coprotein (P-gly), that acts as an ATP-dependent active efflux pump of chemotherapeutic agents. Furthermore, an increased detoxification of compounds mediated by high levels of glutathione (GSH) and glutathione S-transferase (GST), has been found in resistant cells. We developed a study aiming to evaluate the evolution of the main drug resistance markers in tumour cells: P-gly, GSH and GST, during the acquisition of resistance to colchicine, for the purpose of studying the adaptation process and its contribution to the MDR phenomenon. A human colon adenocarcinoma cell line was exposed to colchicine during 82 days, being P-gly, GSH levels and GST activity evaluated by flow cytometry, spectrofluorimetry and spectrophotometry, during exposure time. P-gly and GSH levels increased gradually during the exposure to colchicine, reaching 2.35 and 3.21 fold each. On day 82, GST activity increased 1.84 fold at the end of the exposure period. Moreover, an increment in drug cross-resistance was obtained that ranges from 2.62 to 5.22 fold for colchicine, vinblastine, vincristine and mitomycin C. The increments obtained in P-gly, GSH and GST could probably contribute to the MDR phenomenon in this human colon adenocarcinoma cell line.

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