Repurposed Drugs in Gastric Cancer

Gastric cancer (GC) is one of the major causes of death worldwide, ranking as the fifth most incident cancer in 2020 and the fourth leading cause of cancer mortality. The majority of GC patients are in an advanced stage at the time of diagnosis, presenting a poor prognosis and outcome. Current GC treatment approaches involve endoscopic detection, gastrectomy and chemotherapy or chemoradiotherapy in an adjuvant or neoadjuvant setting. Drug development approaches demand extreme effort to identify molecular mechanisms of action of new drug candidates. Drug repurposing is based on the research of new therapeutic indications of drugs approved for other pathologies. In this review, we explore GC and the different drugs repurposed for this disease.     

血清六种微量元素与胃癌的相关性

为研究胃癌患者血清微量元素与胃癌的相关性 ,探讨其在胃癌诊断中的应用 ,取甘肃省武威市 2 0例胃癌患者血清作为胃癌组 (C组 ) ,3 0例当地健康志愿者血清作为对照组 (N组 ) ,用电感耦合等离子体原子发射光谱仪 (ICP -AES)进行了 6种微量元素的测定 ,并将结果用SPSS软件作统计分析。结果表明 ,胃癌组血清微量元素值高于对照组的元素有Cu、Cu/Zn、Fe (P <0 0 1 ) :低于对照组的元素有Zn、Mn (P <0 0 5 )。经Logistic回归分析 ,进入方程的为Zn元素 (P<0 0 5 )。多种微量元素联合诊断胃癌的准确率为 87% ,误诊率为 8%。提示 ,甘肃省武威市胃癌患者血清中Cu、Cu/Zn、Fe的升高以及Zn、Mn的降低与胃癌的发生具有相关性。其中Zn与胃癌的发生关系最为密切 ,且Zn降低可能为胃癌发生的癌前因素。测定血清微量元素值可以作为早期诊断胃癌的一种工具。     

新型丁烯内酯衍生物的设计合成及诱导胃癌细胞凋亡研究

开发了一条合成天然产物Uncinine的新方法,基于此设计合成了一系列新型的丁烯内酯衍生物.通过噻唑蓝(MTT)法评价了目标化合物对胃癌细胞的增殖抑制活性,分析了其构效关系.其中,3-吗啉甲基-4-(4-叔丁基苯基)亚基丁烯内酯(9l)对MGC803的IC50为2.9μmol/L,对胃癌细胞MGC803、HGC27以及SGC7901具有明显的选择性增殖抑制作用,而对正常的胃粘膜上皮细胞GES1具有较小的毒性.初步的作用机制研究表明,化合物9l诱导胃癌细胞MGC803凋亡依赖Caspase 9/3激活.     

Microbial Proteins in Stomach Biopsies Associated with Gastritis,Ulcer, and Gastric Cancer

(1) Background: Gastric cancer (GC) is the fourth leading cause of cancer-related deaths worldwide. Helicobacter pylori infection is a major risk factor, but other microbial species may also be involved. In the context of an earlier proteomics study of serum and biopsies of patients with gastroduodenal diseases, we explored here a simplified microbiome in these biopsies (H. pylori, Acinetobacter baumannii, Escherichia coli, Fusobacterium nucleatum, Bacteroides fragilis) on the protein level. (2) Methods: A cohort of 75 patients was divided into groups with respect to the findings of the normal gastric mucosa (NGM) and gastroduodenal disorders such as gastritis, ulcer, and gastric cancer (GC). The H. pylori infection status was determined. The protein expression analysis of the biopsy samples was carried out using high-definition mass spectrometry of the tryptic digest (label-free data-independent quantification and statistical analysis). (3) Results: The total of 304 bacterial protein matches were detected based on two or more peptide hits. Significantly regulated microbial proteins like virulence factor type IV secretion system protein CagE from H. pylori were found with more abundance in gastritis than in GC or NGM. This finding could reflect the increased microbial involvement in mucosa inflammation in line with current hypotheses. Abundant proteins across species were heat shock proteins and elongation factors. (4) Conclusions: Next to the bulk of human proteins, a number of species-specific bacterial proteins were detected in stomach biopsies of patients with gastroduodenal diseases, some of which, like those expressed by the cag pathogenicity island, may provide gateways to disease prevention without antibacterial intervention in order to reduce antibiotic resistance.     

水溶性量子点荧光探针用于胃癌细胞相关抗原CA242的检测

基于量子点荧光探针对胃癌细胞相关抗原CA242进行了检测。首先在水溶液中直接合成性能优良的量子点荧光纳米颗粒,并在其表面成功修饰了羊抗小鼠IgG和聚乙二醇,制得功能化的水溶性量子点荧光探针,并利用探针对胃癌细胞相关抗原CA242进行检测,进一步与传统的基于荧光染料标记的免疫荧光分析方法进行了比较。实验结果表明:该功能化的探针能够有效地识别胃癌细胞相关抗原CA242,并且在光稳定性和灵敏度方面都较传统的基于荧光染料标记的免疫荧光分析方法有明显的改善,从而为CA242的相关检测以及胃癌的诊断与愈后判断提供了新的方法。     

Gastric Cancer Pre-Stage Detection and Early Diagnosis of Gastritis Using Serum Protein Signatures

Background: A gastric cancer (GC) diagnosis relies on histopathology. Endoscopy rates are increasing. Helicobacter pylori infection is a major GC risk factor. In an effort to elucidate abundant blood biomarkers, and potentially reduce the number of diagnostic surgical interventions, we investigated sera and biopsies from a cohort of 219 H. pylori positive and negative patients diagnosed with GC, gastritis, and ulcers. This allowed the comparative investigation of the different gastroduodenal diseases, and the exclusion of protein changes resulting from bacterial infection or inflammation of the gastric mucosa when searching for GC-dependent proteins. Methods: High-definition mass spectrometry-based expression analysis of tryptically digested proteins was performed, followed by multivariate statistical and network analyses for the different disease groups, with respect to H. pylori infection status. Significantly regulated proteins differing more than two-fold between groups were shortlisted, and their role in gastritis and GC discussed. Results: We present data of comparative protein analyses of biopsies and sera from patients suffering from mild to advanced gastritis, ulcers, and early to advanced GC, in conjunction with a wealth of metadata, clinical information, histopathological evaluation, and H. pylori infection status. We used samples from pre-malignant stages to extract prospective serum markers for early-stage GC, and present a 29-protein marker panel containing, amongst others, integrin β-6 and glutathione peroxidase. Furthermore, ten serum markers specific for advanced GC, independent of H. pylori infection, are provided. They include CRP, protein S100A9, and kallistatin. The majority of these proteins were previously discussed in the context of cancer or GC. In addition, we detected hypoalbuminemia and increased fibrinogen serum levels in gastritis. Conclusion: Two protein panels were suggested for the development of multiplex tests for GC serum diagnostics. For most of the elements contained in these panels, individual commercial tests are available. Thus, we envision the design of multi-protein assays, incorporating several to all of the panel members, in order to gain a level of specificity that cannot be achieved by testing a single protein alone. As their development and validation will take time, gastritis diagnosis based on the fibrinogen to albumin serum ratio may be a quick way forward. Its determination at the primary/secondary care level for early diagnosis could significantly reduce the number of referrals to endoscopy. Preventive measures are in high demand. The protein marker panels presented in this work will contribute to improved GC diagnostics, once they have been transferred from a research result to a practical tool.     

胃癌与微量元素相关性研究

报道了胃癌患者发中微量元素的变化信息。认为胃癌患者较正常人Zn、Zn/Cu、Mg、Ca均呈显著降低 (P <0 0 5 ) ,胃癌与胃溃疡相比 ,Zn、Zn/Cu、Mg均呈显著降低 (P <0 0 5 )。因此 ,发中微量元素化学信息的变化 ,可作为本地区胃癌的辅助诊断和胃癌与胃溃疡的区别及辅助诊断的依据之一。     

超声造影和MRI在胃癌新辅助治疗后再分期的一致性

将2017年1月至2018年12月于西宁市第二人民医院行新辅助治疗的72例胃癌患者纳入研究,同时给予患者超声造影(contrast-enhanced ultrasonography,CEUS)检查及磁共振成像(magnetic resonance imaging, MRI)增强扫描,比较并分析二者对治疗后分期及肿瘤周围侵犯情况的检查结果,以探究CEUS在评估胃癌新辅助治疗后分期及侵犯情况方面与MRI的一致性。研究结果显示,MRI和CEUS评估胃癌T分期的诊断一致率为91.67%,具有较高一致性;CEUS和MRI评估病灶的左右径、纵轴直径和前后径具有较好的一致性,且两者无明显差异;CEUS与MRI评估其侵袭横结肠及其系膜、肝/脾、十二指肠/胰腺的诊断,具有较高的一致性。本研究证实,CEUS与MRI在评估胃癌T分期、病灶大小及周围组织侵犯情况时结果基本一致。     

Targeting Cytotoxin-Associated Antigen A,a Virulent Factor of Helicobacter pylori-Associated Gastric Cancer: Structure-Based In Silico Screening of Natural Compounds

Gastric cancer is the fifth most frequent cancer and the third major cause of mortality worldwide. Helicobacter pylori, a bacterial infection linked with GC, injects the cytotoxin-associated antigen A (CagA; an oncoprotein) into host cells. When the phosphorylated CagA protein enters the cell, it attaches to other cellular components, interfering with normal cellular signaling pathways. CagA plays an important role in the progression of GC by interacting with phosphatidylserine of the host cell membrane. Therefore, disrupting the CagA–phosphatidylserine connection using small molecules appears to be a promising therapeutic approach. In this report, we screened the natural compounds from ZINC database against the CagA protein using the bioinformatics tools. Hits were initially chosen based on their physicochemical, absorption, distribution, metabolism, excretion, and toxicity (ADMET) characteristics, as well as other drug-like characteristics. To locate safe and effective hits, the PAINS filter, binding affinities estimation, and interaction analysis were used. Three compounds with high binding affinity and specificity for the CagA binding pocket were discovered. The final hits, ZINC153731, ZINC69482055, and ZINC164387, were found to bind strongly with CagA protein, with binding energies of −11.53, −10.67, and −9.21 kcal/mol, respectively, which were higher than that of the control compound (−7.25 kcal/mol). Further, based on binding affinity and interaction pattern, two leads (ZINC153731, ZINC69482055) were chosen for molecular dynamics (MD) simulation analysis. MD results showed that they displayed stability in their vicinity at 100 ns. This study suggested that these compounds could be used as possible inhibitors of CagA protein in the fight against GC. However, additional benchwork tests are required to validate them as CagA protein inhibitors.     

血清CEA、CA19-9检测诊断老年胃癌的价值探讨

目的对应用血清CEA、CA19-9联合检测方式对患有胃癌疾病的老年患者的病情实施诊断的临床价值进行研究。方法选择广丰县中医院收治的患有胃癌疾病和胃部良性疾病的老年患者各60例,再抽取同期接受健康体检的健康老年人资料60例,分别将其定义为研究1组、研究2组、对照组。采用化学发光法对三组研究对象的血清CEA、CA19-9水平进行测定,对比分析检测结果和两项指标的阳性率。结果研究1组的血清CEA、CA19-9水平明显高于对照组和研究2组,组间数据比较差异显著(P0.05);研究2组的血清CEA、CA19-9水平明显高于对照组,组间数据比较差异显著(P0.05)。研究1组的CEA、CA19-9水平检测阳性人数明显多于对照组和研究2组,组间数据比较差异显著(P0.05);研究2组的CEA、CA19-9水平检测阳性人数明显多于对照组,组间数据比较差异显著(P0.05)。结论患有胃癌疾病的老年患者的血清CEA、CA19-9水平会异常升高,临床上可以将其作为老年胃癌疾病诊断的重要依据。     

Volatilomic Signatures of AGS and SNU-1 Gastric Cancer Cell Lines

In vitro studies can help reveal the biochemical pathways underlying the origin of volatile indicators of numerous diseases. The key objective of this study is to identify the potential biomarkers of gastric cancer. For this purpose, the volatilomic signatures of two human gastric cancer cell lines, AGS (human gastric adenocarcinoma) and SNU-1 (human gastric carcinoma), and one normal gastric mucosa cell line (GES-1) were investigated. More specifically, gas chromatography mass spectrometry has been applied to pinpoint changes in cell metabolism triggered by cancer. In total, ten volatiles were found to be metabolized, and thirty-five were produced by cells under study. The volatiles consumed were mainly six aldehydes and two heterocyclics, whereas the volatiles released embraced twelve ketones, eight alcohols, six hydrocarbons, three esters, three ethers, and three aromatic compounds. The SNU-1 cell line was found to have significantly altered metabolism in comparison to normal GES-1 cells. This was manifested by the decreased production of alcohols and ketones and the upregulated emission of esters. The AGS cells exhibited the increased production of methyl ketones containing an odd number of carbons, namely 2-tridecanone, 2-pentadecanone, and 2-heptadecanone. This study provides evidence that the cancer state modifies the volatilome of human cells.     

纳米TiO2对胃癌细胞的光催化氧化杀伤效应

纳米TiO2对胃癌细胞的光催化氧化杀伤效应;胃癌细胞(BGC-823);抗癌剂     

超声双重造影及MRI对胃癌诊断及术前T分期的对比研究

选取2017年8月~2019年2月我院收治的胃癌患者130例作为研究对象,依据患者病理诊断结果作为金标准,分析磁共振成像(magnetic resonance imaging,MRI)与超声双重造影对胃癌的诊断价值及术前T分期的价值。结果显示,超声双重造影共检出120例胃癌患者,出现10例漏诊,MRI共检出109例胃癌患者,出现21例漏诊。金标准共检出52例T1期、32例T2期、26例T3期、20例T4期患者,超声双重造影诊断出T1期48例,符合率92.31%;T2期30例,符合率93.75%;T3期24例,符合率92.31%;T4期18例,符合率90.00%,进一步分析显示,超声双重造影对不同胃癌T分期的诊断价值均高于MRI。因此,超声双重造影对胃癌的诊断价值及对术前T分期诊断价值均高于MRI。     

胃和结直肠癌的傅里叶变换红外光谱研究

利用傅里叶变换红外光谱仪及带ATR探头的中红外光纤系统测定了手术切除的胃癌、结直肠癌及相应的正常组织共31对标本粘膜面的反射红外光谱. 结果表明, 与正常组织相比, 癌组织的红外光谱发生明显变化: (1) 与脂类相关的谱带2955, 2920, 2870, 2850和1740 cm-1出现几率明显低于正常组织(P<0.001), I1460/I1400(I为峰强度)明显降低(P<0.001), 表明癌组织的脂类相对含量降低; (2) 与蛋白质相关谱带N—H和O—H明显红移(P=0.025), 表明N—H和O—H的氢键化程度增加, 癌组织的I3375/I1460, I1640/I1460和I1550/I1460明显升高(P<0.01), 表明癌组织的蛋白质相对于脂类的含量增加, 癌组织的HW1550/I1550(HW为半高宽)明显升高(P=0.036), HW1550则明显降低(P=0.05), 表明癌组织中蛋白质的二级结构发生显著变化; (3) 与醣类相关谱带中癌组织的I1160/I1460降低(P=0.002), 结合组织化学染色, 推测可能是癌组织表面的糖蛋白明显减少造成的, 而I1120/I1460升高(P=0.019)则可能是癌组织表面的糖原颗粒增加所致. (4) 与核酸相关谱带中癌组织的PO的反对称伸缩振动蓝移(P=0.033), 表明癌组织中磷酸基团的氢键化程度降低. 研究结果表明, 红外光谱有望成为诊断恶性肿瘤的有力工具.     

PAK1 as a Potential Therapeutic Target in Male Smokers with EGFR-Mutant Non-Small Cell Lung Cancer

P21-activated kinases (PAKs) are serine/threonine protein kinases that contribute to several cellular processes. Here, we aimed to determine the prognostic value of PAK1 and its correlation with the clinicopathological characteristics and five-year survival rates in patients with non-small cell lung cancer (NSCLC). We evaluated PAK1 mRNA and protein expression in NSCLC cells and resected tumor specimens, as well as in healthy human bronchial epithelial cells and adjacent healthy lung tissues, respectively, for effective comparison. Immunohistochemical tissue microarray analysis of 201 NSCLC specimens showed the correlation of PAK1 expression with clinicopathological characteristics. The mRNA and protein expression of PAK1 were 2.9- and 4.3-fold higher in six of seven NSCLC cell types and human tumors (both, p < 0.001) than in healthy human bronchial epithelial BEAS-2B cells and adjacent healthy lung tissues, respectively. Decreased survival was significantly associated with PAK1 overexpression in the entire cohort (χ² = 8.48, p = 0.0036), men (χ² = 17.1, p < 0.0001), and current and former smokers (χ² = 19.2, p < 0.0001). Notably, epidermal growth factor receptor (EGFR) mutation-positive lung cancer patients with high PAK1 expression showed higher mortality rates than those with low PAK1 expression (91.3% vs. 62.5%, p = 0.02). Therefore, PAK1 overexpression could serve as a molecular target for the treatment of EGFR mutation-positive lung cancer, especially among male patients and current/former smokers.     

Innovative Purification Method of Ovatodiolide from Anisomeles indica to Induce Apoptosis in Human Gastric Cancer Cells

Ovatodiolide (Ova), found in the plant Anisomeles indica (AI), has been reported to have an anti-proliferation effect in various cancer cells. However, little information is available regarding the anti-cancer effect of Ova in human gastric cancer cells. In this study, we investigated the inhibitory effects and the mechanisms of action responsible for these effects on human AGS cell lines from a newly developed purification technique for Ova from AI extract. Extract obtained at the optimum condition of 95% ethanol extraction of AI was sequentially partitioned by using different polarity solvents. Enriched content of Ova (35.9% purity) from the n-hexane fraction was then applied to the purification by using centrifugal partition chromatography (CPC) in a two-phase solvent system consisting of n-hexane:ethyl acetate:methanol:water (1.0:1.0:1.0:1.0, v/v/v/v) to reach purity over >95.0%. In evaluation of the anti-proliferation effect on AGS cells, Ova induced cell apoptosis with IC₅₀ values of 13.02 and 6.18 μM at 24 and 48 h, respectively, and arrested the cells at the G2/M phase. Quantification of Bax/Bcl2 mRNA expressions using qPCR showed a 2.5-fold increase in the Ova (5 μM)-treated cells at 48 h than in the control group. Specific protein expression data warrant further research to further confirm the proposed Ova-induced apoptotic pathway in AGS cells.     

Orexins/Hypocretins and Cancer: A Neuropeptide as Emerging Target

Over 20 years ago, orexin neuropeptides (Orexin-A/hypocretin-1 and Orexin-B/hypocretins-2) produced from the same precursor in hypothalamus were identified. These two neurotransmitters and their receptors (OX1R and OX1R), present in the central and peripheral nervous system, play a major role in wakefulness but also in drug addiction, food consumption, homeostasis, hormone secretion, reproductive function, lipolysis and blood pressure regulation. With respect to these biological functions, orexins were involved in various pathologies encompassing narcolepsy, neurodegenerative diseases, chronic inflammations, metabolic syndrome and cancers. The expression of OX1R in various cancers including colon, pancreas and prostate cancers associated with its ability to induce a proapoptotic activity in tumor cells, suggested that the orexins/OX1R system could have a promising therapeutic role. The present review summarizes the relationship between cancers and orexins/OX1R system as an emerging target.     

Triptonoterpene,a Natural Product from Celastrus orbiculatus Thunb,Has Biological Activity against the Metastasis of Gastric Cancer Cells

Cancer is one of the greatest threats to human health. Gastric cancer (GC) is the fifth most common malignant tumor in the world. Invasion and metastasis are the major difficulties in the treatment of GC. Herbal medicines and their extracts have a lengthy history of being used to treat tumors in China. The anti-tumoral effects of the natural products derived from herbs have received a great deal of attention. Our previous studies have shown that the traditional Chinese herb Celastrus orbiculatus Thunb extract (COE) can inhibit the invasion and metastasis of GC cells, but the specific anti-cancer components of COE are still unclear. Dozens of natural products from COE have been isolated and identified by HPLC spectroscopy in our previous experiments. Triptonoterpene is one of the active ingredients in COE. In this study, we focused on revealing whether Triptonoterpene has an excellent anti-GC effect and can be used as an effective component of Celastrus orbiculatus Thunb in the treatment of tumors. We first observed that Triptonoterpene reduces GC cell proliferation through CCK-8 assays and colony formation experiments. The cell adhesion assays have shown that Triptonoterpene inhibits adhesion between cells and the cell matrix during tumor invasion. In addition, the cell migration assay has shown that Triptonoterpene inhibits the invasion and migration of GC cells. The high-connotation cell dynamic tracking experiment has also shown the same results. The effects of Triptonoterpene on epidermal mesenchymal transition (EMT)-related and matrix metalloproteinases (MMPs)-related proteins in gastric cancer cells were detected by Western blots. We found that Triptonoterpene could significantly inhibit the changes in EMT-related and invasion and metastasis-related proteins. Altogether, these results suggest that Triptonoterpene is capable of inhibiting the migration and invasion of GC cells. Triptonoterpene, as a natural product from Celastrus orbiculatus Thunb, has significant anti-gastric cancer effects, and is likely to be one of the major equivalent components of Celastrus orbiculatus Thunb.