C-Dimethylated Flavones as Possible Potential Anti-Tubercular and Anticancer Agents.

The present investigation describes an intramolecular Oxa-Michael addition of penta-substituted phenols to the enone of the tether in the presence of iodine as the oxidizing agent. Ten C-Dimethylated flavones with moderate to good yields ( 10a – j , 60–89 %) were isolated by heating the corresponding C-dimethylated chalcones using iodine in DMSO. Using the Microplate Alamar Blue test (MABA) technique, the drugs′ quantitative drug susceptibility against the H37Rv strain of replicating Mycobacterium TB was determined. The sensitivity of two of the developed compounds ( 10e , 10h ) was up to 6.25 g/mL. The human lung adenocarcinoma cell lines (A549) were used in the anticancer study, which was carried out using the MTT cell proliferation assay. In A549 cell lines, four flavones demonstrated anticancer activity with IC₅₀ values between 39 and 48 μM. The C-dimethylated flavones, 10b (3,4-dimethoxy), 10c (2,3,4-trimethoxy), 10e (p-fluoro) and 10 g (N-methyl indole) substitutions on ring ‘B’ showed good anticancer activity with IC₅₀ values 39.17, 39.21, 48.43 and 43.48 μM, respectively. The compounds 10b , 10c , 10d , 10e , and 10i had improved binding and interaction profiles among all the compounds examined during the current In Silico research, as shown by the docking simulations against two targets EGFR and MTB MurI.     

Venom-Derived Bioactive Compounds as Potential Anticancer Agents: A Review

International Journal of Peptide Research and Therapeutics - Biologically active compounds with potential anticancer activity have been isolated from various animal sources. Recent research is...     

Microwave-assisted Synthesis of Novel Thiazolocarbazoles and Evaluation as Potential Anticancer Agents. Part III

Novel 6-substituted thiazolocarbazole derivatives have been synthesized under microwave irradiation via the corresponding imino-1,2,3-dithiazoles. In vitro antitumor potential of these polyheterocyclic compounds was evaluated. Among all the tested thiazolocarbazoles, compound 10 is the most effective in inhibiting cell growth.     

腹腔镜肝癌切除术与开放式肝癌切除术的疗效比较研究

目的：探讨腹腔镜肝癌切除手术治疗原发性肝癌的可行性及安全性。方法：选取2008年6月至2011年1月在我院行腹腔镜肝癌切除术的30例患者作为研究对象,另外选择同期在我院行开放式肝癌切除术的30例患者作为对照。结果：30例均在腹腔镜下成功地完成手术,其中22例行腹腔镜局部切除术,8例行肝左外叶切除术。手术时间103—142min,出血量60-480mL,术后均未发生严重并发症,术后平均住院8．6d。术后随访18～36个月,局部复发或种植性转移率与对照组无显著差异。结论：腹腔镜肝癌切除术是安全可行治疗原发性肝癌的手术方式.     

Valorization of Lipopeptides Biosurfactants as Anticancer Agents

International Journal of Peptide Research and Therapeutics - Biosurfactants are natural compounds produced biologically by certain bacterial strains. They are promising alternatives in several...     

腹腔镜肝癌切除术与开放式肝癌切除术的疗效比较研究

目的:探讨腹腔镜肝癌切除手术治疗原发性肝癌的可行性及安全性。方法:选取2008年6月至2011年1月在我院行腹腔镜肝癌切除术的30例患者作为研究对象,另外选择同期在我院行开放式肝癌切除术的30例患者作为对照。结果:30例均在腹腔镜下成功地完成手术,其中22例行腹腔镜局部切除术,8例行肝左外叶切除术。手术时间103-142 min,出血量60-480mL,术后均未发生严重并发症,术后平均住院8.6 d。术后随访18~36个月,局部复发或种植性转移率与对照组无显著差异。结论:腹腔镜肝癌切除术是安全可行治疗原发性肝癌的手术方式。     

Synthesis of Bis(Aziridinyl) Phosphinic Amide Derivatives of Thymidine as Potential Anticancer Agents

Abstract

3′- and 5′-Bis(aziridinyl)phosphinic amide derivatives of thymidine have been synthesized as potential anticancer agents from 3′-amino-3′-deoxythymidine and 5′-amino-5′-deoxythymidine, respectively. The aziridine-containing compounds were tested for their cytotoxic action in vitro against the L1210 leukemia; the 3′-bis(aziridinyl)phosphinic amide derivative was found to be about 11-times more active than its 5′-counterpart in inhibiting the replication of these leukemic cells, with ED₅₀ values of 0.6 and 7 μM, respectively, being obtained.     

Hepatocellular Carcinoma Displays Distinct DNA Methylation Signatures with Potential as Clinical Predictors

Background

Hepatocellular carcinoma (HCC) is characterized by late detection and fast progression, and it is believed that epigenetic disruption may be the cause of its molecular and clinicopathological heterogeneity. A better understanding of the global deregulation of methylation states and how they correlate with disease progression will aid in the design of strategies for earlier detection and better therapeutic decisions.

Methods and Findings

We characterized the changes in promoter methylation in a series of 30 HCC tumors and their respective surrounding tissue and identified methylation signatures associated with major risk factors and clinical correlates. A wide panel of cancer-related gene promoters was analyzed using Illumina bead array technology, and CpG sites were then selected according to their ability to classify clinicopathological parameters. An independent series of HCC tumors and matched surrounding tissue was used for validation of the signatures. We were able to develop and validate a signature of methylation in HCC. This signature distinguished HCC from surrounding tissue and from other tumor types, and was independent of risk factors. However, aberrant methylation of an independent subset of promoters was associated with tumor progression and etiological risk factors (HBV or HCV infection and alcohol consumption). Interestingly, distinct methylation of an independent panel of gene promoters was strongly correlated with survival after cancer therapy.

Conclusion

Our study shows that HCC tumors exhibit specific DNA methylation signatures associated with major risk factors and tumor progression stage, with potential clinical applications in diagnosis and prognosis.     

二氢丹参酮通过抑制Akt信号通路激活来增强索拉非尼对肝细胞癌的抗癌作用

目的 索拉非尼是唯一被批准用于治疗晚期肝细胞癌（hepatocellular carcinoma,HCC）的一线药物。然而索拉非尼的耐药性使得治疗效果并不理想。尽管索拉非尼耐药性的机制尚不清楚,但在HCC中的耐药性可能通过Akt信号通路的激活而发生。二氢丹参酮（dihydrotanshinone,DHT）是中药丹参的亲脂性成分,具有多种抗肿瘤活性并可抑制Akt活化。DHT联合索拉非尼治疗HCC的作用机制尚未明确。本文旨在研究DHT是否可增强索拉非尼对HCC的抗癌活性。方法 采用细胞计数试剂盒8（cell counting kit-8,CCK-8）和流式细胞仪检测索拉非尼和DHT对HCC细胞Huh7和HepG2细胞活力、细胞凋亡和药物敏感性的影响。通过蛋白质印迹分析Akt、P-Akt、Caspase3、GSK-3β、P-GSK3-β、核糖体蛋白S6激酶（S6K）、P-S6K、细胞周期蛋白D1、Bcl-xl、Bcl-2和Bax的表达水平。使用单因素方差分析（analysis of variance,ANOVA）和Dunnett检验对所有数据进行统计学比较。采用SPSS 20.0统计软件进行统计分析。结果 DHT通过减少Akt的激活来抑制HCC细胞的增殖和促进细胞凋亡。DHT抑制Akt下游因子的表达和激活,包括GSK-3β和S6K,这些因子调节细胞凋亡反应,并被索拉非尼激活和上调。索拉非尼和DHT均下调细胞周期蛋白D1的表达,DHT上调Bax的表达并下调Bcl-2和Bcl-xl的表达。索拉非尼对Bcl-2家族蛋白质表达的影响不大。结论 DHT可能通过抑制Akt信号通路的激活来增强索拉非尼的HCC细胞增殖抑制作用和凋亡诱导作用。     

Organometallic Ruthenium and Osmium Compounds of Pyridin-2- and -4-ones as Potential Anticancer Agents

Organometallic Ru(II) compounds are among the most widely studied anticancer agents. Functionalizing metal centers with biomolecule-derived ligands has been shown to be a promising strategy to improve the antiproliferative activity of metal-based chemotherapeutics. Herein, the synthesis of a series of novel 3-hydroxypyridin-2-one-derived ligands and their M(II) (η(6) -p-cymene) half-sandwich complexes (M=Ru, Os) is described. The compounds were characterized by 1D- and 2D-NMR spectroscopy, and elemental analysis.     

Global Gene Expression Profiling Reveals SPINK1 as a Potential Hepatocellular Carcinoma Marker

Background

Liver cirrhosis is the most important risk factor for hepatocellular carcinoma (HCC) but the role of liver disease aetiology in cancer development remains under-explored. We investigated global gene expression profiles from HCC arising in different liver diseases to test whether HCC development is driven by expression of common or different genes, which could provide new diagnostic markers or therapeutic targets.

Methodology and Principal Findings

Global gene expression profiling was performed for 4 normal (control) livers as well as 8 background liver and 7 HCC from 3 patients with hereditary haemochromatosis (HH) undergoing surgery. In order to investigate different disease phenotypes causing HCC, the data were compared with public microarray repositories for gene expression in normal liver, hepatitis C virus (HCV) cirrhosis, HCV-related HCC (HCV-HCC), hepatitis B virus (HBV) cirrhosis and HBV-related HCC (HBV-HCC). Principal component analysis and differential gene expression analysis were carried out using R Bioconductor. Liver disease-specific and shared gene lists were created and genes identified as highly expressed in hereditary haemochromatosis HCC (HH-HCC) were validated using quantitative RT-PCR. Selected genes were investigated further using immunohistochemistry in 86 HCC arising in liver disorders with varied aetiology. Using a 2-fold cut-off, 9 genes were highly expressed in all HCC, 11 in HH-HCC, 270 in HBV-HCC and 9 in HCV-HCC. Six genes identified by microarray as highly expressed in HH-HCC were confirmed by RT qPCR. Serine peptidase inhibitor, Kazal type 1 (SPINK1) mRNA was very highly expressed in HH-HCC (median fold change 2291, p = 0.0072) and was detected by immunohistochemistry in 91% of HH-HCC, 0% of HH-related cirrhotic or dysplastic nodules and 79% of mixed-aetiology HCC.

Conclusion

HCC, arising from diverse backgrounds, uniformly over-express a small set of genes. SPINK1, a secretory trypsin inhibitor, demonstrated potential as a diagnostic HCC marker and should be evaluated in future studies.     

Synthesis and Biological Evaluation of Matijin‐Su Derivatives as Potential Antihepatitis B Virus and Anticancer Agents

A series of Matijin‐Su (MTS, (2S)‐2‐{[(2S)‐2‐benzamido‐3‐phenylpropanoyl]amino}‐3‐phenylpropyl acetate) derivatives were synthesized and evaluated for their anti‐HBV and cytotoxic activities in vitro. Six compounds ( 4g , 4j , 5c , 5g , 5h and 5i ) showed significant inhibition against HBV DNA replication with the IC₅₀ values in range of 2.18 – 8.55 μm , which were much lower than that of positive control lamivudine (IC₅₀ 82.42 μm ). In particular, compounds 5h (IC₅₀ 2.18 μm ; SI 151.59) and 5j (IC₅₀ 5.65 μm ; SI 51.16) displayed relatively low cytotoxicities, resulting in high SI values. Notably, besides the anti‐HBV DNA replication activity, compound 4j also exhibited more potent in vitro cytotoxic activity than 5‐fluorouracil in two hepatocellular carcinoma cell (HCC) lines (QGY‐7701 and SMMC‐7721), indicating that 4j may be a promising lead for the exploration of drugs with dual therapeutic effects on HBV infection and HBV‐induced HCC.     

Synthesis of Ester-Linked Ursolic Acid-Based Hybrid Compounds: Potential Antibacterial and Anticancer Agents

The molecular hybridization of two or more drugs into a single molecule is an effective drug design approach to reduce pill burden and improve patient treatment adherence. Ursolic acid-based hybrid compounds were synthesized and characterized followed by molecular docking studies. In vitro studies against various bacterial strains and human cancer cells (MDA-MB-231, HeLa, and MCF-7) were performed. Compounds 14 – 19 , 21 , 34 , 31 , and 30 demonstrated significant antibacterial activities with MIC values of 15.625 μg/ml. Compounds 29 and 34 were more cytotoxic than ursolic acid, with IC₅₀ values of 46.99 and 48.18 μg/ml. Compounds 29 and 34 in the docking studies presented favourable binding interactions and better docking energy against the Epidermal Growth Factor Receptor (EGFR) than the parent compound, ursolic acid. The findings revealed that the ursolic acid scaffold is a promising precursor for the development of molecules with promising anticancer and antimicrobial activities. However, more studies are needed to fully understand their mode of action.     

Identification of Serum Monocyte Chemoattractant Protein-1 and Prolactin as Potential Tumor Markers in Hepatocellular Carcinoma

Early diagnosis of hepatocellullar carcinoma (HCC) remains a challenge. The current practice of serum alpha-fetoprotein (AFP) measurement is inadequate. Here we utilized a proteomic approach to identify novel serum biomarkers for distinguishing HCC patients from non-cancer controls. We profiled the serum proteins in a group of 58 resectable HCC patients and 11 non-HCC chronic hepatitis B (HBV) carrier samples from the Singapore General Hospital (SGH) using the RayBio® L-Series 507 Antibody Array and found 113 serum markers that were significantly modulated between HCC and control groups. Selected potential biomarkers from this list were quantified using a multiplex sandwich enzyme-linked immunosorbent assay (ELISA) array in an expanded SGH cohort (126 resectable HCC patients and 115 non-HCC chronic HBV carriers (NC group)), confirming that serum prolactin and monocyte chemoattractant protein-1 (MCP-1) were significantly upregulated in HCC patients. This finding of serum MCP-1 elevation in HCC patients was validated in a separate cohort of serum samples from the Mochtar Riady Institute for Nanotechnology, Indonesia (98 resectable HCC, 101 chronic hepatitis B patients and 100 asymptomatic HBV/HCV carriers) by sandwich ELISA. MCP-1 and prolactin levels were found to correlate with AFP, while MCP-1 also correlated with disease stage. Subsequent receiver operating characteristic (ROC) analysis of AFP, prolactin and MCP-1 in the SGH cohort and comparing their area under the ROC curve (AUC) indicated that neither prolactin nor MCP-1 on their own performed better than AFP. However, the combination of AFP+MCP-1 (AUC, 0.974) had significantly superior discriminative ability than AFP alone (AUC, 0.942; p<0.001). In conclusion, prolactin and MCP-1 are overexpressed in HCC and are conveniently quantifiable in patients’ sera by ELISA. MCP-1 appears to be a promising complementary biomarker for HCC diagnosis and this MCP-1+AFP model should be further evaluated as potential biomarker on a larger scale in patients at-risk of HCC.     

Serum LncRNAs Profiles Serve as Novel Potential Biomarkers for the Diagnosis of HBV-Positive Hepatocellular Carcinoma

Background

Hepatocellular carcinoma (HCC) is a common malignancy that has a poor prognosis because there is lack of methods for early diagnosis. We aimed to utilize two serum long non-coding RNAs (lncRNAs), uc001ncr and {"type":"entrez-nucleotide","attrs":{"text":"AX800134","term_id":"37653391"}}AX800134, to diagnose hepatitis B virus (HBV)–positive HCC.

Methods

lncRNA microarrays were utilized to measure the differential expression of lncRNAs between tumor tissues and corresponding non-tumor tissues in HBV-positive hapatocellular carcinoma. uc001ncr and {"type":"entrez-nucleotide","attrs":{"text":"AX800134","term_id":"37653391"}}AX800134 were selected as candidate lncRNAs and detected in three independent cohorts containing a total of 684 participants (healthy individuals and chronic HBV patients and HBV-positive HCC patients) who were recruited between March 2011 and December 2012. A logistic regression model was constructed using a training cohort (n = 353) and validated using an independent cohort (n = 181). The area under the receiver operating characteristic curve (AUC) was utilized to evaluate the diagnostic accuracy.

Results

We determined that a panel based on the expression of uc001ncr and {"type":"entrez-nucleotide","attrs":{"text":"AX800134","term_id":"37653391"}}AX800134 accurately diagnosed HBV-positive HCC (AUC values of 0.9494 and 0.9491 for the training and validation cohorts, respectively). The diagnostic performance of the panel remained high in patients with AFP≤400 ng/ml (AUC values of 0.9371 and 0.9527 for the training and validation cohorts, respectively). The panel also diagnosed early HCC (AUC values of 0.9450 and 0.9564 for the training and validation cohorts, respectively).

Conclusion

Our results indicated that the serum expression of uc001ncr and {"type":"entrez-nucleotide","attrs":{"text":"AX800134","term_id":"37653391"}}AX800134 has potential as novel potential biomarker for the diagnosis of HCC, especially in patients with AFP≤400 ng/ml or early-stage disease (BCLC 0+A).     

磺酰化乳糖基神经酰胺表达水平对肝癌细胞转移潜能的影响

研究磺酰化乳糖基神经酰胺（SM3）的表达水平与肝癌细胞转移潜能的关系.采用免疫荧光染色和细胞酶联免疫两种方法,观察了不同转移潜能的肝癌细胞中磺酰化乳糖基神经酰胺的表达水平,发现高转移性肝癌细胞表达SM3的水平明显高于低转移性肝癌细胞.高转移性肝癌细胞经过10 μmol/L维甲酸处理,抑制肝癌细胞的转移潜能以后,SM3的表达水平显著下降（P＜0.05）,接近低转移性肝癌细胞水平,但是SM3的前体分子半乳糖基神经酰胺水平并不降低,提示磺酰化作用受到了抑制.通过脑苷脂磺酰基转移酶(CST)基因的转染,使Hep3B肝癌细胞高表达SM3.发现CST转染的肝癌细胞与转移相关的行为显著改变,经黏附试验发现,CST基因转染的肝癌细胞对层粘连蛋白和玻连蛋白（vitronectin）的黏附显著增强,比未转染的或转染载体的肝癌细胞升高3～4倍.裸鼠体内试验表明,这种具有高度表达CST基因的Hep3B细胞比对照组细胞具有更高的转移能力(P＜0.05).说明磺酰化乳糖基神经酰胺可能与肝癌细胞的转移有关.     

miR-155对肝癌细胞增殖的影响

目的:在肝癌细胞系中过表达miR-155,研究其对肝癌细胞增殖的影响。方法:将pc DNA3.0-miR-155表达载体瞬时转染Huh7.5.1及Hcclm3肝癌细胞系,通过实时定量PCR技术对miR-155在转录水平的表达进行检测,采用CCK8法及克隆形成实验检测miR-155过表达后对Huh7.5.1及Hcclm3肝癌细胞系增殖的影响。结果:转染细胞后72 h,经实时定量PCR检测,Huh7.5.1及Hcclm3肝癌细胞中成熟miR-155的表达分别上调约431及16倍(P0.01),说明其能有效高表达;CCK8法及克隆形成实验结果显示,miR-155能够明显促进肝癌细胞增殖(P0.01)。结论:pc DNA3.0-miR-155转染Huh7.5.1及Hcclm3肝癌细胞系后能高效表达成熟miR-155,同时证明过表达miR-155能使肝癌细胞的增殖受到非常明显的促进。     

RPN2与肝癌患者预后及对肝癌细胞生长的作用

目的:探讨核糖蛋白2(ribophorin II,RPN2)在肝细胞肝癌(HCC)组织中的表达和对HCC患者生存的影响,同时分析RPN2对肝癌HepG2细胞生长和克隆形成的作用。方法:应用免疫组化方法和HCC公共芯片数据,从蛋白和m RNA水平检测HCC组织中RPN2的表达,同时分析RPN2与HCC患者临床参数的关系及预后相关性;进一步利用MTS法和克隆形成实验在肝癌HepG2细胞中检测RPN2对细胞生长的作用。结果:98例肝癌组织中,RPN2阳性表达率88.78%,对应癌旁肝组织中,RPN2阳性表达率74.49%;癌组织中RPN2染色评分为5.80±3.15,癌旁肝组织RPN2染色评分为2.13±1.59,肝癌组织中RPN2表达显著上调(P0.001)。3个肝癌公共芯片数据(共522例肝癌)中RPN2的m RNA表达水平同样显著升高(均P0.001)。98例肝癌患者RPN2表达水平与肿瘤直径(P=0.004)、门脉侵袭(P=0.012)和TNM分期(P=0.009)相关;RPN2高表达的患者总体生存期(OS)和无复发生存期(RFS)较RPN2低表达的患者短(OS:P=0.027;RFS:P=0.036)。肝癌HepG2细胞转染RPN2小干扰RNA后,细胞生长能力显著受抑制。结论:RPN2在肝癌中表达显著升高,RPN2的表达与肝癌的恶性进展有关,RPN2显著促进肝癌细胞生长。     

The Enhanced Metastatic Potential of Hepatocellular Carcinoma (HCC) Cells with Sorafenib Resistance

Acquired resistance towards sorafenib treatment was found in HCC patients, which results in poor prognosis. To investigate the enhanced metastatic potential of sorafenib resistance cells, sorafenib-resistant (SorR) cell lines were established by long-term exposure of the HCC cells to the maximum tolerated dose of sorafenib. Cell proliferation assay and qPCR of ABC transporter genes (ABCC1-3) were first performed to confirm the resistance of cells. Migration and invasion assays, and immunoblotting analysis on the expression of epithelial to mesenchymal transition (EMT) regulatory proteins were performed to study the metastatic potential of SorR cells. The expression of CD44 and CD133 were studied by flow cytometry and the gene expressions of pluripotency factors were studied by qPCR to demonstrate the enrichment of cancer stem cells (CSCs) in SorR cells. Control (CTL) and SorR cells were also injected orthotopically to the livers of NOD-SCID mice to investigate the development of lung metastasis. Increased expressions of ABCC1-3 were found in SorR cells. Enhanced migratory and invasive abilities of SorR cells were observed. The changes in expression of EMT regulatory proteins demonstrated an activation of the EMT process in SorR cells. Enriched proportion of CD44⁺ and CD44⁺CD133⁺ cells were also observed in SorR cells. All (8/8) mice injected with SorR cells demonstrated lung metastasis whereas only 1/8 mouse injected with CTL cells showed lung metastasis. HCC cells with sorafenib resistance demonstrated a higher metastatic potential, which may be due to the activated EMT process. Enriched CSCs were also demonstrated in the sorafenib resistant cells. This study suggests that advanced HCC patients with acquired sorafenib resistance may have enhanced tumor growth or distant metastasis, which raises the concern of long-term sorafenib treatment in advanced HCC patients who have developed resistance of sorafenib.