Parthenolide Induces Apoptosis in Glioblastomas Without Affecting NF-κB

Department of Biological Sciences, Western Michigan University, Kalamazoo 49008, USA.
Journal of Pharmacological Sciences (Impact Factor: 2.36). 03/2008; 106(2):318-20. DOI: 10.1254/jphs.SC0060164
Source: PubMed

ABSTRACT Parthenolide is a sesquiterpene lactone that has been isolated from Tanacetum parthenium (feverfew). Parthenolide has several biological activities including the induction of apoptosis and inhibition of NF-kappaB. Because of its activities against several tumor types and because it is relatively well tolerated, in clinical trial, parthenolide is an attractive compound for the treatment of brain tumors. However, there have been no reports concerning its ability to induce apoptosis in any brain tumor cell lines. In this report we demonstrate that treatment of glioblastoma cells with parthenolide resulted in rapid apoptosis through caspase 3/7 without a suppression of NF-kappaB activity.

2 Reads
  • Source
    • "To explore whether RIP3-MCF-7/MDA-MB-231 cells were more sensitive to PTL-induced apoptosis than control cells, control and RIP3-MCF-7/MDA-MB-231 cells treated with 12.5 μmol/L PTL for 48 h were stained by phosphatidylserine exposure to Annexin V-FITC and analyzed using flow cytometry. The results showed that PTL induced an increase in Annexin-V fluorescence from 6.2% in control cells to 29.2% in MCF-7 cells and from 9.7% in control cells to 17.9% in MDA-MB-231 cells1,2,15,16, and RIP3 overexpression with cotreatment of PTL resulted in an increase from 29.2% to 37.7% in MCF-7 cells and from 17.9% to 27.5% in MDA-MB-231 cells with PTL treatment only (Figure 3A). These findings indicate that MCF-7 and MDA-MB-231 cells expressing higher RIP3 levels are more sensitive to PTL-induced cell death. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Aim: Receptor-interacting protein 3 (RIP3) is involved in tumor necrosis factor receptor signaling, and results in NF-κB-mediated prosurvival signaling and programmed cell death. The aim of this study was to determine whether overexpression of the RIP3 gene could sensitize human breast cancer cells to parthenolide in vitro. Methods: The expression of RIP3 mRNA in human breast cancer cell lines (MCF-7, MDA-MB-231, MDA-MB-435 and T47D) was detected using RT-PCR. Both MDA-MB-231 and MCF-7 cells were transfected with RIP3 expression or blank vectors via lentivirus. Cell viability was measured with MTT assay; intracellular ROS level and cell apoptosis were analyzed using flow cytometry. Results: RIP3 mRNA expression was not detected in the four human breast cancer cell lines tested. However, the transfection induced higher levels of RIP3 protein in MCF-7 and MDA-MB-231 cells. Furthermore, overexpression of RIP3 decreased the IC50 values of parthenolide from 17.6 to 12.6 μmol/L in MCF-7 cells, and from 16.6 to 9.9 μmol/L in MDA-MB-231 cells. Moreover, overexpression of RIP3 significantly increased parthenolide-induced apoptosis and ROS accumulation in MCF-7 and MDA-MB-231 cells. Pretreatment with N-acetyl-cysteine abrogated the increased sensitivity of RIP3-transfected MCF-7 and MDA-MB-231 cells to parthenolide. Conclusion: Overexpression of RIP3 sensitizes MCF-7 and MDA-MB-231 breast cancer cells to parthenolide in vitro via intracellular ROS accumulation.
    Acta Pharmacologica Sinica 06/2014; 35(7). DOI:10.1038/aps.2014.31 · 2.91 Impact Factor
  • Source
    • "Due to its anti-inflammatory and low toxicity properties, parthenolide has been used to treat migraine and rheumatoid arthritis [10]. In addition, many studies have investigated the effect of parthenolide treatment on human malignancies [5-7,9], although only two have examined the effect of parthenolide on glioblastoma cell proliferation in vitro [11,12]. However, their results were contradictory. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Glioblastoma is the most common and most aggressive form of malignant glioma and is very difficult to treat. Controlling tumour cell invasion and angiogenesis is essential to improve the prognosis of glioblastoma patients. Since constitutive activation of nuclear factor-κB (NF-κB) is necessary for tumour progression, NF-κB may be an important pharmacological target for this disease. Our study aimed to evaluate the antitumour effects of parthenolide, a NF-κB inhibitor, in two human glioblastoma cell lines (U87MG and U373) and in glioblastoma xenografts. Furthermore, we aimed to investigate the molecular mechanisms underlying these effects. Methods The anti-invasive and anti-angiogenic effects of parthenolide were analysed using in vitro invasion and angiogenesis assays. Parthenolide-induced growth inhibition of glioblastoma cells in vitro was determined using the MTT (methyl thiazolyl tetrazolium) assay. In addition, the effect of parthenolide on orthotropic implantation in vivo was evaluated using an intracerebral human glioblastoma xenograft model. Results We found that parthenolide suppresses proliferation, invasion, and tumour- induced angiogenesis of glioblastoma cells. Molecular studies demonstrated that parthenolide suppresses gene and protein expression of angiogenic factors. Furthermore, parthenolide reduced Akt phosphorylation and activated mitochondrial signalling, suggesting that the antitumour function of parthenolide may be mediated not only by the inhibition of NF-κB but also by the inhibition of Akt signalling and the activation of apoptotic proteins. Parthenolide suppressed neovascularity and tumour growth in glioblastoma xenografts. Conclusion The present study identified parthenolide as a new therapeutic agent for glioblastomas.
    BMC Cancer 10/2012; 12(1):453. DOI:10.1186/1471-2407-12-453 · 3.36 Impact Factor
  • Source
    • "Parthenolide is a sesquiterpene lactone, derived from Mexican India medicinal plants and feverfew (Tanacetum parthenium), which belongs to a variety of natural products that have been used for their potential anti-inflammatory [11] and anti-oxidative [12] properties. Importantly, related to its inhibitory properties and its lipophilic character that favors a good BBB-permeability [13], parthenolide seems to be effective in models of migraine therapy [14] and emerges to be a therapeutic agent for cancer treatment including glioblastomas [15] [16]. In vitro studies revealed that parthenolide inhibits the NFjB pathway by targeting the inhibitor (I)jB kinase activation [17] or IjBa degradation [18]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Parthenolide, a sesquiterpene lactone, has been reported to exhibit a variety of anti-inflammatory and immunomodulatory effects. To test the effect of parthenolide on brain inflammatory responses, brain oxidative stress and fever, we treated rats with parthenolide (1 mg/kg), simultaneously or 1 h prior to a systemic (i.p.) challenge with a moderate dose (100 μg/kg) of lipopolysaccharide (LPS). The initial hypothermia was exaggerated; the second phase of the biphasic LPS-induced fever and circulating interleukin-6 (IL-6) and tumor necrosis factor α (TNFα) were significantly attenuated only in parthenolide-pretreated animals. In the hypothalamus, markers of NFκB/NF-IL6 pathway activation (inhibitor κBα, NF-IL6 and the serin/threonin kinase-like protein mRNA expression) and markers of oxidative stress (including nuclear respiratory factor 1) and NFκB immunoreactivity were significantly reduced while NF-IL6 immunoreactivity and suppressor of cytokine signaling 3 mRNA expression remained unaltered, 8 h after LPS-stimulation with parthenolide-pretreatment. Importantly, this response was accompanied by decreased mRNA expression of the rate limiting enzyme in prostaglandin synthesis, cyclooxygenase 2 (COX2), known for its critical role in fever induction pathways. A direct action of parthenolide on brain cells was also confirmed in a primary neuro-glial cell culture of the vascular organ of the lamina terminalis a pivotal brain structure for fever manifestation with a leaky blood-brain barrier. In summary, pretreatment with parthenolide attenuates the febrile response during LPS-induced systemic inflammation by reducing circulating IL-6 and TNFα and decreasing hypothalamic NFκB/NF-IL6 activation, oxidative stress and expression of COX2. Thus parthenolide appears to have the potential to reduce brain inflammation.
    Cytokine 12/2011; 56(3):739-48. DOI:10.1016/j.cyto.2011.09.022 · 2.66 Impact Factor
Show more