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J. Biol. Chem., Vol. 277, Issue 41, 38954-38964, October 11, 2002

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Oxidative Stress-mediated Apoptosis
THE ANTICANCER EFFECT OF THE SESQUITERPENE LACTONE PARTHENOLIDE^*

Jing Wen, Kyung-Ran You, So-Youn Lee, Chang-Ho Song, and Dae-Ghon Kim^§

From the Division of Gastroenterology and Hepatology, Departments of Internal Medicine and  Anatomy Research Institute for Clinical Medicine, Chonbuk National University Medical School and Hospital, Chonju, Chonbuk 561-712, Republic of Korea

The sesquiterpene lactone parthenolide, the principal active component in medicinal plants, has been used conventionally to treat migraines, inflammation, and tumors. However, the antitumor effects of parthenolide and the mechanism(s) involved are poorly understood. We found that parthenolide effectively inhibits hepatoma cell growth in a tumor cell-specific manner and triggers apoptosis of hepatoma cells. Parthenolide triggered apoptosis in invasive sarcomatoid hepatocellular carcinoma cells (SH-J1) as well as in other ordinary hepatoma cells at 5-10 µM concentrations and arrested the cell growth (at G₂/M) at sublethal concentrations (1-3 µM). During parthenolide-induced apoptosis, depletion of glutathione, generation of reactive oxygen species, reduction of mitochondrial transmembrane potential, activation of caspases (caspases-7, -8, and -9), overexpression of GADD153 (an oxidative stress or anticancer agent inducible gene), and subsequent apoptotic cell death was observed. This induced apoptosis could be effectively inhibited or abrogated by an antioxidant N-acetyl-L-cysteine, whereas L-buthionine-(S,R)-sulfoximine enhanced it. Furthermore, stable overexpression of GADD153 sensitized the cells to apoptosis induced by parthenolide, and this susceptibility could be reversed by transfection with an antisense to GADD153. Parthenolide did not alter the expression of Bcl-2 or Bcl-X_L proteins during apoptosis in hepatoma cells. Oxidative stress may contribute to parthenolide-induced apoptosis and to GADD153 overexpression in a glutathione-sensitive manner. The sensitivity of tumor cells to parthenolide appears to result from the low expression level of the multifunctional detoxification enzyme glutathione S-transferase . Finally, parthenolide and its derivatives may be useful chemotherapeutic agents to treat these invasive cancers.

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