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간암 세포에서 doxorubicin 저항성 극복을 위한 전략 연구
- Alternative Title
- Study on the Strategies to Overcome Doxorubicin Resistance in Hepatoma Cells
- Author(s)
- 박석순
- Alternative Author(s)
- Seok Soon Park
- Advisor
- 최경숙
- Department
- 일반대학원 분자과학기술학과
- Publisher
- The Graduate School, Ajou University
- Publication Year
- 2010-02
- Language
- eng
- Keyword
- Cdc2; Cdk2; doxorubicin; mitotic catastrophe; apoptosis; hepatoma; Bcl-xL; PDTC; autophagy; 간암세포
- Alternative Abstract
- Study on the strategies to overcome doxorubicin resistance in hepatoma cells In Huh-7 hepatoma cells, low dose (LD) doxorubicin treatment induces cell death through mitotic catastrophe accompanying the formation of large cells with multiple micronuclei, whereas high dose (HD) doxorubicin induces apoptosis. In part I, I investigated the role of Cdc2 and Cdk2 kinase in the regulation of the two modes of cell death induced by doxorubicin, apoptosis and cell death through mitotic catastrophe. During HD doxorubicin-induced apoptosis, the histone H1-associated activities of Cdc2 and Cdk2 both progressively declined in parallel with reductions in cyclin A and cyclin B protein levels. In contrast, during LD doxorubicin-induced cell death through mitotic catastrophe, the Cdc2 and Cdk2 kinases were transiently activated 1 day post-treatment, with similar changes seen in the protein levels of cyclin A, cyclin B and Cdc2. Treatment with roscovitine, a specific inhibitor of Cdc2 and Cdk2, significantly blocked LD doxorubicin-induced mitotic catastrophe and cell death, but did not affect HD doxorubicin-induced apoptosis in Huh-7, SNU-398 and SNU-449 hepatoma cell lines. Our results demonstrate that differential regulation of Cdc2 and Cdk2 activity by different doses of doxorubicin may contribute to the induction of two distinct modes of cell death in hepatoma cells, either apoptosis or cell death through mitotic catastrophe. Bcl-xL is often overexpressed in human hepatocellular carcinoma cells, contributing to resistance to various chemotherapeutic agents. I investigated the role of Bcl-xL in two modes of cell death induced by different doses of doxorubicin, apoptosis and cell death through mitotic catastrophe. Bcl-xL overexpression in various hepatoma cells effectively blocked apoptosis induced by high dose doxorubicin, inhibiting the loss of mitochondrial membrane potential, release of mitochondrial cytochrome c and caspase activation. Contrastingly, Bcl-xL overexpression did not block low dose doxorubicin-induced mitotic catastrophe and subsequent non-apoptotic cell death, without affecting abnormal cell cycle progression, formation of multiple micronuclei, loss of mitochondrial membrane potential, release of mitochondrial cytochrome c, and the clonogenicity of cells exposed to low dose doxorubicin. These findings indicate that low dose doxorubicin-induced cell death through mitotic catastrophe may provide an alternative therapeutic strategy for Bcl-xL-overexpressing hepatoma cells, which are resistant to pro-apoptotic treatments. In part II, I investigated whether co-treated pyrrolidine dithiocarbamate (PDTC) might overcome Bcl-xL-mediated resistance to doxorubicin in hepatoma cells. I found that combined treatment with PDTC and doxorubicin induced the cell death accompanying autophagy in Bcl-xL-overexpressing Chang liver and hepatoma cells. Contrastingly, co-treated PDTC attenuated doxorubicin-induced apoptosis in Chang liver cells and hepatocytes. Thus, combined regimen with PDTC and doxorubicin may provide a safe and effective therapeutic strategy for malignant hepatoma with Bcl-xL-mediated apoptotic defects.
- Fulltext
- Appears in Collections:
- Graduate School of Ajou University > Department of Molecular Science and Technology > 3. Theses(Master)
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