Abstract Background Propolis and Hypericum perforatum L. are natural products which contain many active compounds and have numerous beneficial effects, including an antitumor effect. Gliobmastoma multiforme (GBM) is a common primary brain tumor with poor prognosis and limited treatment options. In this study, the effect of propolis (EEP) combined with H. perforatum L. (HPE) on glioblastoma cell line U87MG was investigated for the first time.
Methods Anti-proliferative activity of EEP, HPE and their combination (EEP + HPE) was determined by a cytotoxicity test, DNA binding by [3H]-thymidine incorporation and cell migration assay. Anti-metastatic properties in U87MG treated with EEP, HPE and EEP + HPE were estimated on cells migration test (scratch assay) and metalloproteinases (MMP2 and MMP9) secretion (gelatin zymography).
Results Combination of HPE and EEP extracts was found to have a time- and dose-dependent inhibitory effect on the viability of U87MG cells. This effect was significantly higher (p < 0.05) when compared to these two extracts applied separately, which was confirmed by the significant reduction of DNA synthesis and significantly higher mitochondrial membrane permeabilization. A significant decreasing in migration cells and in pro-MMP9 and pro-MMP2 secretion in U87MG cells were demonstrated after exposure to combination of EEP (30 μg/ml) with HPE (6.25 μg/ml).
Conclusions In this study, the combination of ethanolic extract from propolis and ethanolic extract of fresh-cut H. perforatum L. was proved the ability to reduce invasiveness of glioma cells through the inhibition of MMP2 and MMP9 secretion and suppression of cell migration. It has a more potent anti-proliferative effect on U87MG glioma cell line compared to using propolis and H. perforatum L. separately. Further studies are required to verify whether the examined extracts can activate apoptotic pathways.
Resveratrol Reduces TNF-α-induced U373MG Human Glioma Cell Invasion through Regulating NF-κB Activation and uPA/uPAR Expression
Abstract Background: High invasiveness of glioma cells is one of the reasons that patients with malignant glioma have a poor prognosis. Resveratrol, a plant compound abundant in the peel of grapes, has been suggested as a potential cancer chemopreventive agent. Therefore, we investigated the effect of resveratrol on glioma cell invasion.
Materials and Methods: The effect of resveratrol on U373MG human glioma cell invasion was assessed by Matrigel assay and methylthiazoltetrazolium assay. Western blotting and reverse transcription-polymerase chain reaction were performed to elucidate the action mechanism of resveratrol.
Results: Resveratrol reduced tumor necrosis factor (TNF)-α-induced U373MG human glioma cell invasion. In addition, resveratrol repressed nuclear factor kappa B (NF-κB) activation and down-regulated mRNA expression of urokinase plasminogen activator (uPA) and its receptor in TNF-α-treated glioma cells.
Conclusion: These findings suggest that resveratrol could prevent glioma cell invasion via inhibiting proteolysis of extracellular matrix.
The Methanol Extract of Angelica sinensis Induces Cell Apoptosis and Suppresses Tumor Growth in Human Malignant Brain Tumors Yu-Ling Lin,1,2 Wen-Lin Lai,3,4 Horng-jyh Harn,5 Pei-Hsiu Hung,6,7 Ming-Chang Hsieh,4 Kai-Fu Chang,3 Xiao-Fan Huang,3 Kuang-Wen Liao,1,8 Ming-Shih Lee,3,4 and Nu-Man Tsai3,4
1College of Biological Science and Technology, National Chiao Tung University, Hsinchu 30010, Taiwan 2Center for Bioinformatics Research, National Chiao Tung University, Hsinchu 30010, Taiwan 3School of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung 40201, Taiwan 4Clinical Laboratory, Chung Shan Medical University Hospital, Taichung 40201, Taiwan 5Department of Pathology, China Medical University Hospital, Taichung 40402, Taiwan 6Department of Traditional Chinese Medicin, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi 60002, Taiwan 7Department of Bioindustry Technology, Da-Yeh University, Changhua 51591, Taiwan 8Institute of Molecular Medicine and Bioengineering, National Chiao Tung University, Hsinchu 30010, Taiwan
Abstract Glioblastoma multiforme (GBM) is a highly vascularized and invasive neoplasm. The methanol extract of Angelica sinensis (AS-M) is commonly used in traditional Chinese medicine to treat several diseases, such as gastric mucosal damage, hepatic injury, menopausal symptoms, and chronic glomerulonephritis. AS-M also displays potency in suppressing the growth of malignant brain tumor cells. The growth suppression of malignant brain tumor cells by AS-M results from cell cycle arrest and apoptosis. AS-M upregulates expression of cyclin kinase inhibitors, including p16, to decrease the phosphorylation of Rb proteins, resulting in arrest at the G0-G1 phase. The expression of the p53 protein is increased by AS-M and correlates with activation of apoptosis-associated proteins. Therefore, the apoptosis of cancer cells induced by AS-M may be triggered through the p53 pathway. In in vivo studies, AS-M not only suppresses the growth of human malignant brain tumors but also significantly prolongs patient survival. In addition, AS-M has potent anticancer effects involving cell cycle arrest, apoptosis, and antiangiogenesis. The in vitro and in vivo anticancer effects of AS-M indicate that this extract warrants further investigation and potential development as a new antibrain tumor agent, providing new hope for the chemotherapy of malignant brain cancer.
Jaceosidin Induces Apoptosis in U87 Glioblastoma Cells through G2/M Phase Arrest Muhammad Khan,1 Bo Yu,2 Azhar Rasul,1 Ali Al Shawi,1 Fei Yi,1 Hong Yang,2 and Tonghui Ma1,3
1Membrane Channel Research Laboratory, Northeast Normal University, Changchun 130024, China 2College of Life Sciences, Liaoning Normal University, Dalian 116029, China 3Second Clinical Hospital, Jilin University, Changchun 130041, China
Abstract Artemisia argyi is a widely used medicinal plant in China. The present study was designed to identify the bioactive constituents with antiglioma activity from leaves of Artemesia argyi. A bioactivity guided approach based on MTT assay for cells growth inhibition led to the isolation of a flavonoid, “jaceosidin” from ethanol extract of leaves of Artemesia argyi. The growth inhibitory effect of jaceosidin was explored using flow cytometry and Western blot studies. Our results showed that jaceosidin exerts growth inhibitory effect by arresting the cells at G2/M phase and induction of apoptosis. Furthermore, our study revealed that induction of apoptosis was associated with cell cycle arrest at G2/M phase, upregulation of p53 and Bax, decrease in mitochondrial membrane potential, release of cytochrome c, and activation of caspase 3. This mitochondrial-caspase-3-dependent apoptosis pathway was confirmed by pretreatment with caspase 3 inhibitor, Ac-DEVD-CHO. Our findings suggested that jaceosidin induces mitochondrial-caspase-3-dependent apoptosis in U87 cells by arresting the cell cycle at G2/M phase.
....In conclusion, our data demonstrated that jaceosidin inhibited the growth of U87 glioblastoma cells and induced apoptosis through cell cycle arrest, upregulation of p53 and Bax, lowering MTP, release of cytochrome c, and cleavage of caspase 3. Thus, jaceosidin could be developed into a novel chemotherapeutic or chemopreventive agent against glioblastoma.
Source : Evidence-Based Complementary and Alternative Medicine Volume 2012 (2012), Article ID 703034, 12 pages doi:10.1155/2012/703034 Link to Full Article
Cannabidiol Enhances the Inhibitory Effects of Δ9-Tetrahydrocannabinol on Human Glioblastoma Cell Proliferation and Survival Jahan P. Marcu1, Rigel T. Christian1, Darryl Lau1, Anne J. Zielinski1, Maxx P. Horowitz1, Jasmine Lee1, Arash Pakdel1, Juanita Allison1,Chandani Limbad1, Dan H. Moore1,2, Garret L. Yount1, Pierre-Yves Desprez1 and Sean D. McAllister1
Abstract The cannabinoid 1 (CB1) and cannabinoid 2 (CB2) receptor agonist Δ9-tetrahydrocannabinol (THC) has been shown to be a broad-range inhibitor of cancer in culture and in vivo, and is currently being used in a clinical trial for the treatment of glioblastoma. It has been suggested that other plant-derived cannabinoids, which do not interact efficiently with CB1 and CB2 receptors, can modulate the actions of Δ9-THC. There are conflicting reports, however, as to what extent other cannabinoids can modulate Δ9-THC activity, and most importantly, it is not clear whether other cannabinoid compounds can either potentiate or inhibit the actions of Δ9-THC. We therefore tested cannabidiol, the second most abundant plant-derived cannabinoid, in combination with Δ9-THC. In the U251 and SF126 glioblastoma cell lines, Δ9-THC and cannabidiol acted synergistically to inhibit cell proliferation. The treatment of glioblastoma cells with both compounds led to significant modulations of the cell cycle and induction of reactive oxygen species and apoptosis as well as specific modulations of extracellular signal-regulated kinase and caspase activities. These specific changes were not observed with either compound individually, indicating that the signal transduction pathways affected by the combination treatment were unique. Our results suggest that the addition of cannabidiol to Δ9-THC may improve the overall effectiveness of Δ9-THC in the treatment of glioblastoma in cancer patients.
Abstract Purpose: In this study, we have examined the antitumor effects of chloroform extract of Angelica sinensis (AS-C), a traditional Chinese medicine, on glioblastoma multiforme (GBM) brain tumors in vitro and in vivo.
Experimental Design:In vitro, GBM cells were treated with AS-C, and the cell proliferation, changes in distributions of cell cycle, and apoptosis were determined. In vivo, human DBTRG-05MG and rat RG2 GBM tumor cells were injected s.c. or i.c. and were treated with AS-C. Effects on tumor growth were determined by tumor volume, magnetic resonance imaging, survival, and histology analysis.
Results: The AS-C displays potency in suppressing growth of malignant brain tumor cells without cytotoxicity to fibroblasts. Growth suppression of malignant brain tumor cells by AS-C results from cell cycle arrest and apoptosis. AS-C can up-regulate expression of cdk inhibitors, including p21, to decrease phosphorylation of Rb proteins resulting in cell arrest at the G0-G1 phase for DBTRG-05MG and RG2 cells. The apoptosis-associated proteins are dramatically increased and activated in DBTRG-05MG cells and RG2 cells by AS-C but RG2 cells without p53 protein expression. In vitro results showed AS-C triggered both p53-dependent and p53-independent pathways for apoptosis. In in vivo studies, AS-C not only can suppress growths of malignant brain tumors of rat and human origin but also shrink the volumes of in situ GBM, significantly prolonging survivals.
Conclusions: The in vitro and in vivo anticancer effects of AS-C indicate that it has sufficient potential to warrant further investigation and development as a new anti–brain tumor agent.
Ruta 6 selectively induces cell death in brain cancer cells but proliferation in normal peripheral blood lymphocytes: A novel treatment for human brain cancer
SEN PATHAK1,2, ASHA S. MULTANI1, PRATIP BANERJI3 and PRASANTA BANERJI3
Departments of 1Cancer Biology and 2Laboratory Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA; 3PBH Research Foundation, 10/3/1 Elgin Road, Kolkata 700 020, West Bengal, India
Abstract. Although conventional chemotherapies are used to treat patients with malignancies, damage to normal cells is problematic. Blood-forming bone marrow cells are the most adversely affected. It is therefore necessary to find alternative agents that can kill cancer cells but have minimal effects on normal cells. We investigated the brain cancer cell-killing activity of a homeopathic medicine, Ruta, isolated from a plant, Ruta graveolens. We treated human brain cancer and HL-60 leukemia cells, normal B-lymphoid cells, and murine melanoma cells in vitro with different concentrations of Ruta in combination with Ca3(PO4)2. Fifteen patients diagnosed with intracranial tumors were treated with Ruta 6 and Ca3(PO4)2. Of these 15 patients, 6 of the 7 glioma patients showed complete regression of tumors. Normal human blood lymphocytes, B-lymphoid cells, and brain cancer cells treated with Ruta in vitro were examined for telomere dynamics, mitotic catastrophe, and apoptosis to understand the possible mechanism of cell-killing, using conventional and molecular cytogenetic techniques. Both in vivo and in vitro results showed induction of survival-signaling pathways in normal lymphocytes and induction of death-signaling pathways in brain cancer cells. Cancer cell death was initiated by telomere erosion and completed through mitotic catastrophe events. We propose that Ruta in combination with Ca3(PO4)2 could be used for effective treatment of brain cancers, particularly glioma.