Parthenolide induces significant apoptosis and production of reactive oxygen species in high-risk pre-B leukemia cells

doi:10.1016/j.canlet.2007.03.002

Cancer Letters

Volume 254, Issue 1, 28 August 2007, Pages 119-127

https://doi.org/10.1016/j.canlet.2007.03.002 Get rights and content

Abstract

We investigated whether parthenolide, the principal bioactive component of the herb feverfew (Tanacetum parthenium) induced apoptosis in pre-B acute lymphoblastic leukemia (ALL) lines, including cells carrying the t(4;11)(q21;q23) chromosomal translocation. Parthenolide induced rapid apoptotic cell death distinguished by loss of nuclear DNA, externalization of cell membrane phosphatidylserine, and depolarization of mitochondrial membranes at concentrations ranging from 5 to 100 μM. Using reactive oxygen species (ROS)-specific dyes, an increase in nitric oxide and superoxide anion was detected in the cells by 4 h after exposure to parthenolide. Parthenolide-induced elevation of hypochlorite anion was observed only in the two t(4;11) lines. These data suggest parthenolide may have potential as a potent and novel therapeutic agent against pre-B ALLs.

Introduction

Chromosomal abnormalities in the ALL-1 gene (also known as MLL, HRX, and HTRX1) on chromosome 11 are frequently involved in childhood ALL. The chromosomal translocation t(4;11)(q21;q23) is found in greater than 60% of infants, 2% of children, and 3–6% of adults diagnosed with ALL and the presence of this chromosomal abnormality is strongly associated with an exceedingly poor prognosis [1]. More recently, the frequency of the t(4;11) translocation in infants with ALL was placed at 85% [2]. The t(4;11) ALLs are often classified as pre-B cells, but display a mixed-lineage phenotype with both B and myeloid cell surface markers. Dual-lineage markers suggest that these leukemias may represent pluripotent hematopoietic progenitors that can potentially differentiate into lymphoid, myeloid, or other hematopoietic cells. This high-risk subgroup of ALL is highly resistant to conventional chemotherapeutics and has an exceedingly poor prognosis.

Parthenolide is a sesquiterpene lactone and the principal bioactive component of the medicinal herb feverfew (Tanacetum parthenium). Feverfew has been used for centuries as a folk medicine to treat migraines and rheumatoid arthritis [3]. Parthenolide has shown anti-inflammatory and anti-cancer activities [4], [5]. Potent anti-cancer activity of this substance is due in part to its ability to inhibit the transcription factor NF-κB, thereby reducing survival potential in a number of cancer cells [6], [7]. Parthenolide-induced generation of reactive oxygen species (ROS) in cancer cells has also been shown to play a role in promoting apoptotic cell death [8].

We have previously shown that a number of phytochemicals can effectively induce apoptotic cell death in cell lines that were established from patients with high-risk, B-lineage acute lymphoblastic leukemia (ALL) carrying the t(4;11)(q21;q23) chromosomal translocation, as well as other ALL lines without the translocation [9], [10], [11]. In the current study, the ability of parthenolide from the herb feverfew to induce apoptosis was examined in two t(4;11) pre-B ALL-derived cell lines and a pre-B ALL line without the translocation. We hypothesized that parthenolide would be effective in killing these leukemia cells. Parthenolide produced significant apoptotic death accompanied by mitochondrial dysfunction in the ALL lines and the t(4;11) lines were more sensitive to this agent than cells without the translocation. Parthenolide increased the production of nitric oxide and superoxide anion in the ALL lines. The production of the potent oxidant hypochlorite anion was also increased in the mixed-lineage t(4;11) lines, but not the cells without the translocation, in response to parthenolide treatment. These data suggest that parthenolide may be useful as a novel therapeutic agent against high-risk t(4;11) as well as other ALLs.

Section snippets

Reagents

Parthenolide was purchased from EMD Biosciences (San Diego, CA) and stock solutions were dissolved dimethylsulfoxide (DMSO, Sigma Chemical Co., St. Louis, Mo.) before use. JC-1 (5,5′,6,6′-tetrachloro-1,1′,3,3′-tetraethylbenzimidazolylcarbocyanine iodide) was purchased from Molecular Probes (Eugene, OR) and stock solutions were prepared in DMSO. Alexa Fluor 488-conjugated Annexin V and propidium iodide (PI) were obtained from Molecular Probes and Sigma, respectively. The cell permeable dye

Parthenolide induces apoptotic cell death in B-ALL lines

Time course and dose–response analyses were performed with two pre-B t(4;11) ALL lines SEM and RS4;11 and the pre-B ALL line REH which has no t(4;11) translocation. The cells were treated once with 0, 5, 10, 25, 50, and 100 μM parthenolide, and percent cell death was measured at 24, 48, and 72 h by PI staining of nuclei and evaluation by FACS (Fig. 1). Both SEM and RS4;11 cells showed greater sensitivity to parthenolide at a dose of 10 μM compared to REH. By 72 h post-treatment, SEM and RS4;11

Discussion

Pre-B ALL with chromosomal translocation t(4;11) are commonly refractory to conventional chemotherapeutics after relapse. A need exists for novel approaches to treat high-risk leukemia. Parthenolide, derived from the medicinal herb feverfew, has shown promise as a potential new chemotherapeutic agent. In our study, we show that parthenolide induced significant depolarization of mitochondrial membranes and apoptotic cell death in several pre-B ALL lines. The pre-B ALL lines SEM and RS4;11 with

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Parthenolide induces significant apoptosis and production of reactive oxygen species in high-risk pre-B leukemia cells

Abstract

Introduction

Section snippets

Reagents

Parthenolide induces apoptotic cell death in B-ALL lines

Discussion

Blood

J. Ethnopharmacol.

J. Biol. Chem.

J. Biol. Chem.

Cancer Lett.

Cancer Lett.

Blood

J. Immunol. Methods

Exp. Cell Res.

J. Biol. Chem.

J. Immunol. Methods

Fed. Eur. Biochem. Soc. Lett.

Fed. Eur. Biochem. Soc. Lett.

Arch. Biochem. Biophys.