Mapping of two tumor suppressor genes in the pig

Mutations in the breast cancer 1, early onset (BRCA1) gene confer an increased risk of breast and ovarian cancer in humans. The human MAD (mothers against decapentaplegic, Drosophila) homolog 4 (MADH4) locus is a target for deletion in pancreatic and other cancers. Given the role of the pig in biomedical studies, pig orthologs of BRCA1 and MADH4 were identified and localized in the porcine genome.     

Semisynthesis and cytotoxic activities of andrographolide analogues

Andrographolide 1, a diterpenoid lactone of the plant Andrographis paniculata, known to possess antitumour activity in in vitro and in vivo breast cancer models was subjected to semisynthesis leading to the preparation of a number of novel compounds. These compounds exhibited in vitro antitumour activity with moderate to excellent growth inhibition against MCF-7 (breast) and HCT-116 (colon) cancer cells. Compounds 3,19-(2-chlorobenzylidene)andrographolide(5), 3,19-(3-chlorobenzylidene)andrographolide(6), 3,19-(3-fluorobenzylidene)andrographolide(7), 3,19-(4-fluorobenzylidene)andrographolide(8), 3,19-(2-fluorobenzylidene)andrographolide(10), 3,19-(2-chloro-5-nitrobenzylidene)andrographolide (21), 3,19-(4-chlorobenzylidene)andrographolide(30) and 3,19-(2-chloro-4-fluorobenzylidene) andrographolide(31) were also screened against 60 NCI (National Cancer Institute, USA) human tumour cell lines derived from nine cancer cell types.     

Anticancer evaluation and molecular modeling of multi-targeted kinase inhibitors based pyrido[2,3-d]pyrimidine scaffold

An efficient synthesis of substituted pyrido[2,3-d]pyrimidines was carried out and evaluated for in vitro anticancer activity against five cancer cell lines, namely hepatic cancer (HepG-2), prostate cancer (PC-3), colon cancer (HCT-116), breast cancer (MCF-7), and lung cancer (A-549) cell lines. Regarding HepG-2, PC-3, HCT-116 cancer cell lines, 7-(4-chlorophenyl)-2-(3-methyl-5-oxo-2,3-dihydro-1H-pyrazol-1-yl)-5-(p-tolyl)- pyrido[2,3-d]pyrimidin-4(3H)-one (5a) exhibited strong, more potent anticancer (IC₅₀: 0.3, 6.6 and 7?µM) relative to the standard doxorubicin (IC₅₀: 0.6, 6.8 and 12.8?µM), respectively. Kinase inhibitory assessment of 5a showed promising inhibitory activity against three kinases namely PDGFR β, EGFR, and CDK4/cyclin D1 at two concentrations 50 and 100?µM in single measurements. Further, a molecular docking study for compound 5a was performed to verify the binding mode towards the EGFR and CDK4/cyclin D1 kinases.     

Cytotoxicity and DNA interactions of some platinum(II) complexes with substituted benzimidazole ligands

In the present study, four Pt(II) complexes with 2-ethyl (1)/or benzyl (2)/or p-chlorobenzyl (3)/or 2-phenoxymethyl (4) benzimidazole carrier ligands were evaluated for their in vitro cytotoxic activities against the human HeLa cervix, oestrogen receptor-positive MCF-7 breast, and oestrogen receptor-negative MDA-MB 231 breast cancer cell lines. The plasmid DNA interactions and inhibition of the BamHI restriction enzyme activities of the complexes were also studied. Complex 3 was found to be more active than carboplatin for all examined cell lines and comparable with cisplatin, except for the HeLa cell line.     

Plasma hepcidin in early-stage breast cancer patients: no relationship with interleukin-6, erythropoietin and erythroferrone

Objective: Hepcidin-25 production is stimulated by systemic inflammation, and it interferes with iron utilization, leading to anemia. This study aimed to investigate the relationships between the plasma levels of hepcidin, interleukin-6 (IL-6), erythropoietin (EPO) and erythroferrone (ERFE) in patients with benign breast disease or cancer. Methods: Plasma samples from a cohort of 131 patients (47 with benign breast disease and 84 with breast cancer) were subjected to the evaluation of hepcidin, IL-6, EPO and ERFE using SELDI-TOF-MS or immunoassays. Results: An elevated hepcidin was observed in malignant breast tumors compared to benign ones. No correlation was observed between hepcidin and IL-6, EPO or ERFE. Conclusion: Since the study included a cohort of patients (87%) with breast cancers smaller than 2 cm, these results may support our previous evidence about the potential role of hepcidin in breast cancer disease.     

Allicin induces cell cycle arrest and apoptosis of breast cancer cells in vitro via modulating the p53 pathway

Background

The tumor suppressor protein p53 is a most promising target for the development of anticancer drugs. Allicin (diallylthiosulfinate) is one of the most active components of garlic (Alliium sativum L.) and possesses a variety of health-promoting properties with pharmacological applications. However, whether allicin plays an anti-cancer role against breast cancer cells through the induction of p53-mediated apoptosis remains unknown.

Methods and results

In this study, we investigate the anti-breast cancer effect of allicin in vitro by using MCF-7 and MD-MBA-231 cells. We found that allicin reduces cell viability, induces apoptosis and cell cycle arrest in both cells. Allicin activated p53 and caspase 3 expressions in both cells but produced different effects on the expression of p53-related biomarkers. In MDA-MB-231 cells, allicin up-regulated the mRNA and protein expression of A1BG and THBS1 while down-regulated the expression of TPM4. Conversely, the mRNA and protein expression of A1BG, THBS1 and TPM4 were all reduced in MCF-7 cells. Hence, allicin induces cell cycle arrest and apoptosis in breast cancer cells through p53 activation but it effects on the expression of p53-related biomarkers were dependent upon the specific type of breast cancer involved.

Conclusions

These findings suggest that allicin induces apoptosis and regulates biomarker expression in breast cancer cell lines through modulating the p53 signaling pathway. Furthermore, our results promote the utility of allicin as compound for further studies as an anticancer drug targeting p53.

     

VEGFR-2 inhibitors and apoptosis inducers: synthesis and molecular design of new benzo[g]quinazolin bearing benzenesulfonamide moiety

Two series of novel 4-(2-(2-(2-(substituted) hydrazinyl)-2-oxoethylthio)-4-oxobenzo[g]quinazolin-3(4H)-yl) benzenesulfonamide 5–17 and 4-(2-(2-(substituted-1H-pyrazol-1-yl)-2-oxoethylthio)-4-oxobenzo[g]quinazolin-3(4H)-yl) benzenesulfonamide 18–24 were synthesised from the starting material 4-(2-(2-hydrazinyl-2-oxoethylthio)-4-oxobenzo[g]quinazolin-3(4H)-yl) benzenesulfonamide 5, to be evaluated for their inhibitory activity towards VEGFR-2. The target compounds 5–24, were screened for their cytotoxic activity against MCF-7 breast cancer cell line and the percentage inhibition against VEGFR-2. Compounds 9, 20, 22 and 23, showed excellent VEGFR-2 inhibitory activity with IC₅₀ ranging from 0.64 to 1.04?µm. Being the most potent, compound 9 was evaluated for its apoptotic inducer effect by studying the effect on caspase-3, it was found to increase its level. Compound 9 boosted the level of Bax and reduced the level of BCl2, compared to the control. Cell cycle analysis was conducted, compound 9 showed cell cycle arrest at G2/M phase. Moreover, mild cytotoxic effect (IC₅₀?=?29.41?µm, respectively) in normal breast cells MCF-12?A, was observed when treated with the same compound. Finally, a molecular docking study was performed to investigate the possible binding interaction inside the active site of the VEGFR-2 enzyme.     

Multicomponent synthesis of some new (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-dithiocarbamates and their in vitro anti-proliferative activity against CaSki,MDA-MB-231 and SK-Lu-1 tumour cells as apoptosis inducing agents without necrosis

Identification of a new class of antitumor agent capable to induce apoptosis without triggering necrotic cell death event is challenging. The present communication describes the multicomponent synthesis of seven new (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-dithiocarbamates and their in vitro antiproliferative activity on cervical cancer cell line (CaSki), breast cancer cell line (MDA-MB231), lung cancer cell line (SK-Lu-1) and human lymphocytes. Among the synthesized dithiocarbamates, compound 9e displayed significant antiproliferative activity without inducing any necrotic cell death (both on tumour cells and lymphocytes) and induced apoptosis in tumor cells by the caspase dependent apoptotic pathway. The compound 9e also exhibited greater tumor selectivity than human lymphocytes. In silico ADME predictions revealed that compound 9e has the potential to be developed as a drug candidate. Rapid chemical modifications of this lead are thus highly necessary for further investigation as a drug like safer antitumor candidate and also to achieve compounds with better activity profile.     

乳腺良性肿块与乳腺癌患者的超声弹性成像对比

目的:对比乳腺良性肿块与乳腺癌患者的超声弹性成像,明确超声弹性成像的应用价值。方法:选取2014年5月-2016年1月我院乳腺肿块患者128人次共146例肿块,根据病理结果分为乳腺良性肿块和乳腺癌,比较超声弹性成像与病理结果。结果:128个患者共计肿块146例,99例结节为良性肿块,其中32例为乳腺纤维腺瘤,29例为乳腺增生结节,20例为乳腺脂肪瘤,6例为乳腺血管脂肪瘤,4例为乳腺导管腺瘤,8例为乳腺导管内乳头状瘤;47例肿块为恶性,其中37例肿块为浸润性导管癌,9例肿块为粘液腺癌,1例肿块为硬癌。乳腺良性肿块患者81人次共99例,其中1分43例(43.43%),2分34例(34.34%),3分18例(18.18%),4分4例(4.04%);乳腺癌患者47例,其中3分9例(19.15%),4分20例(42.55%),5分18例(38.30%)。超声弹性成像鉴别乳腺良性肿块与乳腺癌的灵敏度为95.96%,特异性为80.85%,准确度为91.10%,阴性预测值为90.48%,阳性预测值为91.35%。结论:超声弹性成像鉴别乳腺良性肿块与乳腺癌的灵敏度高达95.96%,具有较高准确度,可辅助诊断乳腺疾病。     

Synthesis and anticancer activity of 3′-[4-fluoroaryl-(1,2,3-triazol-1-yl)]-3′-deoxythymidine analogs and their phosphoramidates

Abstract

A series of novel 4-chlorophenyl N-alkyl phosphoramidates of 3′-[4-fluoroaryl-(1,2,3-triazol-1-yl)]-3′-deoxythymidines (20–49) was synthesized by means of phosphorylation of 3′-[4-aryl-(1,2,3-triazol-1-yl)]-3′-deoxythymidines (7–11) with 4-chlorophenyl phosphoroditriazolide (14), followed by a reaction with the appropriate amine. The synthesized compounds 7–11 and 20–49 were evaluated along with four known anticancer compounds for their cytotoxic activity in human cancer cell lines: cervical (HeLa), nasopharyngeal (KB), breast (MCF-7), osteosarcoma (143B) (only selected compounds 20, 24, 28, 32–36, 38, 40, 46) and normal human dermal fibroblast cell line (HDF) using the sulforhodamine B (SRB) assay. Among 3′-[4-aryl-(1,2,3-triazol-1-yl)]-3′-deoxythymidines (7–11) the highest activity in all the investigated cancer cells was displayed by 3′-[4-(3-fluorophenyl)-(1,2,3-triazol-1-yl)]-3′-deoxythymidine (9) (IC₅₀ in the range of 2.58–3.61?μM) and its activity was higher than that of cytarabine. Among phosphoramidates 20–49 the highest activity was demonstrated by N-n-propyl phosphoramidate of 3′-[4-(3-fluorophenyl)-(1,2,3-triazol-1-yl)]-3′-deoxythymidine (35) in all the cancer cells (IC₅₀ in the range of 0.97–1.94?μM). Also N-ethyl phosphoramidate of 3′-[4-(3-fluorophenyl)-(1,2,3-triazol-1-yl)]-3′-deoxythymidine (33) exhibited good activity in all the used cell lines (IC₅₀ in the range of 4.79–4.96?μM).     

Steroidal Metabolites Transformed by <Emphasis Type="Italic">Marchantia polymorpha</Emphasis> Cultures Block Breast Cancer Estrogen Biosynthesis

Suspension of cultured cells of Marchantia polymorpha have the potential to hydrogenate the olefinic bonds present in androst-1,4-dien-3,17-dione (boldione, 1) to afford dihydroandrost-3,17-dione derivatives including: androst-4-ene-3,17-dione (androstenedione, 4-AD, 2), 5α-androstane-3,17-dione (androstenedione, AD, 4), and the less abundant metabolite 5α-androst-1-ene-3,17-dione (1-androstenedione, 1-AD, 3). After isolation and purification, these metabolites were characterized on the basis of spectroscopic analyses using 1D and 2D NMR as well as mass spectrometry. Cytotoxicity of the biotransformation products against breast adenocarcinoma cells (MCF-7) was assessed by a 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay and cell death (apoptosis or necrosis) was assayed by acridine orange/ethidium bromide staining. Aromatase (cytochrome P450 19 enzyme, CYP19) inhibitory activity was measured by a tritiated water release assay and by direct measurement of bio-transformed steroids using the tritium labeled substrate ³H-androst-4-ene-3,17-dione. CYP19 mRNA expression in MCF-7 cells was analyzed by real-time PCR. Steroidal products 3 and 4 revealed a highly significant inhibition of MCF-7 cell growth that was predominantly due to apoptosis not necrosis. Steroidal products 3 and 4 are both potent inhibitors of aromatase activity and CYP19 mRNA expression, while 2 is a known substrate for aromatase. These data establish that metabolites 3 and 4 are potent chemical agents against breast cancer via aromatase inhibitory mechanism. Results were interpreted via virtual docking of the biotransformation products to the human placental aromatase active site.     

血清HE4、VEGF、MCP-1及CCL20与乳腺癌患者保乳术后局部复发的关系研究

摘要 目的：探讨血清人附睾蛋白4（HE4）、血管内皮生长因子（VEGF）、单核细胞趋化因子-1（MCP-1）及CC趋化因子配体20（CCL20）与乳腺癌患者保乳术后局部复发的关系。方法：选择2015年7月~2018年7月期间本院收治的乳腺癌患者312例作为研究对象,均符合保乳术手术指征,成功实施乳腺癌保乳术,所有患者均随访3年。检测两组血清HE4、VEGF、MCP-1、CCL20水平情况,单因素及多因素Logistic回归分析影响术后局部复发的因素。使用受试者工作特征（ROC）曲线分析HE4、VEGF、MCP-1、CCL20水平单独及联合检测对保乳术后局部复发的预测价值。结果：随访过程中失访6例,剩余的306例患者根据随访结果,分为局部复发组27例、无局部复发组279例,局部复发率为8.82%。局部复发组的血清HE4、VEGF、MCP-1、CCL20水平均高于无局部复发组（P<0.05）。单因素分析结果显示,乳腺癌患者保乳术后局部复发与年龄、淋巴结转移、切缘状态、人表皮生长因子受体2（Her-2）、细胞增殖相关抗原（Ki-67）、术后规范化疗、术后足程放疗有关（P<0.05）。多因素Logistic回归分析结果显示术后规范化疗、年龄偏高、术后足程放疗是保乳术后局部复发的保护因素,HE4、VEGF、MCP-1、CCL20水平偏高,切缘状态、Her-2、Ki-67阳性以及淋巴结转移是保乳术后局部复发的危险因素（P<0.05）。HE4、VEGF、MCP-1、CCL20联合应用预测乳腺癌患者保乳术后局部复发的效能高于单一指标应用。结论：乳腺癌保乳术后局部复发患者体内HE4、VEGF、MCP-1、CCL20水平高表达,四指标联合检测可辅助预测保乳术后局部复发。且乳腺癌患者保乳术后复发还受到切缘状态、Her-2、Ki-67等多种因素的影响。     

RETRACTED ARTICLE: Further in vitro biological activity evaluation of amino-, thio- and ester-derivatives of avarol

The acetylcholinesterase inhibitory and/or antitumour activities of amino-, thio- and ester-derivatives of avarol selected were evaluated for the first time at in vitro conditions. Avarol-3′,4′-dithioglycol (1) and avarol-4′-(3)mercaptopropionic acid (3) were shown to be the best inhibitors of the enzyme tested (0.50?µg and IC50 0.05?mM and 0.50?µg and IC50 0.12?mM, respectively), while 4′-tryptamine-avarone (9) and avarol-3′-(3)mercaptopropionic acid (2) exhibited the highest cytotoxicity against the human breast T-47D cancer cell line (IC50 0.66?µg/mL and 1.25?µg/mL, respectively). According to experimental data obtained, the sesquiterpenoid hydroquinone structure of bioactive avarol derivatives may inspire development of new pharmacologically useful substances to be used in the treatment of Alzheimer's disease and/or human breast tumour.     

TGF-β signalling-related markers in cancer patients with bone metastasis

Abstract

We measured transforming growth factor (TGF)-β-dependent biomarkers in plasma and in peripheral blood mononuclear cells (PBMCs) to identify suitable pharmacodynamic markers for future clinical trials with TGF-β inhibitors. Forty-nine patients with bone metastasis were enrolled in the study, including patients with breast (n=23) and prostate cancer (n=15). Plasma TGF-β1 levels were elevated in more than half of the cancer patients (geometric mean 2.63 ng ml^?1) and positively correlated with increased platelet factor 4 (PF4) levels, parathyroid-related protein (PTHrP), von Willebrand Factor (vWF) and interleukin (IL)-10. PBMC were stimulated ex vivo to determine the individual biological variability of an ex vivo assay measuring pSMAD expression. This assay performed sufficiently well to allow its future use in a clinical trial of a TGF-β inhibitor.     

Factors associated with oxidative stress and cancer risk in the Breast and Prostate Cancer Cohort Consortium

Abstract

Both endogenous factors (genomic variations) and exogenous factors (environmental exposures, lifestyle) impact the balance of reactive oxygen species (ROS). Variants of the ND3 (rs2853826; G10398A) gene of the mitochondrial genome, manganese superoxide dismutase (MnSOD; rs4880 Val16Ala) and glutathione peroxidase (GPX-1; rs1050450 Pro198Leu), are purported to have functional effects on regulation of ROS balance. In this study, we examined associations of breast and prostate cancer risks and survival with these variants, and interactions between rs4880–rs1050450, and alcohol consumption—rs2853826. Nested case-control studies were conducted in the Breast and Prostate Cancer Cohort Consortium (BPC3), consisting of nine cohorts. The analyses included over 10726 post-menopausal breast and 7532 prostate cancer cases with matched controls. Logistic regression models were used to evaluate associations with risk, and proportional hazard models were used for survival outcomes. We did not observe significant interactions between polymorphisms in MnSOD and GPX-1, or between mitochondrial polymorphisms and alcohol intake and risk of either breast (p-interaction of 0.34 and 0.98, respectively) or prostate cancer (p-interaction of 0.49 and 0.50, respectively). We observed a weak inverse association between prostate cancer risk and GPX-1 Leu198Leu carriers (OR 0.87, 95% CI 0.79–0.97, p = 0.01). Overall survival among women with breast cancer was inversely associated with G10398 carriers who consumed alcohol (HR 0.66 95% CI 0.49–0.88). Given the high power in our study, it is unlikely that interactions tested have more than moderate effects on breast or prostate cancer risk. Observed associations need both further epidemiological and biological confirmation.     

Association between chemokine receptor 5 delta32 polymorphism and susceptibility to cancer: a meta-analysis

Abstract

Objective: To explore whether the functional chemokine receptor 5 delta32 (CCR5-Δ32) polymorphism is associated with susceptibility to cancer. Methods: A meta-analysis was conducted on the association between the CCR5-Δ32 polymorphism and cancer using (i) allele contrast and (ii) the dominant model. Results: Thirteen articles, including 16 comparative studies on a total of 3087 patients and 3735 controls, were included in the meta-analysis. These studies encompassed breast cancer (n?=?3), bladder cancer (n?=?3), cervical cancer (n?=?2), pancreatic cancer (n?=?2), prostate cancer (n?=?2), head and neck cancer (n?=?2), lymphoma (n?=?1), gallbladder cancer (n?=?1), skin cancer (n?=?1) and mixed cancer (n?=?1). The meta-analysis revealed an association between cancer and the CCR5-Δ32 allele (OR?=?1.368, 95% CI?=?1.064–1.758, p?=?0.014), and stratification by ethnicity showed an association between the CCR5-Δ32 allele and cancer in Indians (OR?=?2.480, 95% CI?=?1.247–4.932, p?=?0.010). The meta-analysis also revealed an association between breast cancer and the CCR5-Δ32 allele (OR?=?1.689, 95% CI?=?1.012–2.821, p?=?0.045). However, allele contrast and the dominant model failed to reveal an association between the CCR5-Δ32 polymorphism and bladder cancer, cervical cancer, pancreatic cancer, prostate cancer, and head and neck cancer. Conclusions: This meta-analysis demonstrates that the CCR5-Δ32 polymorphism is associated with susceptibility to cancer in Indians and is associated with breast cancer.     

FGFR4 mRNA及蛋白在乳腺癌组织中的表达及临床意义

目的:研究乳腺癌组织与乳腺癌癌旁组织中FGFR4 mRNA及蛋白的表达及其临床意义。方法:分别以实时荧光定量RT-PCR、Western blot的方法检测52例乳腺癌组织和52例癌旁正常组织中FGFR4 mRNA和蛋白的表达,分析FGFR4 mRNA和蛋白的表达与临床病理特征的相关性。结果:在乳腺癌组织中,FGFR4 mRNA及蛋白的表达均高于在乳腺癌癌旁正常组织(P0.05),并且FGFR4的表达与患者淋巴结转移和Her-2相关,而与患者年龄、肿瘤大小、分化程度、ER和PR无明显相关性(P0.05)。结论:FGFR4 mRNA及蛋白在乳腺癌组织中表达升高,与淋巴结转移和Her-2有关,有望成为预测乳腺癌的转移和预后的参考指标之一。