Reversion of malignant phenotypes of human glioblastoma cells by β-elemene through β-catenin-mediated regulation of stemness-, differentiation- and epithelial-to-mesenchymal transition-related molecules

Abstract

BackgroundGlioblastoma is the most common and lethal type of primary brain tumor. β-Elemene, a natural plant drug extracted from Curcuma wenyujin, has shown strong anti-tumor effects in various tumors with low toxicity. However, the effects of β-elemene on malignant phenotypes of human glioblastoma cells remain to be elucidated. Here we evaluated the effects of β-elemene on cell proliferation, survival, stemness, differentiation and the epithelial-to-mesenchymal transition (EMT) in vitro and in vivo, and investigated the mechanisms underlying these effects.MethodsHuman primary and U87 glioblastoma cells were treated with β-elemene, cell viability was measured using a cell counting kit-8 assay, and treated cells were evaluated by flow cytometry. Western blot analysis was carried out to determine the expression levels of stemness markers, differentiation-related molecules and EMT-related effectors. Transwell assays were performed to further determine EMT of glioblastoma cells. To evaluate the effect of β-elemene on glioblastoma in vivo, we subcutaneously injected glioblastoma cells into the flank of nude mice and then intraperitoneally injected NaCl or β-elemene. The tumor xenograft volumes were measured every 3 days and the expression of stemness-, differentiation- and EMT-related effectors was determined by Western blot assays in xenografts.Resultsβ-Elemene inhibited proliferation, promoted apoptosis, impaired invasiveness in glioblastoma cells and suppressed the growth of animal xenografts. The expression levels of the stemness markers CD133 and ATP-binding cassette subfamily G member 2 as well as the mesenchymal markers N-cadherin and β-catenin were significantly downregulated, whereas the expression levels of the differentiation-related effectors glial fibrillary acidic protein, Notch1, and sonic hedgehog as well as the epithelial marker E-cadherin were upregulated by β-elemene in vitro and in vivo. Interestingly, the expression of vimentin was increased by β-elemene in vitro; this result was opposite that for the in vivo procedure. Inhibiting β-catenin enhanced the anti-proliferative, EMT-inhibitory and specific marker expression-regulatory effects of β-elemene.Conclusionsβ-Elemene reversed malignant phenotypes of human glioblastoma cells through β-catenin-involved regulation of stemness-, differentiation- and EMT-related molecules. β-Elemene represents a potentially valuable agent for glioblastoma therapy.

β-Elemene enhances the efficacy of gefitinib on glioblastoma multiforme cells through the inhibition of the EGFR signaling pathway

“…Comparatively, β-elemene, as a traditional anti-cancer Chinese herbal medicine, has been approved by the state Food and Drug Administration of China for the treatment of malignant effusion and some solid tumors. It also exhibited a wide range of anticancer effects with low toxicity and few side-effects in vitro and in vivo (20,28). Numerous basic studies have concluded that β-elemene has strong antitumor activity on human GBM cell lines, as well as on rats and glioblastomabearing nude mice by inhibiting cell proliferation, inducing tumor cell apoptosis, and arresting cell cycle processes (29)(30)(31).…”

The Antitumor Efficacy of β‐Elemene by Changing Tumor Inflammatory Environment and Tumor Microenvironment

“…The combination of elemene and gefitinib profoundly impairs epithelial cell transformation to mesenchymal cells, in a large part due to the regulation of the enhancer of zeste homolog 2 (EZH2), a carcinogenic histone methyltransferase and gene transcription regulator, thereby modulating the subsequent effector molecule required for cancer progression [153]. β-Catenin may also be the target of β-elemene in reversing the malignant phenotype of tumor cells; moreover, notch1, sonic hedgehog, and the epithelial marker of Ecadherin are upregulated by β-elemene in human glioblastoma cells in vitro and in vivo [19]. β-Elemene-mediated blockade of the phenotype transition of type 3 EMT in metastatic malignant tumors under the continuous stimulation of inflammation may also be an important antitumor mechanism of β-elemene.…”

“…Currently, β-elemene and its derivatives have been utilized to treat various tumors including lung cancer [10], liver cancer [11], brain cancer [19], breast cancer [20], ovarian cancer [21], stomach cancer [16], prostate cancer, and other tissues for over 20 years [22]. Their practical and effective medicinal value has been confirmed gradually.…”

Drug delivery systems for elemene, its main active ingredient β-elemene, and its derivatives in cancer therapy

“…Furthermore, β-elemene regulates several key molecules of tumor angiogenesis and metastasis, such as VEGF and matrix metalloproteinase, in addition to modulating the expression of ncRNAs that contribute to anticancer activities. [21][22][23][24][25][26][27][28][29][30][31][32][33][34] However, the clinical application of elemene has been limited by its poor solubility in water, poor stability, and low bioavailability. Therefore, studying a new drug delivery system for elemene has important significance.…”