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Ting Liu - One of the best experts on this subject based on the ideXlab platform.
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the plant alkaloid Tetrandrine inhibits metastasis via autophagy dependent wnt β catenin and metastatic tumor antigen 1 signaling in human liver cancer cells
Journal of Experimental & Clinical Cancer Research, 2018Co-Authors: Zhenxing Zhang, Ting LiuAbstract:Tetrandrine is a bisbenzylisoquinoline alkaloid isolated from the Chinese medicinal herb Stephania tetrandra S. Moore. We previously demonstrated that Tetrandrine exhibits potent antitumor effects in many types of cancer cells. In this study, we investigated the effects of Tetrandrine on human hepatocellular carcinoma (HCC) metastasis. The invasion and migration effects were evaluated via wound healing and transwell assays. Immunofluorescence and western blotting analyses were used to investigate the levels of epithelial-mesenchymal transition (EMT)-related protein. A metastasis model was established to investigate the inhibitory effect of Tetrandrine on hepatocellular carcinoma metastasis in vivo. Tetrandrine inhibits HCC invasion and migration by preventing cell EMT. The underlying mechanism was closely associated with Tetrandrine-induced human liver cell autophagy, which inhibits Wnt/β-catenin pathway activity and decreases metastatic tumor antigen 1 (MTA1) expression to modulate cancer cell metastasis. Our findings demonstrate, for the first time, that Tetrandrine plays a significant role in the inhibition of human hepatocellular carcinoma metastasis and provide novel insights into the application of Tetrandrine in clinical HCC treatment.
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c-MYC and reactive oxygen species play roles in Tetrandrine-induced leukemia differentiation
Nature Publishing Group, 2018Co-Authors: Ting LiuAbstract:Abstract Tetrandrine is a broadly used bisbenzylisoquinoline alkaloid component of traditional Chinese medicine that has antitumor effects in some cancer types. In this study, we investigated the effects of Tetrandrine on leukemia in vitro and in vivo. The results showed that Tetrandrine effectively induced differentiation and autophagy in leukemia cells. In addition, Tetrandrine treatment activated the accumulation of reactive oxygen species (ROS) and inhibited c-MYC protein expression. Further, we found that treatment with the ROS scavengers N-acetyl-L-cysteine (NAC) and Tiron as well as overexpression of c-MYC reduced Tetrandrine-induced autophagy and differentiation. Moreover, a small molecular c-MYC inhibitor, 10058-F4, enhanced the Tetrandrine-induced differentiation of leukemia cells. These results suggest that ROS generation and c-MYC suppression play important roles in Tetrandrine-induced autophagy and differentiation, and the results from in vivo experiments were consistent with those from in vitro studies. Therefore, our data suggest that Tetrandrine may be a promising agent for the treatment of leukemia
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The plant alkaloid Tetrandrine inhibits metastasis via autophagy-dependent Wnt/β-catenin and metastatic tumor antigen 1 signaling in human liver cancer cells
BMC, 2018Co-Authors: Zhenxing Zhang, Ting LiuAbstract:Abstract Background Tetrandrine is a bisbenzylisoquinoline alkaloid isolated from the Chinese medicinal herb Stephania tetrandra S. Moore. We previously demonstrated that Tetrandrine exhibits potent antitumor effects in many types of cancer cells. In this study, we investigated the effects of Tetrandrine on human hepatocellular carcinoma (HCC) metastasis. Methods The invasion and migration effects were evaluated via wound healing and transwell assays. Immunofluorescence and western blotting analyses were used to investigate the levels of epithelial-mesenchymal transition (EMT)-related protein. A metastasis model was established to investigate the inhibitory effect of Tetrandrine on hepatocellular carcinoma metastasis in vivo. Results Tetrandrine inhibits HCC invasion and migration by preventing cell EMT. The underlying mechanism was closely associated with Tetrandrine-induced human liver cell autophagy, which inhibits Wnt/β-catenin pathway activity and decreases metastatic tumor antigen 1 (MTA1) expression to modulate cancer cell metastasis. Conclusion Our findings demonstrate, for the first time, that Tetrandrine plays a significant role in the inhibition of human hepatocellular carcinoma metastasis and provide novel insights into the application of Tetrandrine in clinical HCC treatment
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Combination therapy with protein kinase inhibitor H89 and Tetrandrine elicits enhanced synergistic antitumor efficacy
BMC, 2018Co-Authors: Ting Liu, Yicheng ChenAbstract:Abstract Background Tetrandrine, a bisbenzylisoquinoline alkaloid that was isolated from the medicinal plant Stephania Tetrandrine S. Moore, was recently identified as a novel chemotherapy drug. Tetrandrine exhibited a potential antitumor effect on multiple types of cancer. Notably, an enhanced therapeutic efficacy was identified when Tetrandrine was combined with a molecularly targeted agent. H89 is a potent inhibitor of protein kinase A and is an isoquinoline sulfonamide. Methods The effects of H89 combined with Tetrandrine were investigated in vitro with respect to cell viability, apoptosis and autophagy, and synergy was assessed by calculation of the combination index. The mechanism was examined by western blot, flow cytometry and fluorescence microscopy. This combination was also evaluated in a mouse xenograft model; tumor growth and tumor lysates were analyzed, and a TUNEL assay was performed. Results Combined treatment with H89 and Tetrandrine exerts a mostly synergistic anti-tumor effect on human cancer cells in vitro and in vivo while sparing normal cells. Mechanistically, the combined therapy significantly induced cancer cell apoptosis and autophagy, which were mediated by ROS regulated PKA and ERK signaling. Moreover, Mcl-1 and c-Myc were shown to play a critical role in H89/Tetrandrine combined treatment. Mcl-1 ectopic expression significantly diminished H89/Tetrandrine sensitivity and amplified c-Myc sensitized cancer cells in the combined treatment. Conclusion Our findings demonstrate that the combination of Tetrandrine and H89 exhibits an enhanced therapeutic effect and may become a promising therapeutic strategy for cancer patients. They also indicate a significant clinical application of Tetrandrine in the treatment of human cancer. Moreover, the combination of H89/Tetrandrine provides new selectively targeted therapeutic strategies for patients with c-Myc amplification
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Tetrandrine induces autophagy and differentiation by activating ros and notch1 signaling in leukemia cells
Oncotarget, 2015Co-Authors: Ting Liu, Qiuxu Men, Zan Huang, Xin LiuAbstract:// Ting Liu 1 , Qiuxu Men 2 , Guixian Wu 1 , Chunrong Yu 1 , Zan Huang 1 , Xin Liu 2 and Wenhua Li 1 1 College of Life Sciences, Wuhan University, Wuhan, P. R. China 2 Ministry of Education Laboratory of Combinatorial Biosynthesis and Drug Discovery, College of Pharmacy, Wuhan University, Wuhan, P. R. China Correspondence to: Wenhua Li, email: // Xin Liu, email: // Keywords : Tetrandrine, leukemia cells, autophagy, differentiation Received : December 13, 2014 Accepted : February 01, 2015 Published : March 10, 2015 Abstract All-trans retinoic acid (ATRA) is a differentiating agent for the treatment of acute promyelocytic leukemia (APL). However, the therapeutic efficacy of ATRA has limitations. Tetrandrine is a traditional Chinese medicinal herb extract with antitumor effects. In this study, we investigated the effects of Tetrandrine on human PML-RARα-positive acute promyelocytic leukemia cells. Tetrandrine inhibited tumors in vivo. It induced autophagy and differentiation by triggering ROS generation and activating Notch1 signaling. Tetrandrine induced autophagy and differentiation in M5 type patient primary leukemia cells. The in vivo results indicated that low concentrations of Tetrandrine inhibited leukemia cells proliferation and induced autophagy and then facilitated their differentiation, by activating ROS and Notch1 signaling. We suggest that Tetrandrine is a potential agent for the treatment of APL by inducing differentiation of leukemia cells.
Jing Gung Chung - One of the best experts on this subject based on the ideXlab platform.
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Tetrandrine induces programmed cell death in human oral cancer cal 27 cells through the reactive oxygen species production and caspase dependent pathways and associated with beclin 1 induced cell autophagy
Environmental Toxicology, 2017Co-Authors: Jincherng Lien, An Cheng Huang, Meng Wei Lin, Shu Jen Chang, Kuang Chi Lai, Jing Gung ChungAbstract:Tetrandrine, a bisbenzylisoquinoline alkaloid, is extracted from the root of the Chinese herb Radix Stephania tetrandra S Moore. This compound has antitumor activity in different cancer cell types. In this study, the effects of Tetrandrine on human oral cancer CAL 27 cells were examined. Results indicated that Tetrandrine induced cytotoxic activity in CAL 27 cells. Effects were due to cell death by the induction of apoptosis and accompany with autophagy and these effects were concentration- and time-dependent manners. Tetrandrine induced apoptosis was accompanied by alterations in cell morphology, chromatin fragmentation, and caspase activation in CAL 27 cells. Tetrandrine treatment also induced intracellular accumulation of reactive oxygen species (ROS). The generation of ROS may play an important role in Tetrandrine-induced apoptosis. Tetrandrine triggered LC3B expression and induced autophagy in CAL 27 cells. Tetrandrine induced apoptosis and autophagy were significantly attenuated by N-acetylcysteine pretreatment that supports the involvement of ROS production. Tetrandrine induced cell death may act through caspase-dependent apoptosis with Beclin-1-induced autophagy in human oral cancer cells. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 329-343, 2017.
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Tetrandrine induces apoptosis via caspase 8 9 and 3 and poly adp ribose polymerase dependent pathways and autophagy through beclin 1 lc3 i ii signaling pathways in human oral cancer hsc 3 cells
Environmental Toxicology, 2016Co-Authors: Jawchyun Chen, Meng Wei Lin, Shu Jen Chang, Jing Gung Chung, Jiun Long YangAbstract:Tetrandrine is a bisbenzylisoquinoline alkaloid that was found in the Radix Stephania tetrandra S Moore. It had been reported to induce cytotoxic effects on many human cancer cells. In this study, we investigated the cytotoxic effects of Tetrandrine on human oral cancer HSC-3 cells in vitro. Treatments of HSC-3 cells with Tetrandrine significantly decreased the percentage of viable cells through the induction of autophagy and apoptosis and these effects are in concentration-dependent manner. To define the mechanism underlying the cytotoxic effects of Tetrandrine, we investigated the critical molecular events known to regulate the apoptotic and autophagic machinery. Tetrandrine induced chromatin condensation, internucleosomal DNA fragmentation, activation of caspases-3, -8, and -9, and cleavage of poly (ADP ribose) polymerase (PARP) that were associated with apoptosis, and it also enhanced the expression of LC3-I and -II that were associated with the induction of autophagy in human squamous carcinoma cell line (HSC-3) cells. Tetrandrine induced autophagy in HSC-3 cells was significantly attenuated by bafilomycin A1 (inhibitor of autophagy) pre-treatment that confirmed Tetrandrine induced cell death may be associated with the autophagy. In conclusion, we suggest that Tetrandrine induced cell death may be through the induction of apoptosis as well as autophagy in human oral cancer HSC-3 cells via PARP, caspases/Becline I/LC3-I/II signaling pathways. © 2014 Wiley Periodicals, Inc. Environ Toxicol, 2014.
Sheng-hong Tseng - One of the best experts on this subject based on the ideXlab platform.
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The Potential of Tetrandrine against Gliomas.
Anti-cancer agents in medicinal chemistry, 2010Co-Authors: Yun Chen, Sheng-hong TsengAbstract:Patients with malignant gliomas have poor prognoses, and the majority of the patients have local tumor recurrence after various treatments including surgery, radiotherapy, and chemotherapy. Thus it is mandatory to develop better therapies for treatment of these malignant brain tumors. Tetrandrine, a bisbenzylisoquinoline alkaloid, has antitumor effects against some cancers. Tetrandrine affects the cell cycle, production of reactive oxygen species, mitogen-activated protein kinase activity, and reverses multidrug resistance in various cancer cells. Since Tetrandrine is a highly lipid-soluble and hydrophobic molecule with a low molecular weight, it may cross the blood brain barrier; thus, it could be used for the treatment of gliomas. Tetrandrine inhibits the large-conductance, calcium-activated potassium (BK) channels and the expression of BK channel has a positive correlation with tumor malignancy grade in human gliomas. Furthermore, Tetrandrine also exerts cytotoxic effects, and induces apoptosis and radiosensitization in glioma cells by elimination of radiation-induced cell cycle perturbation. It also has anti-angiogenesis effects in gliomas, and exerts an antitumor effect on subcutaneous and intracerebral gliomas. Tetrandrine is a radiosensitizer and also a multidrug resistance reversing agent. Tetrandrine can probably be combined with radiotherapy or other chemotherapeutic agents to treat gliomas. Nonetheless, it is important to determine the balance between the safety and efficacy of Tetrandrine in patients with malignant gliomas before any clinical application.
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Tetrandrine induces apoptosis and growth suppression of colon cancer cells in mice.
Cancer letters, 2009Co-Authors: Yun Chen, Jin-cherng Chen, Tzu-yu Lin, Sheng-hong TsengAbstract:Tetrandrine, a bisbenzylisoquinoline alkaloid, exerts antitumor effects against some cancers. We explored Tetrandrine's effects on colon cancer with cultured mouse CT-26 cells and with subcutaneous tumors. Tetrandrine induced apoptosis in concentration- and time-dependent manner. Tetrandrine increased expression of ERK 1/2 and p38 MAPK; inhibition of p38 MAPK reduced Tetrandrine-induced apoptosis; inhibition of ERK1/2 did not. Tetrandrine had significant effects on tumors including slower growth and longer animal survival time and higher survival rate. Higher dose and earlier treatment were more effective than lower dose and delayed treatment. TUNEL staining showed prominent Tetrandrine-induced apoptosis of tumors. These data suggest that Tetrandrine induced significant apoptosis of cultured and subcutaneous CT-26 cells. Tetrandrine-induced apoptosis might be at least partially related to activation of the p38 MAPK signaling pathway.
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Tetrandrine suppresses tumor growth and angiogenesis of gliomas in rats.
International journal of cancer, 2009Co-Authors: Yun Chen, Jin-cherng Chen, Sheng-hong TsengAbstract:Tetrandrine, a bisbenzylisoquinoline alkaloid, has antitumor effects against some cancers, but its effects on gliomas are unknown. In this study, we investigated the effects of Tetrandrine on the growth and angiogenesis of rat RT-2 gliomas. We treated RT-2 glioma cells with Tetrandrine and then measured cytotoxicity, apoptosis and expression of vascular endothelial growth factor (VEGF). We also examined the cytotoxic effect of Tetrandrine on the ECV304 human umbilical vein endothelial cells and the effects of Tetrandrine on the in vivo angiogenesis. Tumor size and animal survival were followed in Tetrandrine-treated rats with subcutaneous or intracerebral gliomas. Expression of CD31 in Tetrandrine-treated gliomas was followed to study its effect on glioma-induced angiogenesis. Tetrandrine had cytotoxic effects and induced apoptosis of glioma cells in a concentration- and time-dependent manner. Tetrandrine also inhibited the expression of VEGF in glioma cells, induced cytotoxicity effect on the ECV304 cells and suppressed the in vivo angiogenesis. Tetrandrine (150 mg/kg/day) had significant antitumor effects on subcutaneous tumors and led to slower tumor growth rate, longer animal survival time and higher animal survival (p < 0.05). Tetrandrine also affected intracerebral tumors and prolonged animal survival (p < 0.05) without affecting survival rate. Immunohistochemical analyses showed that the subcutaneous gliomas from Tetrandrine-treated rats had fewer microvessel densities than control rats (p = 0.01). The results demonstrate that Tetrandrine is cytotoxic to RT-2 glioma cells, has antitumor effects on subcutaneous and intracerebral gliomas, and inhibits angiogenesis in subcutaneous gliomas. Tetrandrine has potential as a treatment for gliomas.
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Effects of Tetrandrine plus Radiation on Neuroblastoma Cells
Anticancer research, 2009Co-Authors: Yun Chen, Jin-cherng Chen, Sheng-hong TsengAbstract:Background: Tetrandrine, a bisbenzylisoquinoline alkaloid, has cancer cell cytotoxicity. The effects of combined Tetrandrine and radiation, alone or combined, on human SH-SY5Y neuroblastoma cells were examined. Materials and Methods: A combination treatment, using either concomitant irradiation at the beginning or end of the Tetrandrine treatment (designated as the RT-Tet and Tet-RT protocols, respectively), was used to investigate radiosensitization by Tetrandrine. The level of radiosensitization was evaluated by the dose-enhancement ratio and isobologram analysis. The cell cycle distribution of the neuroblastoma cells was examined using flow-activated cell sorter (FACS) analysis. Results: Tetrandrine had a time- and concentration-dependent cytotoxic effect (p
Zebo Huang - One of the best experts on this subject based on the ideXlab platform.
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Tetrandrine induces g1 s cell cycle arrest through the ros akt pathway in eoma cells and inhibits angiogenesis in vivo
International Journal of Oncology, 2015Co-Authors: Wenkai Xiao, Zebo Huang, Yajie Jiang, Qiuxu Men, Ling Yuan, Ting Liu, Xin LiuAbstract:Tetrandrine, a bisbenzylisoquinoline alkaloid, is known to inhibit tumor cell proliferation and induce apoptosis in cancer models in vitro and in vivo. In the present study, Tetrandrine significantly inhibited the proliferation of mouse endothelial cells (EOMA cell) and induced G1/S arrest in EOMA cells, in which the expressions of cyclin D and cyclin E and CDKs were downregulated. Tetrandrine treatment also caused intracellular accumulation of reactive oxygen species (ROS). Pretreatment with NAC, which is a ROS inhibitor, blocked G1/S cell arrest and cyclin regulation induced by Tetrandrine, implying that ROS generation plays an important role in Tetrandrine-induced cell cycle arrest. Furthermore, a decreased phospho-Akt protein level after Tetrandrine treatment was reversible with the removal of the intracellular ROS by NAC. Notably, overexpression of Akt decreased Tetrandrine-induced G1/S arrest. Finally, we verified the antiangiogenic effects of Tetrandrine in vivo in a liver cancer xenograft model in nude mice. In conclusion, Tetrandrine inhibits EOMA cell growth through the ROS/Akt pathway, and it could be a promising compound for cancer therapy as an inhibitor of tumor vascular growth.
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autophagy related gene 7 atg7 and reactive oxygen species extracellular signal regulated kinase regulate Tetrandrine induced autophagy in human hepatocellular carcinoma
Journal of Biological Chemistry, 2012Co-Authors: Ke Gong, Chao Chen, Yao Zhan, Yan Chen, Zebo HuangAbstract:Tetrandrine, a bisbenzylisoquinoline alkaloid isolated from the broadly used Chinese medicinal herb Stephaniae tetrandrae, exhibits potent antitumor effects and has the potential to be used as a cancer chemotherapeutic agent. We previously reported that high concentrations of Tetrandrine induce apoptosis in liver cancer cells. Here, we found that in human hepatocellular carcinoma (HCC) cells, a low dose of Tetrandrine (5 μm) induced the expression of LC3-II, resulted in the formation of acidic autophagolysosome vacuoles (AVOs), and caused a punctate fluorescence pattern with the GFP-LC3 protein, which all are markers for cellular autophagy. Tetrandrine induced the production of intracellular reactive oxygen species (ROS), and treatment with ROS scavengers significantly abrogated the Tetrandrine-induced autophagy. These results suggest that the generation of ROS plays an important role in promoting Tetrandrine-induced autophagy. Tetrandrine-induced mitochondrial dysfunction resulted in ROS accumulation and autophagy. ROS generation activated the ERK MAP kinase, and the ERK signaling pathway at least partially contributed to Tetrandrine-induced autophagy in HCC cells. Moreover, we found that Tetrandrine transcriptionally regulated the expression of autophagy related gene 7 (ATG7), which promoted Tetrandrine-induced autophagy. In addition to in vitro studies, similar results were also observed in vivo, where Tetrandrine caused the accumulation of ROS and induced cell autophagy in a tumor xenograft model. Interestingly, Tetrandrine treatment also induced autophagy in a ROS-dependent manner in C. elegans muscle cells. Therefore, these findings suggest that Tetrandrine is a potent autophagy agonist and may be a promising clinical chemotherapeutic agent.
Ke Gong - One of the best experts on this subject based on the ideXlab platform.
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autophagy related gene 7 atg7 and reactive oxygen species extracellular signal regulated kinase regulate Tetrandrine induced autophagy in human hepatocellular carcinoma
Journal of Biological Chemistry, 2012Co-Authors: Ke Gong, Chao Chen, Yao Zhan, Yan Chen, Zebo HuangAbstract:Tetrandrine, a bisbenzylisoquinoline alkaloid isolated from the broadly used Chinese medicinal herb Stephaniae tetrandrae, exhibits potent antitumor effects and has the potential to be used as a cancer chemotherapeutic agent. We previously reported that high concentrations of Tetrandrine induce apoptosis in liver cancer cells. Here, we found that in human hepatocellular carcinoma (HCC) cells, a low dose of Tetrandrine (5 μm) induced the expression of LC3-II, resulted in the formation of acidic autophagolysosome vacuoles (AVOs), and caused a punctate fluorescence pattern with the GFP-LC3 protein, which all are markers for cellular autophagy. Tetrandrine induced the production of intracellular reactive oxygen species (ROS), and treatment with ROS scavengers significantly abrogated the Tetrandrine-induced autophagy. These results suggest that the generation of ROS plays an important role in promoting Tetrandrine-induced autophagy. Tetrandrine-induced mitochondrial dysfunction resulted in ROS accumulation and autophagy. ROS generation activated the ERK MAP kinase, and the ERK signaling pathway at least partially contributed to Tetrandrine-induced autophagy in HCC cells. Moreover, we found that Tetrandrine transcriptionally regulated the expression of autophagy related gene 7 (ATG7), which promoted Tetrandrine-induced autophagy. In addition to in vitro studies, similar results were also observed in vivo, where Tetrandrine caused the accumulation of ROS and induced cell autophagy in a tumor xenograft model. Interestingly, Tetrandrine treatment also induced autophagy in a ROS-dependent manner in C. elegans muscle cells. Therefore, these findings suggest that Tetrandrine is a potent autophagy agonist and may be a promising clinical chemotherapeutic agent.
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Tetrandrine induces apoptosis by activating reactive oxygen species and repressing akt activity in human hepatocellular carcinoma
International Journal of Cancer, 2011Co-Authors: Chaoyang Liu, Ke Gong, Xin MaoAbstract:Tetrandrine, a bisbenzylisoquinoline alkaloid component of broadly used traditional Chinese medicine, has antitumor effects against some cancers. In our study, we investigated the effects of Tetrandrine on the human hepatocellular carcinoma (HCC) in vitro and in vivo. The results showed that Tetrandrine effectively induced apoptosis of liver cancer cell in a dose- and time-dependent manner accompanied by alteration of cell morphology, chromatin fragmentation and caspase activation. Tetrandrine treatment also induced intracellular accumulation of reactive oxygen species (ROS), and ROS scavengers (LNAC and GSH) completely blocked the effects of Tetrandrine-induced apoptosis, suggesting that the generation of ROS plays an important role in Tetrandrine-induced apoptosis. Although the activities of JNK and ERK were inhibited significantly by Tetrandrine treatment, JNK and ERK are not involved in the Tetrandrine-induced apoptosis. In contrast, Akt activity was found to be closely related to Tetrandrine-induced apoptosis. The data demonstrated that Akt activity inhibitor LY294002 synergistically promoted Tetrandrine-induced apoptosis of HCC, whereas ectopic expression of Akt contrastly abrogated partial of the Tetrandrine-induced apoptosis. These data suggest that Akt signal is the downstream event of ROS generation in the Tetrandrine-induced HCC cell apoptosis. Moreover, the results of xenograft in nude mice were consistent with that of the in vitro studies. Therefore, our data suggest that Tetrandrine may be a promising agent for the treatment of HCC as a regulator of ROS/Akt pathway.