Expression of the Multidrug-Resistant Gene in Hepatocarcinogenesis and Regenerating Rat Liver

Thorgeirsson, SS; Be, Huber; Sorrell, Susan H.; Fojo, Antonio Tito; Pastan, Ira; Gottesman, M M

doi:10.1126/science.3576227

Cited by 251 publications

(82 citation statements)

References 27 publications

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“…We (Deng et al, 2001a) and others (Silverman and Hill, 1995;Fairchild et al, 1987;Thorgeirsson et al, 1987) have previously demonstrated that expression of rat mdr1b in hepatoma cells can be induced by 2-AAF. To investigate whether 2-AAF could induce human MDR1 expression in cultured cells, we treated HepG2 cells with AAAF at concentrations ranging from 10 to 40 mM for 8 h. AAAF is an active metabolite of 2-AAF.…”

Section: -Aaf and Aaaf Up-regulate Human Mdr1 Mrna Expressionmentioning

confidence: 99%

“…Likewise, enhanced expression of mdr1a and mdr1b are observed in rodent HCC induced by various hepatocarcinogenetic programs (Fairchild et al, 1987;Teeter et al, 1990Thorgeirsson et al, 1987). In rats, hepatic expression of mdr1b can be induced by the hepatocarcinogen 2-acetylamino¯uorene (2-AAF) Thorgeirsson et al, 1987). 2-AAF is a model hepatocarcinogen used in many experimental liver cancer studies (Verna et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

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Induction of human MDR1 gene expression by 2-acetylaminofluorene is mediated by effectors of the phosphoinositide 3-kinase pathway that activate NF-κB signaling

et al. 2002

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The expression of P-glycoprotein encoded by the multidrug resistance (MDR1) gene is associated with the emergence of the MDR phenotype in cancer cells. Human MDR1 and its rodent homolog mdr1a and mdr1b are frequently overexpressed in liver cancers. However, the underlying mechanisms are largely unknown. The hepatocarcinogen 2-acetylamino¯uorene (2-AAF) e ciently activates rat mdr1b expression in cultured cells and in Fisher 344 rats. We recently reported that activation of rat mdr1b in cultured cells by 2-AAF involves a cis-activating element containing a NFkB binding site located 7167 to 7158 of the rat mdr1b promoter. 2-AAF activates IkB kinase (IKK), resulting in degradation of IkBb and activation of NF-kB. In this study, we report that 2-AAF could also activate the human MDR1 gene in human hepatoma and embryonic ®broblast 293 cells. Induction of MDR1 by AAF was mediated by DNA sequence located at 76092 which contains a NF-kB binding site. Treating hepatoma cells with 2-AAF activated phosphoinositide 3-kinase (PI3K) and its downstream e ectors Rac1, and NAD(P)H oxidase. Transient transfection assays demonstrated that constitutively activated PI3K and Rac1 enhanced the activation of the MDR1 promoter by 2-AAF. Treatment of hepatoma cells with 2-AAF also activated another PI3K downstream e ector Akt. Transfection of recombinant encoding a dominant activated Akt also enhanced the activation of MDR1 promoter activation by 2-AAF. These results demonstrated that 2-AAF up-regulates MDR1 expression is mediated by the multiple e ectors of the PI3K signaling pathway.

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Section: -Aaf and Aaaf Up-regulate Human Mdr1 Mrna Expressionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Induction of human MDR1 gene expression by 2-acetylaminofluorene is mediated by effectors of the phosphoinositide 3-kinase pathway that activate NF-κB signaling

et al. 2002

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“…Daunorubicin-resistant mutant cell line, AH66DR, has been previously reported (Ohkawa et al, 1989a) to show cross- (Thorgeirsson et al, 1987;Ueda et al, 1987;Huang et al, 1992;Miyamoto et al, 1992 (Theibaut et al, 1987).…”

Section: Discussion O \\mentioning

confidence: 99%

Chemotherapeutic efficacy of the protein-doxorubicin conjugates on multidrug resistant rat hepatoma cell line in vitro

Ohkawa

Hatano²,

Tsutsumi³

et al. 1993

Br J Cancer

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“…Indeed, the expressions of p-glycoprotein are observed in Vin R KB and Adr R MCF-7 cells and in vivo DEN-induced preneoplastic lesion model, consist in previous literatures. 12,16,24 The trans-membrane p-glycoprotein exists the intracellular drug binding sites and two specific ATP binging sites that corporate the transport of drug to extra membrane and become targets for chemosensitization. The calcium channel antagonist verapamil could compete the drug-binding site so that block the p-glycoprotein transport.…”

Section: Discussionmentioning

confidence: 99%

“…[3][4][5][6][7][8][9] Recently, the chemoprevention of Bicyclol against the preneoplastic lesions in rat liver induced by diethylnitrosamie (DEN) 10 is revealed (in the process of publication), consistent with the similar study of DDB for in vitro model. 11 Interestingly, as an intrinsic multiple drug resistant (MDR) model, 12 the DEN induced the expression of p-glycoprotein, the Mdr-1 gene product, in the rat hepatic preneoplastic lesions. It was suppressed by Bicyclol treatment (Fig.…”

Section: Introductionmentioning

confidence: 99%

Chemosensitizing multiple drug resistance of human carcinoma by bicyclol involves attenuated P-glycoprotein, GST-P and Bcl-2

Zhu

Liu²,

Zhao³

et al. 2006

Cancer Biology & Therapy

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Bicyclol, a second generation of synthetic hepatoprotectant being used in China for anti-hepatitis therapy, shows chemosensitizing effect on reverting multiple drug resistance (MDR) of cytostatic agents in two established MDR carcinoma cell lines, vincristine resistant human stomatic epidermoid carcinoma Vin R KB and adriamycin resistant human breast carcinoma Adr R MCF-7. The reversal rate of drug resistance was calculated from the changes of the IC 50 of cell growth inhibition. Bicyclol at the concentration of 25, 50, 100 µM induced 2.8 7.3 and 20.7 fold, respectively, reversal of vincristine resistance in Vin R KB cell. Bicyclol also reversed the cross-resistance of Vin R KB cell to taxol and Adr R MCF-7 cell resistance to adriamycin at the similar range of potency. Further, Bicyclol recovered the reduced accumulation of adriamycin in Adr R MCF-7 cell partially to the level in drugsensitive MCF-7 cell, indicate the inhibition of MDR related membrane efflux pump system. Overexpression of membrane p-glycoprotein coded by Mdr-1 genes, the most common efflux pump correlated to MDR, was found in both Vin R KB and Adr R MCF-7 cells by Western blot and immunocytochemistry as compared with drug-sensitive cells. The p-glycoprotein was decreased to the levels in drug-sensitive cells when Vin R KB and Adr R MCF-7 cells were treated with Bicyclol for 12-72 hours. Both Vin R KB and Adr R MCF-7 cells showed increased GSH contents, and Adr R MCF-7 cell showed increased GST activity and the overexpression of Bcl-2 protein, by which molecules are tightly related to the MDR formation besides Mdr-1 p-glycoprotein. Bicyclol reduced the GSH contents, GST activities and Bcl-2 expression. All these data demonstrate that, by modifying the expressions of Mdr-1, GSH/GST and Bcl-2, Bicyclol increases the intracellular drug concentration and sensitizes the resistant cells to the anti-carcinoma agents.

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Expression of the Multidrug-Resistant Gene in Hepatocarcinogenesis and Regenerating Rat Liver

Cited by 251 publications

References 27 publications

Induction of human MDR1 gene expression by 2-acetylaminofluorene is mediated by effectors of the phosphoinositide 3-kinase pathway that activate NF-κB signaling

Induction of human MDR1 gene expression by 2-acetylaminofluorene is mediated by effectors of the phosphoinositide 3-kinase pathway that activate NF-κB signaling

Chemotherapeutic efficacy of the protein-doxorubicin conjugates on multidrug resistant rat hepatoma cell line in vitro

Chemosensitizing multiple drug resistance of human carcinoma by bicyclol involves attenuated P-glycoprotein, GST-P and Bcl-2

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