| Budget Amount *help |
¥2,410,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥210,000)
Fiscal Year 2007: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2006: ¥1,500,000 (Direct Cost: ¥1,500,000)
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| Research Abstract |
ABCG2/BCRP, a member of the ATP-binding cassette transporter G family, functions as an efflux pump that excludes such anticancer agents as mitoxantrone, SN-38 (an active metabolite of irinotecan), and topotecan, across cell membrane. Accordingly ABCG2 causes multidrug resistance when overexpressed in cancer cells. We have thus far clarified that estrogen markedly down-regulates ABCG2 expression in estrogen receptor-positive breast cancer cells in the post-transcriptional manner, but use of estrogen in the practical clinic seemed to be limited due to its original physiological function.
We then transfected ABCG2 cDNA to breast cancer MCF-7 cells and gastric cancer MKN1 and NCI-N87 cells, which express endogenous ABCG2, in order to exploring small molecules that affects ABCG2 expression levels, and termed them MCF-7/ABCG2, MKN1/ABCG2, and NCI-N87/ABCG2 cells.
Exogenous ABCG2 protein expression in MCF-7/ABCG2, MKN1/ABCG2, NCI-N87/ABCG2 cells was markedly repressed by p44/p42 mitogen-activat
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ed protein kinase (MAPK), PD98059 and U0126, in the dose-dependent manner. These compounds almost completely overcame mitoxantrone- or SN-38- resistance of MCF-7/ABCG2 and NCI-N87/ABCG2 cells. FACS analyses revealed that the reversal effects were due to increased intracellular uptake of anticancer agents. Quantitative RT-PCR analyses demonstrated that ABCG2 mRNA levels were not affected by the treatment with PD98059 or U0126. In addition, a half life of the ABCG2 protein was significantly short in the presence of PD98059 as compared with that in the control experiment.
PD98059-mediated degradation of ABCG2 protein was not affected by MG132, an ubiquitin/endosome inhibitor, but was completely blocked by bafilomycin A1, an endosomal inhibitor. These data suggest that inhibition of p44/p42 MAPK pathway may accelerate endosomal degradation of ABCG2 protein and makes it possible to overcome ABCG2-mediated multidrug resistance. These data may also suggest that p44/p42 MAPK inhibitors may serve for establishment of safe and effective chemotherapeutic regimen. Less
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