Abstract
BackgroundGlioblastoma 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.MethodsThe 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.ResultsWe 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.ConclusionThe present study identified parthenolide as a new therapeutic agent for glioblastomas.
Highlights
Glioblastoma is the most common and most aggressive form of malignant glioma and is very difficult to treat
We aimed to evaluate the effect of parthenolide on invasion capacity and tumour-induced angiogenesis in the phosphatase and tensin homologue (PTEN)-mutant human glioblastoma cell lines U87MG [13] and U373 [14]
Parthenolide suppresses nuclear factor-κB (NF-κB) transcriptional activity and inhibits tumour cell proliferation In two glioblastoma cell lines treated with parthenolide, we found that NF-κB transcriptional activity decreased as parthenolide concentration increased (Figure 1; *, p < 0.0001; **, p < 0.01)
Summary
Glioblastoma is the most common and most aggressive form of malignant glioma and is very difficult to treat. Many studies have investigated the effect of parthenolide treatment on human malignancies [5,6,7,9], only two have examined the effect of parthenolide on glioblastoma cell proliferation in vitro [11,12]. We aimed to clarify the mechanism involved in parthenolide inhibition of glioblastoma cell proliferation in vitro, and to examine the in vivo effect of parthenolide on tumour growth by using a xenograft model of glioblastoma. To the best of our knowledge, this study is the first to investigate the antitumour effects of parthenolide on human glioblastoma in vivo, and to define the antiinvasive and anti-angiogenic effects of parthenolide treatment on glioblastoma cells in vitro
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