Title: PARTHENOLIDE INDUCES SIGNIFICANT APOPTOSIS AND PRODUCTION OF REACTIVE OXYGEN SPECIES IN HIGH-RISK PRE-B LEUKEMIA CELLS Authors
Submitted to: Cancer Letters
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: March 2, 2007
Publication Date: August 28, 2007
Citation: Zunino, S.J., Ducore, J.H., Storms, D.H. Parthenolide induces significant apoptosis and production of reactive oxygen species in high-risk pre-b leukemia cells. 2007 Cancer Letters 254: 119-127. Interpretive Summary: The herb feverfew has been used for centuries in Europe for treatment of migraines and rheumatoid arthritis. The main active chemical in this plant is parthenolide, which has more recently shown anti-cancer activity against a variety of cancer cells. High-risk infant leukemia is resistant to conventional chemotherapy. Therefore, there is a need to discover novel therapeutic strategies for this disease. We hypothesized that parthenolide could kill leukemia cells and tested this chemical against several cell lines that were established from patients with leukemia. We found that parthenolide could efficiently kill these leukemia cells at low concentrations. We also found that parthenolide acted on the leukemia cells by disrupting the function of the mitochondria, the organelle responsible for generation of energy for each cell. These studies suggest that parthenolide may be useful as a new therapeutic agent in the treatment of acute leukemia, especially the high-risk infant leukemia.
Technical Abstract: Parthenolide is the principal bioactive component of the medicinal herb feverfew and has shown anti-cancer activity. We hypothesized that parthenolide could induce apoptosis in leukemia lines established from patients with acute lymphoblastic leukemia (ALL), including the high-risk, B-lineage ALL carrying the t(4;11)(q21;q23) chromosomal translocation. Using SEM and RS4;11 B-ALL lines with the t(4;11) translocation, the B-ALL line REH, and the T-ALL line Jurkat, we show that parthenolide induced cell death in a dose and time-dependent manner. Concentrations of parthenolide used were from 5 to 100 mM. Apoptosis was determined by annexin V/propidium iodide staining and significant apoptosis was observed at a concentration as low as 5 mM parthenolide after 24 h. Loss of mitochondrial membrane depolarization accompanied apoptotic cell death as measured by staining with the mitochondria-selective dye JC-1. Parthenolide also displayed antioxidant activity in the oxygen radical absorbance capacity (ORAC) assay, suggesting that part of its activity could be due to antioxidant-mediated mechanisms. These data suggest that parthenolide is a potent inducer of apoptosis in ALL lines and may be useful as a novel treatment, especially high-risk infant ALL.