The Experts below are selected from a list of 675 Experts worldwide ranked by ideXlab platform
Jing Gung Chung - One of the best experts on this subject based on the ideXlab platform.
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Bufalin induces apoptotic cell death in human nasopharyngeal carcinoma cells through mitochondrial ros and trail pathways
The American Journal of Chinese Medicine, 2019Co-Authors: Yung Lin Chu, Jing Gung Chung, Shu Fen Peng, An Cheng Huang, Wen Wen Huang, Fu Shin Chueh, Yi Shih, Ching Lung LiaoAbstract:The aim of this study was to investigate the effects of Bufalin on human nasopharyngeal carcinoma NPC-TW 076 cells in vitro. Bufalin is a cardiotonic steroid and a key active ingredient of the Chin...
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Bufalin induced apoptosis in scc 4 human tongue cancer cells by decreasing bcl 2 and increasing bax expression via the mitochondria dependent pathway
Molecular Medicine Reports, 2017Co-Authors: Han Yu Chou, Wen Wen Huang, Fu Shin Chueh, Ming Jen Fan, Yi Shih, Ching Lung Liao, Yung Lin Chu, Jing Gung ChungAbstract:The aim of the present study was to investigate the cytotoxic effects of Bufalin on SCC‑4 human tongue cancer cells. Cell morphological changes and viability were examined using phase contrast microscopy and flow cytometry, respectively. The results indicated that Bufalin induced morphological changes and reduced total viable cells. Apoptotic cell death was analyzed by DAPI staining and DNA gel electrophoresis; the results revealed that Bufalin induced cell apoptosis. Levels of reactive oxygen species (ROS), Ca2+, nitric oxide (NO) and mitochondrial membrane potential (ΔΨm) were measured by flow cytometry, and Bufalin was observed to increase Ca2+ and NO production, decrease the ΔΨm and reduce ROS production in SCC‑4 cells. In addition, western blotting was performed to detect apoptosis‑associated protein expression. The results demonstrated that Bufalin reduced the expression of the anti‑apoptotic protein B‑cell lymphoma 2 (Bcl‑2) and increased the expression of the pro‑apoptotic protein, Bcl‑2‑associated X protein. However, Bufalin treatment also increased the expression of other apoptosis‑associated proteins such as apoptosis‑inducing factor and endonuclease G in SCC‑4 cells. Based on these findings, Bufalin may induce apoptotic cell death via mitochondria‑dependent pathways in human tongue cancer SCC‑4 cells.
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Bufalin induces apoptosis in vitro and has antitumor activity against human lung cancer xenografts in vivo
Environmental Toxicology, 2017Co-Authors: Da Tian Bau, Jing Gung Chung, Yung Ting Hsiao, Te Chun Hsia, Jincherng Lien, Wuhuei Hsu, Su Tso Yang, Yi Ping HuangAbstract:Bufalin has been shown to be effective against a variety of cancer cells, but its role in lung cancer has never been studied in an animal model. In this study, we evaluated Bufalin effects in a human lung cancer cell line NCI-H460 both in vitro and in vivo. Bufalin caused significant cytotoxicity in NCI-H460 cells at a concentration as low as 1 μM. DNA condensation was observed in Bufalin-treated cells in a dose-dependent manner. Mitochondrial membrane potential (ΔΨm ) was reduced and reactive oxygen species (ROS) were increased in Bufalin-treated NCI-H460 cells. Levels of several proapoptotic proteins such as Fas, Fas-ligand, cytochrome c, apoptosis protease activating factor-1, endonuclease G, caspase-3 and caspase-9 were increased after Bufalin treatment. At the same time, anti-apoptotic B-cell lymphoma 2 protein levels were reduced. Bufalin decreased glucose regulated protein-78 gene expression but increased growth arrest- and DNA damage-inducible 153 gene expression. Bufalin injected intraperitoneally in a dose-dependent manner reduced tumor size in BALB/C nu/nu mice implanted with NCI-H460 cells. Bufalin injection did not produce significant drug-related toxicity in experimental animals except at a high dose (0.4 mg kg-1 ). In conclusion, low concentrations of Bufalin can induce apoptosis in the human lung cancer cell line NCI-H460 in vitro. Bufalin also reduced tumor size in mice injected with NCI-H460 cells without significant drug-related toxicity. These results indicate that Bufalin may have potential to be developed as an agent for treating human non-small cell lung cancer. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1305-1317, 2017.
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Bufalin induces apoptosis of human osteosarcoma u 2 os cells through endoplasmic reticulum stress caspase and mitochondria dependent signaling pathways
Molecules, 2017Co-Authors: Ching Hsiao Lee, Yung Luen Shih, Yung Liang Chen, Mei Hui Lee, Jing Gung ChungAbstract:Bone cancer is one of the cancer-related diseases, and there are increased numbers of patients with bone cancer worldwide. Therefore the efficacy of treatment of bone cancer is considered extremely vital. Bufalin has been showed to have biological activities including anticancer activities in vitro and in vivo. However, the exact associated mechanisms for Bufalin induced apoptosis in human bone cancer cells are still unclear. In the present study, we investigated the effect of Bufalin on the cytotoxic effects in U-2 OS human osteosarcoma cells. For examining apoptotic cell deaths, we used flow cytometry assay, Annexin V/PI double staining, and TUNNEL assay. Reactive oxygen species (ROS), Ca2+, mitochondrial membrane potential (ΔΨm), and caspase-8, -9 and -3 activities were measured by flow cytometry assay. Furthermore, western blotting and a confocal laser microscopy examination were used for measuring the alterations of apoptotic associated protein expression and translocation, respectively. The results indicated that Bufalin induced cell morphological changes, decreased the viable cell number, induced apoptotic cell death, and increased the apoptotic cell number, and affected apoptotic associated protein expression in U-2 OS cells. Bufalin increased apoptotic proteins such as Bak, and decreased anti-apoptotic proteins such as Bcl-2 and Bcl-x in U-2 OS cells. Furthermore, Bufalin increased the protein levels of cytochrome c (Cyto c), AIF (Apoptosis inducing factor) and Endo G (Endonuclease G) in cytoplasm that were also confirmed by confocal microscopy examination. Based on those findings, Bufalin induced apoptotic cell death in U-2 OS cells may be via endoplasmic reticulum (ER) stress, caspase-, and mitochondria-dependent pathways; thus, we may suggest that Bufalin could be used as an anti-cancer agent for the treatment of osteosarcoma in the future, and further in vivo studies are needed.
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Bufalin inhibits migration and invasion in human hepatocellular carcinoma sk hep1 cells through the inhibitions of nf kb and matrix metalloproteinase 2 9 signaling pathways
Environmental Toxicology, 2015Co-Authors: Ya Yin Chen, Jing Gung Chung, Shu Chun Hsu, Chao Lin Kuo, Shu Jen Chang, Jen Jyh Lin, Jia You Liu, Ching Hsiao Lee, Jin Biou ChangAbstract:Metastasis plays an important role in mortality of cancer patients. Migration and invasion are the major characteristics of tumor metastasis. The induction of matrix metalloproteinases (MMPs) such as MMP-2 and -9 are particularly important for the invasiveness of various cancer cells. Bufalin, a class of toxic steroids, was purified from the skin glands of Bufo gargarizans or Bufo melanostictus; it is known to inhibit proliferation of human cancer cells. In this study, we investigated the antiinvasive mechanisms of Bufalin in the human hepatocellular cancer cell line SK-Hep1. Bufalin significantly reduced serum-induced cell invasion and migration. Furthermore, Bufalin markedly inhibited MMP-2 and -9 activity, mRNA expression and protein levels in SK-Hep1 cells. Bufalin attenuated phosphoinisitide-3-kinase (PI3K) and phosphorylation of AKT which was associated with reduced levels of nuclear factor kappa B (NF-κB). Bufalin also suppressed protein levels of FAK and Rho A, VEGF, MEKK3, MKK7, and uPA and it diminished NF-κB translocation. Based on these observations, we propose that Bufalin is acts as an antiinvasive agent by inhibiting MMP-2 and -9 and involving PI3K/AKT and NF-κB pathways. Bufalin is a potential therapeutic agent that may have efficacy in preventing the invasion and metastasis of malignant liver tumors.
Yunpeng Liu - One of the best experts on this subject based on the ideXlab platform.
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Bufalin induces protective autophagy by cbl b regulating mtor and erk signaling pathways in gastric cancer cells
Cell Biology International, 2019Co-Authors: Jing Liu, Kezuo Hou, Xiaofang Che, Yibo Fan, Yunpeng LiuAbstract:Bufalin, a natural small-molecule compound derived from the traditional Chinese medicine Chan su, has shown promising anti-cancer effects against a broad variety of cancer cells through different mechanisms. It has been reported to induce autophagy in gastric cancer cells. However, the molecular mechanism involved is not fully elucidated. In the present study, we aimed to investigate the molecular mechanism by which Bufalin induce autophagy in human gastric cancer cells. We found that Bufalin induced apoptosis and autophagy in gastric cancer cells, and autophagy prevented human gastric cancer cells from undergoing apoptosis. Bufalin treatment changed the expression of autophagy-related proteins. Moreover, phosphorylated Akt, mTOR, and p70S6K were all significantly decreased, while phosphorylated ERK1/2 was increased by Bufalin. Pretreatment of MGC803 cells with the ERK1/2-specific inhibitor PD98059 led to the down-regulation of LC3 II. Further study showed that Cbl-b positively regulated autophagy by suppressing mTOR and enhancing ERK1/2 activation. Therefore, our data provide evidence that Bufalin induces autophagy in MGC803 cells via both Akt/mTOR/p70S6K and ERK signaling pathways, and Cbl-b-mediated suppression of mTOR and activation of ERK1/2 might play an important role.
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mir 155 5p antagonizes the apoptotic effect of Bufalin in triple negative breast cancer cells
Anti-Cancer Drugs, 2016Co-Authors: Qian Wang, Yuee Teng, Zhitu Zhu, Xiaofang Che, Yan Wang, Yiding Wang, Huachuan Zheng, Yunpeng LiuAbstract:Bufalin, a cardiotonic steroid isolated from toad venom, has been shown to kill various types of tumor cells. Our previous study showed that triple-negative breast cancer (TNBC) cells were less sensitive to Bufalin than other types of breast cancer cells, but the reason for this lower sensitivity remains unclear. In this study, we showed that Bufalin induced apoptosis in MDA-MB-231 and MCF-7/ADR TNBC cell lines, accompanied by increased miR-155-5p expression. Overexpression of miR-155-5p promoted proliferation and reduced Bufalin-induced apoptosis of TNBC cells. In contrast, downregulation of miR-155-5p increased sensitivity to Bufalin and upregulated the expression of FOXO3A. Bufalin also downregulated DNA methyltransferases 1 and 3a (DNMT1 and DNMT3a), and concurrent inhibition of DNMT1 and DNMT3a significantly increased miR-155-5p expression. These results indicate that miR-155-5p antagonizes Bufalin sensitivity in TNBC cells, and that downregulation of DNMT1 and DNMT3a may be responsible for the Bufalin-induced upregulation of miR-155-5p.
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Bufalin inhibits tgf β induced epithelial to mesenchymal transition and migration in human lung cancer a549 cells by downregulating tgf β receptors
International Journal of Molecular Medicine, 2015Co-Authors: Lei Zhao, Kezuo Hou, Xiaofang Che, Shizhou Liu, Ti Wen, Yibo Fan, Yunpeng LiuAbstract:The epithelial-to-mesenchymal transition (EMT) is a well-known prerequisite for cancer cells to acquire the migratory and invasive capacity, and to subsequently metastasize. Bufalin is one of the major active components of the traditional Chinese medicine Chan Su, and accumulating evidence has shown its anticancer effect in multipe types of cancer. However, the role of Bufalin in transforming growth factor‑β (TGF‑β)‑induced EMT and migration remains unclear. In the present study, the effect of Bufalin on TGF‑β‑induced EMT and migration was investigated in human lung cancer A549 cells. TGF‑β induced EMT in A549 cells and increased their migratory ability, which were markedly suppressed by Bufalin. Additionally, TGF‑β‑induced upregulation of Twist2 and zinc finger E‑box binding homeobox 2 (ZEB2), as well as the phosphorylation of Smad2 and Smad3 were also inhibited by Bufalin. However, the Smad‑independent signaling pathways were not affected. Further analysis showed that the TGF‑β receptor I (TβRI) and TGF‑β receptor II (TβRII) were downregulated in the presence of Bufalin. Pretreatment with SB431542, a potent inhibitor of the phosphorylation of TβRI, significantly attenuated TGF‑β‑induced EMT, mimicking the effect of Bufalin on A549 cells. Taken together, these results suggest that Bufalin suppresses TGF-β-induced EMT and migration by downregulating TβRI and TβRII in A549 cells.
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Bufalin loaded biotinylated chitosan nanoparticles an efficient drug delivery system for targeted chemotherapy against breast carcinoma
European Journal of Pharmaceutics and Biopharmaceutics, 2014Co-Authors: Xin Tian, Yunpeng Liu, Hongzhuan Yin, Shichen Zhang, Ying Luo, Chengguang Sui, Fandong Meng, Youhong Jiang, Jun FangAbstract:Bufalin is a traditional oriental medicine which is known to induce apoptosis in many tumor cells, and it is thus considered as a new anticancer therapeutic. By now, most of the studies of Bufalin are in vitro, however in vivo evaluations of its therapeutic efficacy are less and are in great demand for its development toward anticancer drug. One of the problems probably hampering the development of Bufalin is the lack of tumor selectivity, which may reduce the therapeutic effect as well as showing side effects. To overcome this drawback, in this study, we designed a tumor-targeted drug delivery system of Bufalin based on enhanced permeability and retention (EPR) effect, by using biotinylated chitosan, resulting in Bufalin encapsulating nanoparticles (Bu-BCS-NPs) with mean hydrodynamic size of 171.6 nm, as evidenced by dynamic light scattering and transmission electron microscope. Bu-BCS-NPs showed a relative slow and almost linear release of Bufalin, and about 36.8% of Bufalin was released in 24 h when dissolved in sodium phosphate buffer. Compared to native Bufalin, Bu-BCS-NPs exhibited a stronger cytotoxicity against breast cancer MCF-7 cells (IC50 of 0.582 μg/ml vs 1.896 μg/ml of native Bufalin). Similar results were also obtained in intracellular reactive oxygen species production, apoptosis induction, and decrease in mitochondria membrane potential. These results may contribute to the rapid intracellular uptake of nanoparticles, partly benefiting from the highly expressed biotin receptors in tumor cells. In vivo studies using MCF-7 tumor models in nude mice confirmed the remarkable therapeutic effect of Bu-BCS-NPs. These findings suggest the potential of Bu-BCS-NPs as an anticancer drug with tumor targeting property.
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inhibition of jak stat3 pathway enhances Bufalin induced apoptosis in colon cancer sw620 cells
World Journal of Surgical Oncology, 2012Co-Authors: Zhitu Zhu, Hongzhi Sun, Zhenghua Wang, Yangyang Liu, Yu Gao, Xiaomei Liu, Qingjun Wang, Yunpeng LiuAbstract:The purpose of the research is to investigate the roles of Jak-STAT3 signaling pathway in Bufalin-induced apoptosis in colon cancer SW620 cells. The inhibitory effects of Bufalin on cell proliferation were determined by MTT (Methyl thiazolyltetrazolium) assay. The morphological changes of cells were measured by Wright-Giemsa staining. The cell cycle arrest and apoptosis were tested by flow cytometry analysis. Western Blot was used to determine the protein expression of the apoptosis inhibitors livin and caspase-3, the apoptosis-related proteins Bax and Bcl-2, as well as the key protein kinases in the Jak-stat3 signaling pathway, stat3 and p-stat3. (1) Bufalin inhibited the proliferation of SW620 cells. IC50 at 24 h, 48 h and 72 h were 76.72 ± 6.21 nmol/L, 34.05 ± 4.21 nmol/L and 16.7 ± 6.37 nmol/L. (2) Bufalin induced SW620 cell cycle arrest and apoptosis, indicated by the appearance of apoptotic bodies; (3) The results from flow cytometry demonstrated that there was cell cycle G2/M phase arrest in 20 nmol/L Bufalin treatment group (36.29 ± 2.11% vs 18.39 ± 1.74%, P<0.01); there was a sub-diploid apoptosis peak in 80 nmol/L Bufalin treatment group (19.69 ± 1.63% vs 0.99 ± 0.23%, P <0.01). The apoptosis rate was 34.63 ± 2.57% (vs 19.69 ± 1.63%, P = 0.002) in JAK kinase inhibitor AG490 plus Bufalin treatment group. (4) During the process of Bufalin-induced apoptosis in SW620 cells, transient activation of p-stat3 inhibited the activation of stat3, up-regulated Bax expression, down-regulated livin and Bcl-2 expression (P<0.01), and activated caspase-3. Inhibition of Jak-stat3 signaling pathway by pre-treatment with AG490 significantly enhanced the Bufalin-induced apoptosis (P<0.01), further up-regulated Bax protein expression, down-regulated livin and Bcl-2 protein expression and enhanced caspase-3 activation. Bufalin not only inhibited the growth of colon cancer SW620 cells, but also induced apoptosis of SW620 cells. Activation of caspase-3, up-regulation of Bax, down-regulation of livin and Bcl-2, as well as inhibition of Jak-stat3 signaling pathway might be the important mechanisms for the Bufalin-induced apoptosis.
Kazuyasu Nakaya - One of the best experts on this subject based on the ideXlab platform.
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involvement of tiam1 in apoptosis induced by Bufalin in hela cells
Anticancer Research, 2007Co-Authors: Toshiko Shibayamaimazu, Yutaka Masuda, Shigeo Nakajo, Toshimasa Shinki, Kazuyasu NakayaAbstract:Background: It has been previously demonstrated that Bufalin, an active agent in the Chinese medicine chan' su, induces apoptosis in human leukemia cells by altering the expression of apoptosis-related genes, such as bcl-2 and c-myc. Tiam1 was also found to play a critical role in Bufalin-induced apoptosis th rough the activation of the Rac1, PAK and JNK pathway in human leukemia cell lines. In the present study, the involvement of the Tiam1 gene products in Bufalin-induced apoptosis in human solid tumor HeLa cells was examined. Materials and Methods: HeLa cells were treated with 10 - 8 M Bufalin and apoptosis was measured by ELISA quantification of nucleosomes. Tiam1 mRNA levels were quantified by real- time PCR analysis and inhibited by transfected siRNA specific for Tiam1. Results: Apoptosis was induced in HeLa cells by treatment with 10 - 8 M Bufalin. Expression of both Tiam1 mRNA and its protein was induced 0.5 h after the start of the Bufalin treatment. Transfection of Tiam1-specific siRNA into HeLa cells markedly inhibited Bufalin-induced apoptosis. Conclusion: Our results suggest that Tiam1 is a downstream mediator of Bufalin-induced apoptosis in the human solid tumor HeLa cell line , as well as in leukemia cell lines.
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Tiam1 is involved in the regulation of Bufalin-induced apoptosis in human leukemia cells
Oncogene, 1999Co-Authors: Nobuko Kawazoe, Yutaka Masuda, Shigeo Nakajo, Masahiko Watabe, Kazuyasu NakayaAbstract:Bufalin, a component of the Chinese medicine chan'su , induces apoptosis in various lines of human tumor cells, such as leukemia HL60 and U937 cells, by altering the expression of apoptosis-related genes, for example, bcl-2 and c-myc . In this study, we characterized a gene that is involved in Bufalin-induced apoptosis by the differential display (DD) technique. The partial nucleotide sequence of one of the differentially expressed clones obtained after treatment with Bufalin was identical to that of the human gene for Tiam1. When U937 cells were treated with 10^−7 M Bufalin, expression of both Tiam1 mRNA and the protein was induced 1 h after the start of the treatment. The increase of Tiam1 mRNA was transient but the level of Tiam1 protein continued to increase at least for 6 h. In addition, the activities of Rac1 and p21-activated kinase (PAK) were also stimulated by Bufalin treatment. To evaluate the role of Tiam1 in the apoptotic process, we examined the effects of the expression of sense and antisense RNA for Tiam1 in U937 cells. Apoptosis was strongly induced by Bufalin in cells that expressed sense RNA for Tiam1 as compared to apoptosis in control cells treated with Bufalin only. Cells expressing antisense RNA for Tiam1 were significantly more resistant than the control Bufalin-treated cells to induction of DNA fragmentation in response to Bufalin. Moreover, sense transformants had elevated activities of PAK and c-Jun NH_2-terminal kinase (JNK). These results suggest that Tiam1 might play a critical role in Bufalin-induced apoptosis through the activation of Rac1, PAK, and JNK pathway.
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activation of ap 1 is required for Bufalin induced apoptosis in human leukemia u937 cells
Oncogene, 1998Co-Authors: Masahiko Watabe, Yutaka Masuda, Shigeo Nakajo, Kaori Ito, Kazuyasu NakayaAbstract:In a previous study, we demonstrated that Bufalin caused apoptosis in human leukemia U937 cells by the anomalous activation of mitogen-activated protein kinase (MAPK) via a signaling pathway that included Ras, Raf-1 and MAPK kinase-1. We report here the effect of Bufalin on c-Jun N-terminal protein kinase (JNK), a member of the MAPK family, and on the signaling pathway downstream of MAPKs in U937 cells. When U937 cells were treated with 10(-8) M Bufalin, the activity of JNK1 was markedly elevated 3 h after the start of treatment and remained so for 9 h. This activation of JNK and the induction of apoptosis by Bufalin were suppressed by expression of antisense mRNA for MAPK kinase-1. c-Jun was translocated from the cytoplasm to the nucleus after treatment of U937 cells with Bufalin. The transcriptional activity of AP-1 was transiently enhanced by the treatment with Bufalin and this activation was suppressed by the expression of antisense mRNA for MAPK kinase-1. Both curcumin (1,7-bis[4-hydroxy-3-methoxy-phenyl]-1,6-heptadiene-3,5-dione), an inhibitor of the biosynthesis of AP-1, and the expression of dominant negative c-Jun inhibited the activation of AP-1 and the induction of apoptosis by Bufalin. Expression of a constitutively active mutant form of MAPK kinase-1 induced the activation of AP-1 and subsequent apoptosis in U937 cells. These results suggest that the activation of AP-1 via a MAPK cascade that includes JNK is required for the induction of apoptosis by Bufalin in U937 cells.
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bcl 2 protein inhibits Bufalin induced apoptosis through inhibition of mitogen activated protein kinase activation in human leukemia u937 cells
Cancer Research, 1997Co-Authors: Masahiko Watabe, Nobuko Kawazoe, Yutaka Masuda, Shigeo Nakajo, Kazuyasu NakayaAbstract:In a previous study, we demonstrated that Bufalin, which is an active principle of Chinese medicine, chan'su, caused apoptosis in human leukemia U937 cells by anomalous activation of mitogen-activated protein kinase (MAPK) via the signaling pathway of Ras, Raf-1, and MAPK kinase-1. Here, we report the effect of overexpression of bcl-2 in U937 cells on the signaling pathway of apoptosis that is induced by Bufalin. The results indicated that the apoptosis induced by Bufalin in U937 cells was significantly inhibited by overexpression of the Bcl-2 protein. No significant difference was detected in the activation of MAPK kinase-1 that is induced by Bufalin in wild-type or Bcl-2-overexpressed U937 cells; however, the activation of MAPK by Bufalin was significantly attenuated in the cells overexpressing Bcl-2. Bufalin treatment activated activator protein-1 transcriptional activity; however, this activation was decreased to 40% in bcl-2-overexpressed U937 cells. These results indicate that Bcl-2 acts downstream of MAPK kinase-1 but upstream of MAPK and suggest that, in the signaling pathway of the apoptotic process induced by Bufalin, the transcriptional activity of activator protein-1 may be down-regulated through the inhibition of MAPK activity by Bcl-2.
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Bufalin induces apoptosis and influences the expression of apoptosis related genes in human leukemia cells
Leukemia Research, 1995Co-Authors: Yutaka Masuda, Nobuko Kawazoe, Shigeo Nakajo, Takemi Yoshida, Yukio Kuroiwa, Kazuyasu NakayaAbstract:Abstract A low concentration of Bufalin, a component of bufadienoides in the traditional Chinese medicine chan'su, was shown previously to induce differentiation of a broad range of human leukemia cell lines. In the present study, we found that Bufalin at concentrations of 10 −7 M and higher induced apoptosis in human leukemia cells, such as HL60, ML1, but not in mouse leukemia M1 cells. A mere 15 min pretreatment of HL60 cells with 10 −6 M Bufalin, followed by incubation for 15 h without Bufalin, caused fragmentation of DNA and a decrease in cell viability, indicating that the signal for induction of apoptosis is triggered rapidly upon treatment with Bufalin. Bufalin-induced apoptosis in HL60 cells was inhibited by ZnCl 2 , an inhibitor of endonuclease, but not by cycloheximide, an inhibitor of protein synthesis. Northern blot analysis revealed that the levels of expression of the c-myc and bcl-2 genes in HL60 cells decreased with time after treatment with Bufalin. These results suggest that Bufalin induces apoptosis specifically in human leukemia cells by altering the expression of these genes involved in apoptosis.
Zhiqiang Meng - One of the best experts on this subject based on the ideXlab platform.
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high intensity focused ultrasound enhances the effect of Bufalin by inducing apoptosis in pancreatic cancer cells
OncoTargets and Therapy, 2019Co-Authors: Zhouyu Ning, Zhenfeng Zhu, Haiyong Wang, Chenyue Zhang, Liping Zhuang, Xia Yan, Dan Wang, Peng Wang, Zhiqiang MengAbstract:Purpose High-intensity focused ultrasound (HIFU) has the potential to be an effective therapeutic strategy for pancreatic cancer (PC). However, owing to the high malignancy and poor prognosis of PC, the use of HIFU therapy alone is not sufficient to impair the progression of PC. Bufalin, a compound extracted from traditional medicine, is known to inhibit the growth and progression of PC cells. However, the effect of the combination therapy of HIFU plus Bufalin (HIFU+Bufalin) is still uncertain. Materials and methods A colony formation assay and flow cytometry were performed to measure the growth and induction of apoptosis in PC cells. Western blotting was used to explore the potential mechanism of HIFU and Bufalin therapy. The in vivo efficacy of HIFU+Bufalin was tested in a MiaPaCa2 xenograft model. Results Bufalin inhibited the growth of PC cells more obviously compared to HIFU. Combining Bufalin with HIFU further decreased the growth of MiaPaCa2 cells compared with single therapy in vitro. Flow cytometry results showed that the percentage of surviving MiaPaCa2 cells in the Bufalin-treated group and the HIFU-treated group was approximately three-fold and two-fold higher than in the HIFU+Bufalin-treated group. Contrasting results were found in Panc-1 cells. Biochemical analysis revealed that HIFU+Bufalin treatment elevated PARP expression and increased caspase-8 activation in MiaPaCa2 and Panc-1 cells. HIFU+Bufalin significantly reduced the growth of MiaPaCa2 tumors compared with HIFU or Bufalin treatment alone. HIFU+Bufalin treatment decreased Ki67 staining and increased activated caspase-3 and caspase 8 staining, when compared with HIFU or Bufalin treatment alone in mouse tumors. Conclusion HIFU enhanced the effect of bufailn by inducing apoptosis in PC cells. A combination of HIFU and Bufalin may be employed as an alternative therapeutic strategy for PC.
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New therapeutic aspects of steroidal cardiac glycosides: the anticancer properties of Huachansu and its main active constituent Bufalin
BMC, 2019Co-Authors: Chien Shan Cheng, Jiaqiang Wang, Jie Chen, Kuei Ting Kuo, Jian Tang, Huifeng Gao, Lianyu Chen, Zhen Chen, Zhiqiang MengAbstract:Abstract Aim of the review In the past decade, increasing research attention investigated the novel therapeutic potential of steroidal cardiac glycosides in cancer treatment. Huachansu and its main active constituent Bufalin have been studied in vitro, in vivo and clinical studies. This review aims to summarize the multi-target and multi-pathway pharmacological effects of Bufalin and Huachansu in the last decade, with the aim of providing a more comprehensive view and highlighting the recently discovered molecular mechanisms. Results Huachansu and its major derivative, Bufalin, had been found to possess anti-cancer effects in a variety of cancer cell lines both in vitro and in vivo. The underlying anti-cancer molecular mechanisms mainly involved anti-proliferation, apoptosis induction, anti-metastasis, anti-angiogenesis, epithelial–mesenchymal transition inhibition, anti-inflammation, Na+/K+-ATPase activity targeting, the steroid receptor coactivator family inhibitions, etc. Moreover, the potential side-effects and toxicities of the toad extract, Huachansu, and Bufalin, including hematological, gastrointestinal, mucocutaneous and cardiovascular adverse reactions, were reported in animal studies and clinic trails. Conclusions Further research is needed to elucidate the potential drug–drug interactions and multi-target interaction of Bufalin and Huachansu. Large-scale clinical trials are warranted to translate the knowledge of the anticancer actions of Bufalin and Huachansu into clinical applications as effective and safe treatment options for cancer patients in the future
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Bufalin suppresses hepatocellular carcinoma invasion and metastasis by targeting hif 1α via the pi3k akt mtor pathway
Oncotarget, 2016Co-Authors: Haiyong Wang, Zhouyu Ning, Chenyue Zhang, Kun Zang, Feng Jiang, Huiying Chi, Xiaoyan Zhu, Zhiqiang MengAbstract:It has been reported that there are multiple mechanisms by which Bufalin could exert its antimetastatic effect. HIF-1α has been reported to be involved in tumor migration and invasion by regulating EMT. However, it is not known whether Bufalin could exert the antimetastatic effect by modulating HIF-1α expression in hepatocellular carcinoma. In the present study, we aimed to evaluate the antimetastatic potential of Bufalin in vivo and in vitro. Our results demonstrated that the liver/lung metastases were significantly reduced in Bufalin-treated mice, as tested in the orthotopic transplanted and tail vein injection tumor models. Furthermore, the epithelial-to-mesenchymal transition (EMT) was inhibited in Bufalin-treated tumors, as reflected the upregulation of E-cadherin, and downregulation of N-cadherin, vimentin, Snail. Similar results were observed in SMMC7721 cells treated with Bufalin. Moreover, the transforming growth factor-β1 (TGF-β1)-induced EMT was also abrogated by Bufalin. Mechanistically, our study demonstrated that hypoxia-inducible factor-1α (HIF-1α) played an important role in the antimetastatic effect of Bufalin in hepatocellular carcinoma. Importantly, HIF-1α expression may be regulated through the inhibition of the PI3K/AKT/mTOR pathway. Taken together, our results suggest that Bufalin suppresses hepatic tumor invasion and metastasis and that this process may be related to the PI3K/AKT/mTOR/ HIF-1α axis.
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Bufalin enhances the anti proliferative effect of sorafenib on human hepatocellular carcinoma cells through downregulation of erk
Molecular Biology Reports, 2012Co-Authors: Yang Gao, Peng Wang, Lorenzo Cohen, Peiying Yang, Zhiqiang MengAbstract:The purpose of this study was to investigate the effect of Bufalin on the anti-proliferative activity of sorafenib in the human hepatocellular carcinoma (HCC) cell lines PLC/PRF/5 and Hep G-2 and to determine the relevant molecular mechanism. Concurrent treatment with sorafenib and Bufalin at a fixed ratio (25:1) for 48 h resulted in synergistic growth inhibition in HCC cell lines as determined by CCK-8 cell viability assays. Exposure of both PLC/PRF/5 and Hep G-2 cells to this combination of sorafenib (6.25 μM) and Bufalin (50 nM) resulted in noticeable increases in apoptotic cell death, as evidenced by the disruption of mitochondria, compared to treatment with either agent alone. Although both sorafenib (6.25 μM) and Bufalin (250 nM) alone inhibited the phosphorylation of ERK, the reduction in pERK was more pronounced in the cells treated with a combination of Bufalin (50 nM) and sorafenib (250 nM). Furthermore, the inhibitory effect of Bufalin on pERK was blocked by the PI3kinase inhibitor LY294002, suggesting that the reduction in pERK induced by Bufalin might be mediated by AKT in these two HCC cell lines. Taken together, the results of our study suggest that Bufalin enhances the anti-cancer effects of sorafenib on PLC/PRF/5 and Hep G-2 by contributing to the downregulation of ERK.
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na k atpase α3 mediates sensitivity of hepatocellular carcinoma cells to Bufalin
Oncology Reports, 2011Co-Authors: Peng Wang, Zhiqiang Meng, Xiaoyan Zhu, Yang Gao, Luming Liu, Lorenzo Cohen, Peiying YangAbstract:Bufalin, a major bioactive component of the Chinese medicine Chansu, has been reported to exhibit significant antitumor activity against various cancer cell lines. However, the exact mechanism remains unclear. In this study, we demonstrated that Bufalin inhibited the growth of hepatocellular carcinoma (HCC) cells in a dose-dependent manner, which correlated with the expression level of Na + /K + -ATPase α3 in HCC cells. The IC 50 of Bufalin markedly increased when Na + /K + -ATPase α3 was silenced by RNA interference. Furthermore, we show that Bufalin increased the phosphorylation of Akt and ERK1/2 while inhibited FoxO3a expression. Thus, our study suggests that Na + /K + -ATPase α3 might serve as a therapeutic target for Bufalin in HCC, and its expression status may help predict sensitivity of HCC cells to Bufalin treatment.
Peihao Yin - One of the best experts on this subject based on the ideXlab platform.
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Bufalin targets the src 3 mif pathway in chemoresistant cells to regulate m2 macrophage polarization in colorectal cancer
Cancer Letters, 2021Co-Authors: Jinbao Chen, Yanyan Qiu, Haijing Wang, Linlin Jia, Huan Liu, Yueping Zhan, Zeting Yuan, Yijun Cao, Peihao YinAbstract:M2-polarized macrophages are one of critical factors in tumour chemoresistance. An increasing number of studies have shown that M2 macrophage polarization can be promoted by chemoresistance. A large number of evidences indicate that Bufalin has significant antitumour effect, previous studies have found that Bufalin can reduce the polarization of M2 macrophages to play an anti-tumour effect in vivo, but the mechanism remains unclear. In our study, we found that Bufalin reduced the polarization of M2 macrophages induced by chemoresistant cells both in vivo and in vitro; however, Bufalin had no obvious direct effect on M2 macrophage polarization. Furthermore, we demonstrated that Bufalin targeted the SRC-3 protein to reduce MIF release in chemoresistant cells in order to regulate the polarization of M2 macrophages. More interestingly, we also found that Cinobufacini, Bufalin is its main active monomer, which its could regulate the polarization of M2 macrophages to enhance the anti-tumour effect of oxaliplatin in vivo and in the clinic. Overall, this study provides a theoretical basis for the clinical application of drugs containing Bufalin as the main active ingredient in combination with established chemotherapy for the treatment of colorectal cancer.
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folate receptor targeted Bufalin β cyclodextrin supramolecular inclusion complex for enhanced solubility and anti tumor efficiency of Bufalin
Materials Science and Engineering: C, 2017Co-Authors: Aihua Zou, Xiaotong Zhao, Ulrich A Handge, Vasil M Garamus, Regine Willumeitromer, Peihao YinAbstract:Bufalin (BF), a traditional Chinese medicine, exhibited inhibitory activities against a broad spectrum of tumor cells. The present study elaborates that Bufalin was successfully encapsulated into the cavity of β-cyclodextrin (β-CD), which was determined by Fourier transform infrared spectroscopy (FT-IR), proton nuclear magnetic resonance spectroscopy (1H NMR), differential scanning calorimetry (DSC) and scanning electron microscopy (SEM). The best reaction mole ratio of BF/β-CD was 1:5. The solubilities of Bufalin in water and phosphate buffer solution (pH=7.4) were increased up to 24 and 34 times after encapsulated into the cavity of β-CD respectively. The inclusion efficiency (IE) and drug loading (DL) of Bufalin in the inclusion complex were (94.22±0.85)% and (14.11±0.20)%, respectively. Then β-CD conjugated with folic acid (FA) were further prepared and employed to improve the anti-tumor efficacy of inclusion complex. The in vitro dissolution and solubility study showed better values of inclusion complex and FA targeted inclusion complex than that of pure BF. Cytotoxicity experiments by using HCT116 cell line revealed that the antitumor efficiency of Bufalin were enhanced more than two folds in the presence of β-CD and folate conjugated β-CD (FA-PEI-β-CD), which demonstrated the potential application of β-CD (FA-PEI-β-CD) as delivery vehicles of Bufalin for antitumor therapy.
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Research Article Bufalin Inhibits HCT116 Colon Cancer Cells and Its Orthotopic Xenograft Tumor in Mice Model through Genes Related to Apoptotic and PTEN/AKT Pathways
2016Co-Authors: Jie Wang, Peihao Yin, Yong Zhang, Chao Chen, Zhongxiang Gao, Dianxu Feng, Qinsong Zuo, Ronghua Zhao, Teng ChenAbstract:Copyright © 2015 Jie Wang et al.This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Aims. To investigate the anticolorectal cancer (CRC) effects of Bufalin, a bioactive polyhydroxysteroid fromVenenumBufonis, using HCT116 humanCRC cell and an established orthotopic xenograftmodel inmice, and to explore themechanisms of action.Material and Methods. Cultured HCT116 cells or BALB/c mice with orthotopic tumor were treated by Bufalin (positive control: 5-FU). Cell proliferation, apoptosis, and cycling were determined by MTT, Annexin V/PI staining, and flow cytometry, respectively. In mice, tumor inhibition rate and animal survival were calculated.The expressions of PTEN/phosphate-PTEN, AKT/phosphate-AKT, Bad, Bcl-xl, Bax, orCaspase-3 in cells and/or tumorswere determined byWestern blot or immunohistochemical staining.Results. Bufalin significantly inhibited cell proliferation and induced cell apoptosis and cycle arrest in a dose/time-dependentmanner. In the animal model, Bufalin treatment resulted in significant inhibition of tumor growth and prolonged survival. In the Bufalin-treated cultured cells and/or xenograft tumors, the expressions of PTEN, Bad, Bax, andCaspase-3were significantly increased, while p-AKT andBcl-xL significantly decreased. Conclusions. Our results indicate that Bufalin inhibit cell proliferation and orthotopic tumor growth by inducing cell apoptosis through the intrinsic apoptotic pathway, which is of pivotal significance in the identification of an anticancer drug that may synergize with Bufalin. 1
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Bufalin inhibits hct116 colon cancer cells and its orthotopic xenograft tumor in mice model through genes related to apoptotic and pten akt pathways
Gastroenterology Research and Practice, 2015Co-Authors: Jie Wang, Peihao Yin, Yong Zhang, Chao Chen, Shiying Wang, Zhongxiang Gao, Dianxu Feng, Qinsong Zuo, Ronghua Zhao, Teng ChenAbstract:Aims. To investigate the anticolorectal cancer (CRC) effects of Bufalin, a bioactive polyhydroxysteroid from Venenum Bufonis, using HCT116 human CRC cell and an established orthotopic xenograft model in mice, and to explore the mechanisms of action. Material and Methods. Cultured HCT116 cells or BALB/c mice with orthotopic tumor were treated by Bufalin (positive control: 5-FU). Cell proliferation, apoptosis, and cycling were determined by MTT, Annexin V/PI staining, and flow cytometry, respectively. In mice, tumor inhibition rate and animal survival were calculated. The expressions of PTEN/phosphate-PTEN, AKT/phosphate-AKT, Bad, Bcl-xl, Bax, or Caspase-3 in cells and/or tumors were determined by Western blot or immunohistochemical staining. Results. Bufalin significantly inhibited cell proliferation and induced cell apoptosis and cycle arrest in a dose/time-dependent manner. In the animal model, Bufalin treatment resulted in significant inhibition of tumor growth and prolonged survival. In the Bufalin-treated cultured cells and/or xenograft tumors, the expressions of PTEN, Bad, Bax, and Caspase-3 were significantly increased, while p-AKT and Bcl-xL significantly decreased. Conclusions. Our results indicate that Bufalin inhibit cell proliferation and orthotopic tumor growth by inducing cell apoptosis through the intrinsic apoptotic pathway, which is of pivotal significance in the identification of an anticancer drug that may synergize with Bufalin.
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preparation of Bufalin loaded pluronic polyetherimide nanoparticles cellular uptake distribution and effect on colorectal cancer
International Journal of Nanomedicine, 2014Co-Authors: Bo Liang, Peihao Yin, Ying Sun, Xiaoling Guo, Yijie Bao, Donghao Xie, Ming Zhou, Yourong Duan, Zhihai PengAbstract:A large number of studies have shown that Bufalin can have a significant antitumor effect in a variety of tumors. However, because of toxicity, insolubility in water, fast metabolism, short half-life, and other shortcomings, its application is limited in cancer therapy. In this study, we explored the anti-metastatic role of Bufalin-loaded pluronic polyetherimide nanoparticles on HCT116 colon cancer-bearing mice. Nanoparticle size, shape, drug loading, encapsulation efficiency, and in vitro drug release were studied. Also, cellular uptake of nanoparticles, in vivo tumor targeting, and tumor metastasis were studied. The nanoparticles had a particle size of about 60 nm and an encapsulation efficiency of 75.71%, by weight. The in vitro release data showed that free Bufalin was released faster than Bufalin-loaded pluronic polyetherimide nanoparticles, and almost 80% of free Bufalin was released after 32 hours. Nanoparticles had an even size distribution, were stable, and had a slow release and a tumor-targeting effect. Bufalin-loaded pluronic polyetherimide nanoparticles can significantly inhibit the growth and metastasis of colorectal cancer.
