Irinotecan-Induced Apoptosis Is Inhibited by Increased P-Glycoprotein Expression and Decreased p53 in Human Hepatocellular Carcinoma Cells(Molecular and Cell Biology)
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概要
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Irinotecan, a DNA topoisomerase I inhibitor, is widely used in cancer chemotherapy. However, little is known of the mechanisms of its antitumor effects and the development of drug resistance in human hepatocellular carcinoma (HCC). In this study, we investigated the effects of short-term culture with SN-38, the active metabolite of irinotecan, on apoptosis in Huh7 cells. The cells were cultured with SN-38 for 24, 72, and 120h, and apoptosis was determined using the terminal dUTP nick-end labeling (TUNEL) assay. The expressions of p53, apoptosis-related proteins, and P-glycoprotein (P-gp), a protein conferring the multidrug-resistant phenotype, were analyzed using Western blotting. Induced expression of P-gp was detected using fluorescence microscopy. SN-38 significantly induced apoptosis in Huh7 cells at 24 h. SN-38 also increased the expression of p53, Bax, and caspase-9 and decreased Bcl-xL expression in Huh7 cells. SN-38 decreased p53 expression and increased P-gp expression after 120h, resulting in inhibition of apoptosis. This inhibition was reversed by the addition of verapamil to the culture medium during 120h incubation. SN-38-induced P-gp expression was additionally enhanced by p53 decoy oligodeoxynucleotide. The changes in P-gp expression were directly moderated by p53 gene downregulation, suggesting that it plays a role in the mechanism of drug resistance. These results suggest that the accumulation of irinotecan in HCC leads to the development of drug resistance.
- 公益社団法人日本薬学会の論文
- 2007-08-01
著者
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TAKEBA Yuko
Department of Pharmacology, St. Marianna University School of Medicine
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KUMAI Toshio
Department of Pharmacology, St. Marianna University School of Medicine
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MATSUMOTO Naoki
Department of Pharmacology, St. Marianna University School of Medicine
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NAKAYA Sachiko
Department of Pharmacology, St. Marianna University School of Medicine
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YANAGIDA Yohei
Department of Pharmacology, St. Marianna University School of Medicine
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KOBAYASHI Shinichi
Department of Pharmacology, St. Marianna University School of Medicine
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NAKANO Hiroshi
Department of Internal Medicine, Fujita-Gakuen Health University School of Medicine
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Kobayashi Shinichi
Department Of Pharmacology St Marianna University School Of Medicine
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Kobayashi Shinichi
聖マリアンナ医科大学 小児科学教室
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Matsumoto Naoki
Department Of Pharmacology St Marianna University School Of Medicine
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Matsumoto Naoki
Department Of Cardiology St. Marianna University School Of Medicine
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SEKINE Susumu
Department of Pharmacology, St. Marianna University School of Medicine
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TSUZUKI Yashimitsu
Department of Pharmacology, St. Marianna University School of Medicine
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ASAKURA Takeshi
Department of Surgery, St. Marianna University School of Medicine
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OHTSUBO Takehito
Department of Surgery, St. Marianna University School of Medicine
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Kobayashi Shinichi
Dep. Of Pharmacology St. Marianna Univ. School Of Medicine
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Kobayashi Shinichi
Department Of Pharmacology School Of Medicine Showa University:shionogi Research Laboratories Shiono
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Nakano Hiroshi
Department Of Clinico-laboratory Diagnostics Nara Medical University
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Takeba Yuko
Dep. Of Pharmacology St. Marianna Univ. School Of Medicine
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Kumai T
Dep. Of Pharmacogenomics St. Marianna Univ. School Of Medicine
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Kumai Toshio
Department Of Pharmacology St Marianna University School Of Medicine
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Sekine Susumu
Department Of Pharmacology St. Marianna University School Of Medicine
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Nakaya Sachiko
Department Of Pharmacology St. Marianna University School Of Medicine
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Asakura Takeshi
Department Of Surgery St. Marianna University School Of Medicine
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Tsuzuki Yashimitsu
Department Of Pediatrics St Marianna University School Of Medicine
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Otsubo Takehito
Div. Of Gastroenterological Surgery St. Marianna Univ. School Of Medicine
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Matsumoto Nagisa
Molecular Life Science Division School Of Life Science Tokyo University Of Pharmacy And Life Science
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Ohtsubo Takehito
Department Of Surgery Institute Of Gastroenterology Tokyo Women's Medical College
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Kobayashi Shinichi
Department Of Biomedical Engineering Graduate School Of Medicine University Of Tokyo
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Matsumoto Naoki
Department Of Pharmacology St. Marianna University School Of Medicine
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Sekine Susumu
Department Of Breast Surgery Tokyo Metropolitan Komagome Hospital
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Nakano Hiroshi
Department Of Anesthesia Okazaki City Hospital
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Nakano Hiroshi
Department Of Surgery St. Marianna University School Of Medicine
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Ohtsubo Takehito
Department Of Gastroenterological Surgery Tokyo Women's Medical University
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Yoshida Yutoku
Dep. Of Pharmacogenomics St. Marianna Univ. Graduate School Of Medicine Jpn
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Asakura Takeshi
Department Of Gastroenterological Surgery St. Marianna University Hospital St. Marianna University S
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Yanagida Yohei
Department Of Pharmacogenomics St. Marianna University Graduate School Of Medicine
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Takeba Yuko
Department Of Pharmacology St. Marianna University School Of Medicine
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Kumai Toshio
Department of Pharmacogenomics, St. Marianna University School of Medicine
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Matsumoto Naoki
Department of Anesthesia, Gunma Prefectural Cardiovascular Center
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