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Susceptibility of Cholangiocarcinoma Cells to Parthenolide-Induced Apoptosis

¹ Division of GI and Hepatology, Department of Internal Medicine, Institute for Molecular Biology and Genetics, Chonbuk National University Medical School and Hospital, Jeonju, Jeonbuk and ² Department of Internal Medicine, Seoul National University School of Medicine, Seoul, Republic of Korea

Requests for reprints: Dae-Ghon Kim, Division of GI and Hepatology, Chonbuk National University Medical School and Hospital, 634-18 Keumam-dong, Dukjin-ku, Jeonju, Jeonbuk 561-712, Republic of Korea. Phone: 82-63-250-1681; Fax: 82-63-254-1609; E-mail: daeghon{at}moak.chonbuk.ac.kr.

Cholangiocarcinomas are intrahepatic bile duct carcinomas that are known to have a poor prognosis. Sesquiterpene lactone parthenolide, which is the principal active component in medicinal plants, has been used to treat tumors. Parthenolide effectively induced apoptosis in all four cholangiocarcinoma cell lines in a dose-dependent manner. However, the sarcomatous SCK cells were more sensitive to parthenolide than the other adenomatous cholangiocarcinoma cells. Therefore, this study investigated whether or not the expression of p53, the Fas/Fas ligand (FasL), Bcl-2/Bcl-X_L determines the enhanced drug susceptibility of SCK cells. The results showed that Bcl-2 family molecules, such as Bid, Bak, and Bax, are involved in the parthenolide-induced apoptosis and that the defective expression of Bcl-X_L might contribute to the higher parthenolide sensitivity in the SCK cells than in the other adenomatous cholangiocarcinoma cells. SCK cells, which stably express Bcl-X_L, were resistant to parthenolide, whereas Bcl-X_L-positive Choi-CK cells transfected with the antisense Bcl-X_L showed a higher parthenolide sensitivity than the vector control cells. Molecular dissection revealed that Bcl-X_L inhibited the translocation of Bax to the mitochondria, decreased the generation of intracellular reactive oxygen species, reduced the mitochondrial transmembrane potential (_m), decreased the release of cytochrome c, decreased the cleavage of poly(ADP-ribose) polymerase, and eventually inhibited apoptotic cell death. These results suggest that parthenolide effectively induces oxidative stress-mediated apoptosis, and that the susceptibility to parthenolide in cholangiocarcinoma cells might be modulated by Bcl-X_L expression in association with Bax translocation to the mitochondria.

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