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A series of tertiary sulphonamide derivatives were synthesised and evaluated for their antiproliferative activity against liver cancer cell lines (SNU-475, HepG-2, and Bel-7402). Among these tertiary sulphonamides, compound 17a displayed the best anti-liver cancer activity against Bel-7402 cells with an IC50 value of 0.32 μM. Compound 17a could effectively inhibit tubulin polymerisation with an IC50 value of 1.27 μM. Meanwhile, it selectively suppressed LSD1 with an IC50 value of 63 nM. It also concentration-dependently inhibited migration against Bel-7402 cells. Importantly, tertiary sulphonamide 17a exhibited the potent antitumor activity in vivo. All these findings revealed that compound 17a might be a tertiary sulphonamide-based dual inhibitor of tubulin polymerisation and LSD1 to treat liver cancer.

A series of tertiary sulphonamide derivatives were synthesised and evaluated for their antiproliferative activity against liver cancer cell lines (SNU-475, HepG-2, and Bel-7402). Among these tertiary sulphonamides, compound 17a displayed the best anti-liver cancer activity against Bel-7402 cells with an IC50 value of 0.32 μM. Compound 17a could effectively inhibit tubulin polymerisation with an IC50 value of 1.27 μM. Meanwhile, it selectively suppressed LSD1 with an IC50 value of 63 nM. It also concentration-dependently inhibited migration against Bel-7402 cells. Importantly, tertiary sulphonamide 17a exhibited the potent antitumor activity in vivo. All these findings revealed that compound 17a might be a tertiary sulphonamide-based dual inhibitor of tubulin polymerisation and LSD1 to treat liver cancer. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the inhibitory effect of TAD1822-7, a synthesized taspine derivative, on cancer through its effects on tumor cell growth and angiogenesis via suppression of EphrinB2. The obtained data showed that TAD1822-7 decreased Bel-7402 cell viability and colony formation ability and suppressed cell migration. TAD1822-7 effectively inhibited blood vessel formation in an aortic ring assay to examine angiogenesis. Moreover, it also down regulated the expression of VEGFR2, VEGFR3, CD34, PLCγ, Akt, MMP2, MMP9, and CXCR4, and suppressed the expression of EphrinB2 and its PDZ protein, PICK1, in Bel-7402 cells. These results indicate that TAD1822-7 is a potential anti-angiogenic agent that can inhibit the viability and migration of Bel-7402 cells via suppression of EphrinB2 and the related signaling pathways.

Pine needle oil from crude extract of pine needles has been used as an anti-cancer agent in Traditional Chinese Medicine. The α-pinene is a natural compound isolated from pine needle oil which has been shown anti-cancer activity. In previous study, we found that pine needle oil exhibited significant inhibitory effect on hepatoma carcinoma BEL-7402 cells. In this study, we investigate the inhibition of α-pinene on hepatoma carcinoma BEL-7402 cells in vitro and in vivo and further explore the mechanism. The results show that liver cancer cell growth was inhibited obviously with inhibitory rate of 79.3% in vitro and 69.1% in vivo, Chk1 and Chk2 levels were upregulated, CyclinB, CDC25 and CDK1 levels were downregulated.

Haishengsu (HSS) is an active natural extract isolated from Tegillarca granosa, which has previously been demonstrated to inhibit the proliferation of several types of cancer cells in vitro. Our previous study indicated that HSS may induce apoptosis to suppress growth of human hepatocellular carcinoma BEL‑7402 cells by activating Fas pathway. The present study demonstrated that HSS treatment induces the in vitro apoptosis of BEL‑7402 cells via the mitochondrial‑mediated apoptotic pathway detected by DNA fragmentation assay, caspase activity assay and transmission electron microscopy assay, and inhibits tumor xenograft growth in vivo. Alterations in apoptotic regulatory proteins were detected, including decreased expression of B‑cell lymphoma2 (Bcl‑2), upregulation of Bcl‑2‑associated X protein and mitochondrial cytochrome c release, and downstream activation of apoptotic signaling. Furthermore, apoptotic induction was caspase‑dependent, as indicated by cleavage of the caspase substrate, poly (ADP‑ribose) polymerase. Oral administration of 62.5‑250 mg/kg HSS markedly educed the growth of hepatocellular carcinoma tumor xenografts in nude mice. In addition, immunohistochemical staining for caspase‑3 protein and transmission electron microscopy further indicated the induction of apoptosis in these tumor tissues. Taken together, the present study demonstrated that HSS may effectively induce apoptosis to suppress the growth of BEL‑7402 cells in vitro and in vivo, and therefore may hold promise for further development as a novel cancer therapy. [ABSTRACT FROM AUTHOR]

ABSTRACT A novel multifunctional amphiphilic graft copolymer has been synthesized consisting of a biodegradable poly( l-aspartic acid) backbone that was decorated by water-soluble poly(ethylene glycol) (PEG) and pH-responsive poly( N, N-diethylaminoethyl methacrylate) (PDEAEMA) side-chains as well as thiol pendant groups. This graft copolymer together with doxorubicin (DOX) formed micelles in water at pH = 10.0 with PDEAEMA and DOX acting as the core and PEG serving as the micellar corona. Upon oxidation, the thiol groups dimerized to form disulfide bonds, thus 'locking in' the micellar structure. These crosslinked micelles expanded as the pH was decreased from 7.4 to 5.0 or upon the addition, at pH = 7.4, of glutathione (GSH), a thiol-containing oligopeptide that is present in cancerous cells and cleaves disulfide bonds. At pH = 5.0, GSH addition triggered the disassembly of the micelles. The expansion and disassembly of the micelles have been determined via in vitro experiments to evaluate their DOX release behavior. More importantly, the graft copolymer micelles could enter cells by means of endocytosis and deliver DOX to the nuclei of ovarian cancer BEL-7402 cells. Thus, this polymer and its micelles are promising candidates for drug delivery applications. © 2017 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2017, 55, 1536-1546 [ABSTRACT FROM AUTHOR]

Thalictrum fortunei S. Moore, a perennial plant distributed in the southeastern part of China, has been used in Traditional Chinese Medicine for thousands of years for its antitumor, antibacterial and immunoregulatory effects. In order to investigate the active components and the mechanism of the anti-tumor effects of Thalictrum fortunei, the growth inhibitory effects of eight triterpenoids isolated from the aerial parts of the plant on tumor cell lines were examined by 3-(4,5)-dimethylthiazoy1-3,5-diphenyltetrazolium bromide (MTT) assay. The MTT-assay results showed that the inhibitory activity of 3-O-β-D-glucopyranosyl-(1→4)-β-D-fucopyranosyl(22S,24Z)-cycloart-24-en-3β,22,26-triol 26-O-β-D-glucopyranoside (1) was stronger than that of the other seven tested triterpenoids on human hepatoma Bel-7402 cell line (Bel-7402), human colon lovo cells (LoVo), human non-small cells lung cancer NCIH-460 cells (NCIH-460) and human gastric carcinoma SGC-7901 cells (SGC-7901) after 48 h treatment in vitro, with the IC50 values of 66.4, 84.8, 73.5, 89.6 μM, respectively. Moreover, the antitumor mechanism of compound 1 on Bel-7402 cell was explored through nucleus dyeing, fluorescence assay, flow cytometry and western blot. The flow cytometric analysis results revealed that compound 1 caused apoptosis and mitochondrial membrane potential (MMP) loss in Bel-7402 cells. A fluorescence assay indicated that intracellular reactive oxygen species (ROS) were markedly provoked by compound 1 treatment compared to control cells. Immunoblot results showed that compound 1 significantly increased the expression levels of cleaved caspase-3, P53 and Bax protein, and decreased the expression level of Bcl-2 protein. These findings indicate that compound 1 inhibits the growth activity of tumor cells, probably through the P53 protein-induced apoptosis pathway.

Objective To investigate the antitumor activity of the compound HS-4 and the action mechanism. Methods MTT method was used to test in vitro antitumor activity of the compound HS-4. Orthotopic xenotransplantation tumor model of liver cancer was established in nude mice, and, in vivo antitumor activity of compound HS-4 was tested with a small animal in-vivo imaging system. Sequencing of small RNA library and RNA library was performed in HS-4 treated tumor cell group and control group to investigate the anti-cancer mechanism of HS-4 at level of functional genomics, using high-throughput sequencing technology. Results HS-4 was found to have relatively high in-vitro antitumor activity against liver cancer cells, gastric cancer cells, renal cancer cells, lung cancer cells, breast cancer cells and colon cancer cells. The IC 50 values against SMMC-7721 and Bel-7402 of liver cancer cells were 0.14 and 0.13 nmol/L respectively, while the IC 50 values against MGC-803 and SGC-7901 of gastric cancer cells were 0.19 and 0.21 nmol/L, respectively. It was demonstrated that HS-4 possessed a better therapeutic effect in liver cancer. Conclusions A new reliable orthotopic xenotransplantation tumor model of liver cancer in nude mice is established. The new compounds HS-4 was found to possess relatively high in vivo and in vitro antitumor activity against liver cancer cells. [ABSTRACT FROM AUTHOR]

This study was designed to investigate the apoptosis-inducing properties of Tegillarca granosa extract Haishengsu (HSS) in human hepatocellular carcinoma cell line BEL-7402. Proliferation inhibition of the human hepatocellular carcinoma BEL-7402 cells was determined by the MTT assay, and the cell viability was determined by trypan blue dye exclusion assay. Apoptosis of BEL-7402 cells was demonstrated by fluorescence microscope with flow cytometry with Annexin V-FITC/PI double staining and Hoechst 33258 staining. Western blot analysis and RT-PCR were used to determine the expression levels of Fas. Expressions of caspase-8 and caspase-3 were examined by caspase activity assay and western blot analysis. HSS inhibited the proliferation of human hepatocellular carcinoma BEL-7402 cells in a dose- and time-dependent manner. Our results showed HSS had positive effect on apoptosis through flow cytometry assay and fluorescence microscope. The expressions of Fas protein and mRNA were up-regulated following the treatment. Caspase-8 and caspase-3 were activated in the cells cultured with HSS. In conclusion, HSS induced apoptosis of human hepatocellular carcinoma BEL-7402 cells. The apoptosis was associated with the up-regulation of Fas and the activations of caspase-8 and caspase-3. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Gecko, a kind of reptile, has been widely used as a traditional Chinese medicine to treat various diseases including cancer in China for thousands of years. The aim of this study was to investigate the anti-tumor effect of AG (aqueous extracts of fresh gecko) on human hepatocellular carcinoma cell Bel-7402 in vitro and mouse H22 hepatocellular in vivo . Further to underlie the molecular mechanism of AG inducing the differentiation of Bel-7402 cells. Materials and methods AG was obtained by water extracting method and qualitatively analyzed through High Performance Liquid Chromatography. The total protein concentration of AG was measured by BCA (bicinchoninic acid disodium) assay. The anti-tumor activities in vivo were analyzed through H22 (mouse hepatocellular carcinoma cell line H22) tumor xenografts mice. The cytotoxic activity of AG on Bel-7402 cells was evaluated by MTT assays. AFP (alpha fetoprotein) was detected by radioimmunoassay. ALB (albumin), ALP (alkaline phosphatase) and γ-GT (γ-glutamyl transpeptidase) were detected by biochemical methods with commercial kits. While morphological changes were observed through an inverted microscope. Moreover, the expression level of the proteins involved in MAPK (mitogen-activated protein kinase) signal pathway which was closely related to cellular differentiation was assessed by Western blot. Results AG showed obviously anti-tumor activity in vivo and anti-proliferative activity on Bel-7402 cells in vitro both dose-dependently. The number of clones of Bel-7402 cells treated with AG reduced and the cells were displaying differentiation state such as relatively bigger size and dispersed growth. The biochemical function markers of the cells were significantly changed after being treated with AG. The data showed that AFP secretion of the cells decreased 42.5%, ALB secretion increased 58.9%, the activity of ALP and γ-GT markedly decreased 67.0% and 48.5% separately when the concentration of AG was 10 μl/ml, and those effects were all in a dose-dependent manner. The major original and phosphorylated signal proteins (ERK1/2 (extracellular sigal-regualted kinase 1/2), P38 (p38 MAPK) and JNK1/2 (c-Jun N-terminal kinase 1/2)) involved in MAPK signal pathway were measured and the results showed that AG activated the ERK1/2 of Bel-7402 cells. Conclusions AG has anti-tumor activity in vivo and inhibits Bel-7402 cell proliferation in vitro through inducing cell differentiation, and the mechanism involves the activation of ERK1/2. [ABSTRACT FROM AUTHOR]

Cannabis sativa has long been used as a traditional medicine in China. Among its effective compounds are cannabinoids. This study determined the effect of WIN55,212-2 (WIN), a synthetic cannabinoid, on the BEL-7402 human hepatocellular carcinoma (HCC) cell line. The results showed that WIN could decrease the proliferation of BEL-7402 cells. Moreover, WIN could cause apoptosis of the cells via up-regulation of Bax expression, down-regulation of Bcl-2 expression, induction of the mitochondrial membrane potential, increase of caspase-3, -8 and -9 activities, and induction of the cleavage of caspase-3 and poly-ADP-ribose polymerase (PARP). The WIN-induced apoptosis was accompanied by the up-regulation of PPARγ expression, the activation of PPARγ DNA binding activity, and a down-regulation of PPARγ target oncogene c-myc. Conversely, the effects of WIN could be attenuated by PPARγ antagonist GW9662, and the WIN induced PPARγ expression was partially attenuated by AM630, a cannabinoid receptor-2 antagonist, whereas the WIN-induced reduction of c-myc expression was partially restored by GW9662. Collectively, our results suggest that WIN can decrease the proliferation and cause apoptosis of the BEL-7402 cells via a mitochondrial-caspase pathway and mediated by PPARγ. These results may provide a basis for the application of WIN in HCC treatment. [ABSTRACT FROM AUTHOR]

Highlights: [•] rhddADAM15 inhibited the proliferation and migration of Bel-7402 cells. [•] rhddADAM15 inhibited growth and metastasis of Bel-7402 cells in zebrafish xenograft. [•] rhddADAM15 induced apoptosis in Bel-7402 cells and somatic cells of zebrafish. [•] Cell-cycle in Bel-7402 cells showed a partial G2/S arrest. [•] Activity of caspases 8, 9 and 3 was increased in rhddADAM15-treated Bel-7402 cells. [ABSTRACT FROM AUTHOR]

Thalictrum fortunei S. Moore, a perennial plant distributed in the southeastern part of China, has been used in Traditional Chinese Medicine for thousands of years for its antitumor, antibacterial and immunoregulatory effects. In order to investigate the active components and the mechanism of the anti-tumor effects of Thalictrum fortunei, the growth inhibitory effects of eight triterpenoids isolated from the aerial parts of the plant on tumor cell lines were examined by 3-(4,5)-dimethylthiazoy1-3,5-diphenyltetrazolium bromide (MTT) assay. The MTT-assay results showed that the inhibitory activity of 3-O-β-D-glucopyranosyl-(1→4)-β-D-fucopyranosyl(22S,24Z)-cycloart-24-en-3β,22,26-triol 26-O-β-D-glucopyranoside (1) was stronger than that of the other seven tested triterpenoids on human hepatoma Bel-7402 cell line (Bel-7402), human colon lovo cells (LoVo), human non-small cells lung cancer NCIH-460 cells (NCIH-460) and human gastric carcinoma SGC-7901 cells (SGC-7901) after 48 h treatment in vitro, with the IC50 values of 66.4, 84.8, 73.5, 89.6 μM, respectively. Moreover, the antitumor mechanism of compound 1 on Bel-7402 cell was explored through nucleus dyeing, fluorescence assay, flow cytometry and western blot. The flow cytometric analysis results revealed that compound 1 caused apoptosis and mitochondrial membrane potential (MMP) loss in Bel-7402 cells. A fluorescence assay indicated that intracellular reactive oxygen species (ROS) were markedly provoked by compound 1 treatment compared to control cells. Immunoblot results showed that compound 1 significantly increased the expression levels of cleaved caspase-3, P53 and Bax protein, and decreased the expression level of Bcl-2 protein. These findings indicate that compound 1 inhibits the growth activity of tumor cells, probably through the P53 protein-induced apoptosis pathway. [ABSTRACT FROM AUTHOR]

Abstract: Polo-like kinase 1 (PLK1) is required for multiple stages of mitosis and has been found to be overexpressed in many human malignancies. Previous studies by our group have revealed PLK1 overexpression as an independent prognostic factor for hepatocellular carcinoma (HCC). However, the underlying mechanisms of the tumorigenetic effects of PLK1 in HCC remain unclear. In this study, we depleted PLK1 in human hepatoma BEL-7402 cells using small interfering RNA. Flow cytometry analysis showed that PLK1 depletion resulted in a threefold increase in the G2/M population, with a resultant decrease in the G1 population. Importantly, PLK1 depletion reduced the tumorigenicity of BEL-7402 cells in vivo, evidenced by significantly slower tumor growth following subcutaneous innoculation of tumor cells in the flanks of BALB/c nude mice. Furthermore, more apoptotic bodies associated with decreased Survivin protein expression and increased level of active caspase-3 were observed in tumor tissues of the PLK1 depletion group by TUNEL assay, Western blot and immunohistochemical analysis, respectively. Collectively, our findings imply that PLK1 depletion led to G2/M arrest, inhibition of cell proliferation and promotion of apoptosis via downregulation of Survivin expression, suggesting that PLK1 represents a new therapeutic target for HCC. [Copyright &y& Elsevier]

Objective: To explore the effects of SOM230, octreotide and lanreotide on hepatocellular carcinoma cell line Bel-7402 In vivo and In vitro , and to analyze the differences of their therapeutic efficacy with relevant mechanisms., Methods: At different time points (24, 48, 72 h), the cell counting kit-8 (CCK8) was used to evaluate cell proliferation (drug concentration 1×10 -10 -1×10 -5 mol/L) and the Annexin Ⅴ-FITC/PI staining was used to assess cell apoptosis (drug concentration 1×10 -5 mol/L), while the real-time quantitative PCR was used to detect cellular SSTR expression changes before and after interventions. A transplanted tumor model was set up, and the tumor-bearing nude mice were treated by three drugs with a common dose of 100 μg/ (kg·d) or same volume of normal saline, respectively. After a treatment period of 6 weeks, real-time quantitative PCR and Western blot test were performed to detect the expression changes of SSTR in tumor tissues from the level of gene and protein., Results: All three drugs could inhibit the cell proliferation of Bel-7402. However, they were unable to promote the cell apoptosis. In vitro , the expressions of SSTR1 , SSTR4 genes did not change over time in each group. The expressions of SSTR2 gene were decreased in three intervention groups while the expressions of SSTR5 gene were increased first and then decreased. Compared with the control group, all differences have statistical significance ( P <0.05). All three drugs could improve the survival rate and quality of life for nude mice bearing hepatoma. In vivo , the expression of SSTR1 gene in SOM230 group was increased when compared with that of the other groups; the expressions of SSTR2 gene in three intervention groups were increased when compared with that of the control group; the expressions of SSTR5 gene in SOM230 group and lanreotide group were increased when compared with that of the octreotide group and the control group, and all differences have statistical significance ( P <0.05). The Western blot test confirmed these results from the protein level., Conclusion: In a certain concentration range, the long-term treatment of SSTA with high affinities to SSTR2 and SSTR5 could inhibit the growth of HCC.

Pine needle oil from crude extract of pine needles has been used as an anti-cancer agent in Traditional Chinese Medicine. The α-pinene is a natural compound isolated from pine needle oil which has been shown anti-cancer activity. In previous study, we found that pine needle oil exhibited significant inhibitory effect on hepatoma carcinoma BEL-7402 cells. In this study, we investigate the inhibition of α-pinene on hepatoma carcinoma BEL-7402 cells in vitro and in vivo and further explore the mechanism. The results show that liver cancer cell growth was inhibited obviously with inhibitory rate of 79.3% in vitro and 69.1% in vivo, Chk1 and Chk2 levels were upregulated, CyclinB, CDC25 and CDK1 levels were downregulated., (Copyright © 2015 Japanese Pharmacological Society. Production and hosting by Elsevier B.V. All rights reserved.)

Background: Rhizoma Pinelliae is the dried tuber of Pinellia ternata (Thunb.) Breit. Modern pharmacological studies have shown that Rhizoma Pinelliae has antitussive, antiemetic, glandular secretion inhibiting and antitumor effects., Objectives: To optimize the processing technology of Rhizoma Pinelliae Praeparatum, and to study its anti-tumor effect., Methods: Orthogonal design method was applied to analyze the effects of factors such as licorice concentration volume, soaking time and processing temperature on processing technology of Rhizoma Pinelliae Praeparatum; MTT assay and flow cytometry were used to determine the inhibitory effect of Rhizoma Pinelliae Praeparatum on Bel-7402 cells., Results: During the processing of Rhizoma Pinelliae Praeparatum, the size of influence of licorice concentration volume, soaking time and processing temperature on processing results of Rhizoma Pinelliae was: B>C>A in descending order, i.e. soaking time>processing temperature>licorice concentration volume, different concentrations of Rhizoma Pinelliae Praeparatum ethanol extracts could all exert inhibitory effect on the growth and proliferation of Bel-7402 cells, and with the increase of drug concentration and the extension of culture time, the cell proliferation inhibitory effect of Rhizoma Pinelliae Praeparatum ethanol extract became more and more evident. Apoptotic rate of 1.5 mg/ml Rhizoma Pinelliae Praeparatum ethanol extract group reached 13.53%, the difference was extremely significant compared with the control group. In conclusion the factor most influential to the processing technology of Rhizoma Pinelliae Praeparatum was soaking time, followed by processing temperature, the factor least influential was licorice concentration volume., Conclusion: Rhizoma Pinelliae Praeparatum has inhibitory effect on growth and proliferation of Bel-7402 cells.