Oxidative stress-mediated apoptosis. The anticancer effect of the sesquiterpene lactone parthenolide.
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 microm concentrations and arrested the cell growth (at G(2)/M) at sublethal concentrations (1-3 microm). 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 pi. Finally, parthenolide and its derivatives may be useful chemotherapeutic agents to treat these invasive cancers.
Wen
Jing
J
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.
You
Kyung-Ran
KR
Lee
So-Youn
SY
Song
Chang-Ho
CH
Kim
Dae-Ghon
DG
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000502:physiology*; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy*; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D003574:Cytochrome c Group / Q000378:metabolism; D005434:Flow Cytometry; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D008564:Membrane Potentials / Q000502:physiology; D018384:Oxidative Stress; D012717:Sesquiterpenes / Q000494:pharmacology* / Q000627:therapeutic use*; D051742:Transcription Factor CHOP; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000894:Anti-Inflammatory Agents, Non-Steroidal; D022762:CCAAT-Enhancer-Binding Proteins; D003574:Cytochrome c Group; C497249:DDIT3 protein, human; D012717:Sesquiterpenes; D014157:Transcription Factors; D051742:Transcription Factor CHOP; C002669:parthenolide; D020169:Caspases; D005978:Glutathione