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Identification of the Roles of Coagulation-related Signature and its Key Factor RABIF in Hepatoma Cell Malignancy. 识别凝血相关特征及其关键因子 RABIF 在肝癌细胞恶性肿瘤中的作用
IF 2.5 4区 医学 Q3 ONCOLOGY Pub Date : 2024-01-01 DOI: 10.2174/1574892819666230829151148
Yanying Chen, Yin Li, Bingyi Zhou

Background: Hepatoma is a high morbidity and mortality cancer, and coagulation is a potential oncogenic mechanism for hepatoma development.

Objective: In this study, we aimed to reveal the role of coagulation in hepatoma.

Methods: We applied the LASSO to construct a coagulation-related risk score (CRS) and a clinical nomogram with independent validation. The heterogeneity of various aspects, including functional enrichment, SNV, CN, immunocyte infiltration, immune pathways, immune checkpoint, and genomic instability indexes, was evaluated. Besides, the prognostic value of the CRS genes was tested. We selected the critical risky gene related to coagulation from the LASSO coefficients, for which we applied transwell and clone formation assays to confirm its roles in hepatoma cell migration and clone formation ability, respectively.

Results: The CRS and the nomogram predicted patients' survival with good accuracy in both two datasets. The high-CRS group was associated with higher cell cycle, DNA repair, TP53 mutation rates, amplification, and lower deletion rates at chromosome 1. For immunocyte infiltration, we noticed increased Treg infiltration and globally upregulated immune checkpoints and genomic instability indexes. Additionally, every single CRS gene affected the patient's survival. Finally, we observed that RABIF was the riskiest gene in the CRS. Its knockdown suppressed hepatoma cell migration and clone formation capability, which could be rescued by RABIF overexpression.

Conclusion: We built a robust CRS with great potential as a prognosis and immunotherapeutic indicator. Importantly, we identified RABIF as an oncogene, promoting hepatoma cell migration and clone formation, revealing underlying pathological mechanisms, and providing novel therapeutic targets for hepatoma treatment.

背景:肝癌是一种高发病率和高死亡率的癌症,而凝血是肝癌发展的潜在致癌机制:本研究旨在揭示凝血在肝癌中的作用:方法:我们应用 LASSO 建立了凝血相关风险评分(CRS)和临床提名图,并进行了独立验证。评估了各方面的异质性,包括功能富集、SNV、CN、免疫细胞浸润、免疫通路、免疫检查点和基因组不稳定性指标。此外,还检测了CRS基因的预后价值。我们从LASSO系数中筛选出了与凝血相关的关键风险基因,并对其进行了经孔试验和克隆形成试验,分别证实了其在肝癌细胞迁移和克隆形成能力中的作用:在两个数据集中,CRS和提名图都能准确预测患者的生存期。高CRS组与较高的细胞周期、DNA修复、TP53突变率、扩增和较低的1号染色体缺失率相关。在免疫细胞浸润方面,我们注意到Treg浸润增加,免疫检查点和基因组不稳定性指数全面上调。此外,每个 CRS 基因都会影响患者的生存。最后,我们发现RABIF是CRS中风险最大的基因。它的敲除抑制了肝癌细胞的迁移和克隆形成能力,而RABIF的过表达可以挽救这种能力:结论:我们建立了一个强大的 CRS,它具有作为预后和免疫治疗指标的巨大潜力。重要的是,我们发现 RABIF 是一种促进肝癌细胞迁移和克隆形成的癌基因,揭示了潜在的病理机制,并为肝癌治疗提供了新的治疗靶点。
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引用次数: 0
Comprehensive Genomic Analysis of Puerarin in Inhibiting Bladder Urothelial Carcinoma Cell Proliferation and Migration. 葛根素抑制膀胱尿路上皮癌细胞增殖和迁移的全面基因组分析
IF 2.5 4区 医学 Q3 ONCOLOGY Pub Date : 2024-01-01 DOI: 10.2174/1574892819666230908110107
Yu-Yang Ma, Ge-Jin Zhang, Peng-Fei Liu, Ying Liu, Ji-Cun Ding, Hao Xu, Lin Hao, Deng Pan, Hai-Luo Wang, Jing-Kai Wang, Peng Xu, Zhen-Duo Shi, Kun Pang

Background: Bladder urothelial carcinoma (BUC) ranks second in the incidence of urogenital system tumors, and the treatment of BUC needs to be improved. Puerarin, a traditional Chinese medicine (TCM), has been shown to have various effects such as anti-cancer effects, the promotion of angiogenesis, and anti-inflammation. This study investigates the effects of puerarin on BUC and its molecular mechanisms.

Methods: Through GeneChip experiments, we obtained differentially expressed genes (DEGs) and analyzed these DEGs using the Ingenuity® Pathway Analysis (IPA®), Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) pathway enrichment analyses. The Cell Counting Kit 8 (CCK8) assay was used to verify the inhibitory effect of puerarin on the proliferation of BUC T24 cells. String combined with Cytoscape® was used to create the Protein-Protein Interaction (PPI) network, and the MCC algorithm in cytoHubba plugin was used to screen key genes. Gene Set Enrichment Analysis (GSEA®) was used to verify the correlation between key genes and cell proliferation.

Results: A total of 1617 DEGs were obtained by GeneChip. Based on the DEGs, the IPA® and pathway enrichment analysis showed they were mainly enriched in cancer cell proliferation and migration. CCK8 experiments proved that puerarin inhibited the proliferation of BUC T24 cells, and its IC50 at 48 hours was 218μmol/L. Through PPI and related algorithms, 7 key genes were obtained: ITGA1, LAMA3, LAMB3, LAMA4, PAK2, DMD, and UTRN. GSEA showed that these key genes were highly correlated with BUC cell proliferation. Survival curves showed that ITGA1 upregulation was associated with poor prognosis of BUC patients.

Conclusion: Our findings support the potential antitumor activity of puerarin in BUC. To the best of our knowledge, bioinformatics investigation suggests that puerarin demonstrates anticancer mechanisms via the upregulation of ITGA1, LAMA3 and 4, LAMB3, PAK2, DMD, and UTRN, all of which are involved in the proliferation and migration of bladder urothelial cancer cells.

背景:膀胱尿路上皮癌(BUC)的发病率在泌尿生殖系统肿瘤中位居第二,BUC的治疗亟待改善。葛根素是一种传统中药,具有抗癌、促进血管生成和抗炎等多种作用。本研究探讨了葛根素对 BUC 的影响及其分子机制:通过基因芯片实验,我们获得了差异表达基因(DEGs),并使用 Ingenuity® Pathway Analysis (IPA®)、Kyoto Encyclopedia of Genes and Genomes (KEGG) 和 Gene Ontology (GO) 途径富集分析法对这些 DEGs 进行了分析。细胞计数试剂盒 8(CCK8)检测法用于验证葛根素对 BUC T24 细胞增殖的抑制作用。使用String结合Cytoscape®创建蛋白-蛋白相互作用(PPI)网络,并使用cytoHubba插件中的MCC算法筛选关键基因。基因组富集分析(Gene Set Enrichment Analysis,GSEA®)用于验证关键基因与细胞增殖之间的相关性:结果:基因芯片共获得 1617 个 DEGs。结果:基因芯片共获得 1617 个 DEGs,IPA® 和通路富集分析表明,这些 DEGs 主要富集在癌细胞增殖和迁移中。CCK8实验证明葛根素能抑制BUC T24细胞的增殖,其48小时的IC50为218μmol/L。通过PPI和相关算法,得到了7个关键基因:ITGA1、LAMA3、LAMB3、LAMA4、PAK2、DMD 和 UTRN。GSEA显示,这些关键基因与BUC细胞增殖高度相关。生存曲线显示,ITGA1的上调与BUC患者的不良预后有关:我们的研究结果支持葛根素对 BUC 的潜在抗肿瘤活性。据我们所知,生物信息学研究表明,葛根素通过上调 ITGA1、LAMA3 和 4、LAMB3、PAK2、DMD 和 UTRN 显示出抗癌机制,所有这些物质都参与了膀胱尿路上皮癌细胞的增殖和迁移。
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引用次数: 0
PSMA PET/MR is a New Imaging Option for Identifying Glioma Recurrence and Predicting Prognosis. PSMA PET/MR是识别胶质瘤复发和预测预后的新影像学选择
IF 2.8 4区 医学 Q3 ONCOLOGY Pub Date : 2024-01-01 DOI: 10.2174/1574892818666230519150401
Min Xiong, Zhenghe Chen, Chao Zhou, Xiaochun Yang, Wanming Hu, Yongluo Jiang, Rongliang Zheng, Wei Fan, Yonggao Mou, Xiaoping Lin
<p><strong>Background: </strong>Glioma is characterized by a high recurrence rate, while the results of the traditional imaging methods (including magnetic resonance imaging, MRI) to distinguish recurrence from treatment-related changes (TRCs) are poor. Prostate-specific membrane antigen (PSMA) (US10815200B2, Deutsches Krebsforschungszentrum, German Cancer Research Center) is a type II transmembrane glycoprotein overexpressed in glioma vascular endothelium, and it is a promising target for imaging and therapy.</p><p><strong>Objective: </strong>The study aimed to assess the performance of PSMA positron emission tomography/ magnetic resonance (PET/MR) for diagnosing recurrence and predicting prognosis in glioma patients.</p><p><strong>Materials and methods: </strong>Patients suspected of glioma recurrence who underwent <sup>18</sup>F-PSMA-1007 PET/MR were prospectively enrolled. Eight metabolic parameters and fifteen texture features of the lesion were extracted from PSMA PET/MR. The ability of PSMA PET/MR to diagnose glioma recurrence was investigated and compared with conventional MRI. The diagnostic agreement was assessed using Cohen κ scores and the predictive parameters of PSMA PET/MR were obtained. Kaplan-Meier method and Cox proportional hazard model were used to analyze recurrence- free survival (RFS) and overall survival (OS). Finally, the expression of PSMA was analyzed by immunohistochemistry (IHC).</p><p><strong>Results: </strong>Nineteen patients with a mean age of 48.11±15.72 were assessed. The maximum tumorto- parotid ratio (TPR<sub>max</sub>) and texture features extracted from PET and T1-weighted contrast enhancement (T1-CE) MR showed differences between recurrence and TRCs (all <i>p</i> <0.05). PSMA PET/MR and conventional MRI exhibited comparable power in diagnosing recurrence with specificity and PPV of 100%. The interobserver concordance was fair between the two modalities (<i>κ</i> = 0.542, <i>p</i> = 0.072). The optimal cutoffs of metabolic parameters, including standardized uptake value (SUV, SUV<sub>max</sub>, SUV<sub>mean</sub>, and SUV<sub>peak</sub>) and TPR<sub>max</sub> for predicting recurrence were 3.35, 1.73, 1.99, and 0.17 respectively, with the area under the curve (AUC) ranging from 0.767 to 0.817 (all <i>p</i> <0.05). In grade 4 glioblastoma (GBM) patients, SUV<sub>max</sub>, SUV<sub>mean</sub>, SUV<sub>peak</sub>, TBR<sub>max</sub>, TBR<sub>mean</sub>, and TPR<sub>max</sub> showed improved performance of AUC (0.833-0.867, <i>p</i> <0.05). Patients with SUVmax, SUVmean, or SUVpeak more than the cutoff value had significantly shorter RFS (all <i>p</i> <0.05). In addition, patients with SUVmean, SUVpeak, or TPR<sub>max</sub> more than the cutoff value had significantly shorter OS (all <i>p</i> <0.05). PSMA expression of glioma vascular endothelium was observed in ten (10/11, 90.9%) patients with moderate-to-high levels in all GBM cases (n = 6/6, 100%).</p><p><strong>Conclusion: </strong>This primitive study shows
胶质瘤具有复发率高的特点,而传统的影像学方法(包括磁共振成像,MRI)在区分复发与治疗相关改变(TRCs)方面的效果较差。前列腺特异性膜抗原(PSMA) (US10815200B2, Deutsches Krebsforschungszentrum,德国癌症研究中心)是一种在胶质瘤血管内皮中过表达的II型跨膜糖蛋白,是一种有前景的成像和治疗靶点。本研究旨在评估PSMA正电子发射断层扫描/磁共振(PET/MR)在胶质瘤患者复发诊断和预后预测中的作用。疑似胶质瘤复发并接受18F-PSMA-1007 PET/MR检查的患者被前瞻性纳入研究。通过PSMA PET/MR提取病灶的8个代谢参数和15个纹理特征。研究PSMA PET/MR对胶质瘤复发的诊断能力,并与常规MRI进行比较。采用Cohen κ评分评估诊断一致性,并获得PSMA PET/MR预测参数。采用Kaplan-Meier法和Cox比例风险模型分析无复发生存期(RFS)和总生存期(OS)。最后通过免疫组化分析PSMA的表达(ihcn19例患者,平均年龄48.11±15.72岁)。肿瘤与腮腺的最大比值(TPRmax)以及PET和t1加权对比增强(T1-CE) MR提取的纹理特征在复发与TRCs之间存在差异(均P <0.05)。PSMA PET/MR和常规MRI在诊断复发方面具有相当的能力,特异性和PPV均为100%。两种模式之间的观察者间一致性是公平的(κ=0.542, P=0.072)。标准化摄取值(SUV、SUVmax、SUVmean和SUVpeak)和TPRmax预测复发的最佳截止值分别为3.35、1.73、1.99和0.17,曲线下面积(AUC)范围为0.767 ~ 0.817(均P <0.05)。在4级胶质母细胞瘤(GBM)患者中,SUVmax、SUVmean、SUVpeak、TBRmax、TBRmean和TPRmax的AUC性能均有改善(0.833-0.867,P <0.05)。SUVmax、SUVmean、SUVpeak均大于临界值的患者RFS显著缩短(均P <0.05)。此外,SUVmean、SUVpeak、TPRmax均大于临界值的患者生存期明显缩短(均P <0.05)。在所有GBM病例中,10例(10/11,90.9%)胶质瘤血管内皮中-高水平表达PSMA (n=6/6, 100%)。本初步研究显示,尽管与常规MRI相比,多参数PSMA PET/MR并没有提高诊断性能,但通过提供出色的肿瘤背景比较、肿瘤异质性、复发预测和预后信息,可用于识别胶质瘤(特别是GBM)复发。需要进一步和更大规模的研究来确定其在这种情况下的潜在临床应用。
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引用次数: 0
Fatty Acid Metabolism Signature Contributes to the Molecular Diagnosis of a Malignant Gastric Cancer Subtype with Poor Prognosis and Lower Mutation Burden. 脂肪酸代谢特征有助于对预后较差、突变负担较低的恶性胃癌亚型进行分子诊断
IF 2.5 4区 医学 Q3 ONCOLOGY Pub Date : 2024-01-01 DOI: 10.2174/1574892819666230907145036
Zhengwei Chen, Guoxiong Cheng

Background: Gastric cancer (GC) is a common gastrointestinal tumor with high morbidity and mortality. Fatty acid metabolism (FAM) contributes to GC development. Patents have been issued for the use of compositions comprising fatty acid analogues for the treatment of many clinical conditions. However, its clinical significance and its relationship with tumor-related mutations have not been thoroughly discovered. This study was conducted to analyze and explore FAM-related genes' molecular characteristics, prognostic significance, and association with tumor- related mutations.

Methods: The gastric adenocarcinoma's transcriptome, clinical data, and tumor mutation load (TMB) data were downloaded from TCGA and GEO databases. The differentially expressed FAM genes (FAM DEGs) between cancer and control samples were screened, and their correlation with TMB and survival was analyzed. A PPI network of FAM DEGs was constructed, and a downscaling clustering analysis was performed based on the expression of the FAM DEGs. Further immuno- infiltration and GO/KEGG enrichment analyses of the identified FAM clusters were performed to explore their heterogeneity in biological functions. The effects of FAM score and gastric cancer (STAD) on TMB, MSI, survival prognosis, and drug sensitivity were jointly analyzed, and finally, a single-gene analysis of the obtained core targets was performed.

Results: Through differential analysis, 68 FAM DEGs were obtained, and they were highly associated with STAD tumor mutation load. In addition, a high FAM DEGs CNV rate was observed. The PPI network showed a complex mutual correlation between the FAM DEGs. Consensus clustering classified the patients into three clusters based on the FAM DEGs, and the clusters presented different survival rates. The GSVA and immune infiltration analysis revealed that metabolism, apoptosis, and immune infiltration-related pathways were variated. In addition, FAM genes, STAD prognostic risk genes, and PCA scores were closely associated with the survival status of STAD patients. FAM score was closely correlated with STAD TMB, MSI, and immunotherapy, and the TMB values in the low FAM score group were significantly higher than those in the high FAM score group. Finally, combining the above results, it was found that the core gene PTGS1 performed best in predicting STAD survival prognosis and TMB/MSI/immunotherapy.

Conclusion: Fatty acid metabolism genes affect the development of gastric adenocarcinoma and can predict the survival prognosis, tumor mutational load characteristics, and drug therapy sensitivity of STAD patients, which can help explore more effective immunotherapy targets for GC.

背景:胃癌(GC)是一种常见的胃肠道肿瘤,发病率和死亡率都很高。脂肪酸代谢(FAM)是导致胃癌发生的原因之一。脂肪酸类似物组合物用于治疗许多临床疾病的专利已经获得批准。然而,其临床意义及其与肿瘤相关突变的关系尚未被彻底发现。本研究旨在分析和探讨FAM相关基因的分子特征、预后意义以及与肿瘤相关突变的关系:方法:从 TCGA 和 GEO 数据库下载胃腺癌的转录组、临床数据和肿瘤突变负荷(TMB)数据。筛选了癌症样本和对照样本中差异表达的FAM基因(FAM DEGs),并分析了它们与TMB和生存率的相关性。构建了 FAM DEGs 的 PPI 网络,并根据 FAM DEGs 的表达进行了降尺度聚类分析。进一步对已识别的FAM集群进行免疫浸润和GO/KEGG富集分析,以探讨其生物学功能的异质性。联合分析了 FAM 评分和胃癌(STAD)对 TMB、MSI、生存预后和药物敏感性的影响,最后对获得的核心靶点进行了单基因分析:结果:通过差异分析,获得了68个FAM DEGs,它们与STAD肿瘤突变负荷高度相关。此外,还观察到了较高的 FAM DEGs CNV 率。PPI 网络显示 FAM DEGs 之间存在复杂的相互关联。共识聚类根据 FAM DEGs 将患者分为三个群组,各群组的生存率不同。GSVA和免疫浸润分析显示,新陈代谢、细胞凋亡和免疫浸润相关通路存在差异。此外,FAM基因、STAD预后风险基因和PCA评分与STAD患者的生存状况密切相关。FAM 评分与 STAD TMB、MSI 和免疫治疗密切相关,低 FAM 评分组的 TMB 值明显高于高 FAM 评分组。最后,综合上述结果,发现核心基因PTGS1在预测STAD生存预后和TMB/MSI/免疫治疗方面表现最佳:脂肪酸代谢基因影响胃腺癌的发生发展,并能预测STAD患者的生存预后、肿瘤突变负荷特征和药物治疗敏感性,有助于探索更有效的GC免疫治疗靶点。
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引用次数: 0
Current Strategies for Overcoming Smoking Addiction: A Major Cause of Oral Cancer. 克服烟瘾的现行策略:口腔癌的主要诱因。
IF 2.8 4区 医学 Q3 ONCOLOGY Pub Date : 2024-01-01 DOI: 10.2174/1574892818666230220120507
Rajakumar Govindasamy, Baskar Venkidasamy, Muthu Thiruvengadam
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引用次数: 0
A Patent Review of Human Dihydroorotate Dehydrogenase (hDHODH) Inhibitors as Anticancer Agents and their Other Therapeutic Applications (1999-2022). 人类二氢烟酸脱氢酶 (hDHODH) 抑制剂作为抗癌剂及其他治疗应用的专利回顾(1999-2022 年)。
IF 2.8 4区 医学 Q3 ONCOLOGY Pub Date : 2024-01-01 DOI: 10.2174/1574892818666230417094939
Pinky Gehlot, Vivek K Vyas

Highly proliferating cells, such as cancer cells, are in high demand of pyrimidine nucleotides for their proliferation, accomplished by de novo pyrimidine biosynthesis. The human dihydroorotate dehydrogenase (hDHODH) enzyme plays a vital role in the rate-limiting step of de novo pyrimidine biosynthesis. As a recognised therapeutic target, hDHODH plays a significant role in cancer and other illness. In the past two decades, small molecules as inhibitors hDHODH enzyme have drawn much attention as anticancer agents, and their role in rheumatoid arthritis (RA), and multiple sclerosis (MS). In this patent review, we have compiled patented hDHODH inhibitors published between 1999 and 2022 and discussed the development of hDHODH inhibitors as anticancer agents. Therapeutic potential of small molecules as hDHODH inhibitors for the treatment of various diseases, such as cancer, is very well recognised. Human DHODH inhibitors can rapidly cause intracellular uridine monophosphate (UMP) depletion to produce starvation of pyrimidine bases. Normal cells can better endure a brief period of starvation without the side effects of conventional cytotoxic medication and resume synthesis of nucleic acid and other cellular functions after inhibition of de novo pathway using an alternative salvage pathway. Highly proliferative cells such as cancer cells do not endure starvation because they are in high demand of nucleotides for cell differentiation, which is fulfilled by de novo pyrimidine biosynthesis. In addition, hDHODH inhibitors produce their desired activity at lower doses rather than a cytotoxic dose of other anticancer agents. Thus, inhibition of de novo pyrimidine biosynthesis will create new prospects for the development of novel targeted anticancer agents, which ongoing preclinical and clinical experiments define. Our work brings together a comprehensive patent review of the role of hDHODH in cancer, as well as various patents related to the hDHODH inhibitors and their anticancer and other therapeutic potential. This compiled work on patented DHODH inhibitors will guide researchers in pursuing the most promising drug discovery strategies against the hDHODH enzyme as anticancer agents.

癌细胞等高增殖细胞需要大量嘧啶核苷酸来增殖,而嘧啶核苷酸是通过从头嘧啶生物合成实现的。人类二氢烟酸脱氢酶(hDHODH)在嘧啶从头生物合成的限速步骤中起着至关重要的作用。作为公认的治疗靶点,hDHODH 在癌症和其他疾病中发挥着重要作用。在过去的二十年里,作为 hDHODH 酶抑制剂的小分子化合物作为抗癌药物及其在类风湿性关节炎(RA)和多发性硬化症(MS)中的作用引起了广泛关注。在本专利综述中,我们汇编了 1999 年至 2022 年间公布的 hDHODH 抑制剂专利,并讨论了作为抗癌剂的 hDHODH 抑制剂的发展情况。小分子 hDHODH 抑制剂在治疗癌症等各种疾病方面的治疗潜力已得到广泛认可。人类 DHODH 抑制剂可迅速导致细胞内单磷酸尿苷(UMP)耗竭,从而产生嘧啶碱饥饿。正常细胞可以更好地忍受短暂的饥饿,而不会受到传统细胞毒性药物的副作用影响,并能在抑制新生途径后利用替代性挽救途径恢复核酸合成和其他细胞功能。高增殖细胞(如癌细胞)无法忍受饥饿,因为它们需要大量核苷酸来进行细胞分化,而这需要从头嘧啶生物合成来实现。此外,与其他抗癌剂的细胞毒性剂量相比,hDHODH 抑制剂只需较低剂量就能产生所需的活性。因此,抑制嘧啶的新生物合成将为新型靶向抗癌药的开发开辟新的前景,而目前正在进行的临床前和临床实验也证明了这一点。我们的工作汇集了有关 hDHODH 在癌症中作用的全面专利综述,以及与 hDHODH 抑制剂及其抗癌和其他治疗潜力相关的各种专利。这份有关 DHODH 抑制剂专利的汇编将指导研究人员寻找最有希望的针对 hDHODH 酶的抗癌药物发现策略。
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引用次数: 0
KRAS Pathways: A Potential Gateway for Cancer Therapeutics and Diagnostics. KRAS 通路:癌症治疗和诊断的潜在通道。
IF 2.8 4区 医学 Q3 ONCOLOGY Pub Date : 2024-01-01 DOI: 10.2174/1574892818666230406085120
Pankaj Kumar Tripathi, Khushi R Mittal, Nandini Jain, Naveen Sharma, Chakresh Kumar Jain

One of the major disturbing pathways within cancer is "The Kirsten rat sarcoma viral oncogene homolog (KRAS) pathway", and it has recently been demonstrated to be the most crucial in therapies and diagnostics. KRAS pathway includes numerous genes. This multi-component signaling system promotes cell growth, division, survival, and death by transferring signals from outside the cell to its interior. KRAS regulates the activation of a variety of signaling molecules. The KRAS oncogene is a key player in advancing a wide range of malignancies, and the mutation rank of this gene is a key feature of several tumors. For some malignancies, the mutation type of the gene may offer information about prognostic, clinical, and predictive. KRAS belongs to the RAS oncogene family, which consists of a compilation of minor GTP-binding proteins that assimilate environmental inputs and trigger internal signaling pathways that control survival, cell differentiation, and proliferation. This review aims to examine the recent and fascinating breakthroughs in the identification of new therapies that target KRAS, including the ever-expanding experimental approaches for reducing KRAS activity and signaling as well as direct targeting of KRAS. A literature survey was performed. All the relevant articles and patents related to the KRAS pathway, the mutation in the KRAS gene, cancer treatment, and diagnostics were found on PubMed and Google Patents. One of the most prevalent causes of cancer in humans is a mutation in the K-RAS protein. It is extremely difficult to decipher KRAS-mediated signaling. It allows transducing signals to go from the cell's outer surface to its nucleus, having an influence on a variety of crucial cellular functions including cell chemotaxis, division, dissemination, and cell death. Other involved signaling pathways are RAF, and the phosphatidylinositol 3 kinase also known as AKT. The EGFR pathway is incomplete without KRAS. The activation of PI3K significantly contributes to acquiring resistance to a mixture of MEK inhibitors and anti-EGFR in colorectal cancer cell lines which are mutated by KRAS. A series of recent patent studies towards cancer diagnostics and therapeutics reveals the paramount importance of mutated protein KRAS as an extensive driver in human tumors. For the prognosis, diagnosis, and treatment of colorectal cancer, KRAS plays a critical role. This review concludes the latest and vowing developments in the discovery of novel techniques for diagnosis and drugs that target KRAS, the advancements in experimental techniques for signaling and inhibiting KRAS function, and the direct targeting of KRAS for cancer therapeutics.

癌症的主要干扰途径之一是 "Kirsten 大鼠肉瘤病毒癌基因同源物(KRAS)途径",它最近被证明是治疗和诊断中最关键的途径。KRAS 通路包括许多基因。这一多组分信号系统通过将信号从细胞外部传递到细胞内部,促进细胞生长、分裂、存活和死亡。KRAS 可调控多种信号分子的激活。KRAS 致癌基因是导致多种恶性肿瘤的关键因素,该基因的突变等级是多种肿瘤的主要特征。对于某些恶性肿瘤,该基因的突变类型可提供预后、临床和预测方面的信息。KRAS属于RAS癌基因家族,该家族由一系列小的GTP结合蛋白组成,它们吸收环境输入并触发内部信号通路,从而控制生存、细胞分化和增殖。本综述旨在研究近期在确定针对 KRAS 的新疗法方面取得的令人着迷的突破,包括不断扩展的降低 KRAS 活性和信号转导的实验方法以及直接靶向 KRAS 的方法。我们进行了一项文献调查。在 PubMed 和 Google Patents 上找到了所有与 KRAS 途径、KRAS 基因突变、癌症治疗和诊断有关的文章和专利。K-RAS 蛋白突变是导致人类癌症的最常见原因之一。破解 KRAS 介导的信号转导极为困难。它允许信号从细胞外表面传导到细胞核,对细胞趋化、分裂、扩散和细胞死亡等各种关键细胞功能产生影响。其他涉及的信号通路有 RAF 和磷脂酰肌醇 3 激酶(又称 AKT)。如果没有 KRAS,表皮生长因子受体(EGFR)通路就不完整。PI3K 的激活在很大程度上导致 KRAS 突变的结直肠癌细胞系对 MEK 抑制剂和抗 EGFR 的混合物产生抗药性。最近一系列针对癌症诊断和治疗的专利研究表明,突变蛋白 KRAS 是人类肿瘤的重要驱动因素。对于结直肠癌的预后、诊断和治疗,KRAS 起着至关重要的作用。本综述总结了在发现用于诊断的新技术和靶向 KRAS 的药物方面的最新进展、信号传导和抑制 KRAS 功能的实验技术的进步,以及直接靶向 KRAS 的癌症疗法。
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引用次数: 0
Strategies for Developing Cancer Theranostics Approaches. 开发癌症血清疗法的战略。
IF 2.8 4区 医学 Q3 ONCOLOGY Pub Date : 2024-01-01 DOI: 10.2174/1574892818666230510124139
Zikang Wang, Wanhe Wang, Chung-Hang Leung
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引用次数: 0
1,3,4-Oxadiazoles as Anticancer Agents: A Review. 作为抗癌剂的 1,3,4-恶二唑:综述。
IF 2.8 4区 医学 Q3 ONCOLOGY Pub Date : 2024-01-01 DOI: 10.2174/1574892818666230727102928
Greesh Kumar, Rajnish Kumar, Avijit Mazumder, Salahuddin, Upendra Kumar

Among the deadliest diseases, cancer is characterized by tumors or an increased number of a specific type of cell because of uncontrolled divisions during mitosis. Researchers in the current era concentrated on the development of highly selective anticancer medications due to the substantial toxicities of conventional cytotoxic drugs. Several marketed drug molecules have provided resistance against cancer through interaction with certain targets/growth factors/enzymes, such as Telomerase, Histone Deacetylase (HDAC), Methionine Aminopeptidase (MetAP II), Thymidylate Synthase (TS), Glycogen Synthase Kinase-3 (GSK), Epidermal Growth Factor (EGF), Vascular Endothelial Growth Factor (VEGF), Focal Adhesion Kinase (FAK), STAT3, Thymidine phosphorylase, and Alkaline phosphatase. The molecular structure of these drug molecules contains various heterocyclic moieties that act as pharmacophores. Recently, 1,3,4- oxadiazole (five-membered heterocyclic moiety) and its derivatives attracted researchers as these have been reported with a wide range of pharmacological activities, including anti-cancer. 1,3,4- oxadiazoles have exhibited anti-cancer potential via acting on any of the above targets. The presented study highlights the synthesis of anti-cancer 1,3,4-oxadiazoles, their mechanism of interactions with targets, along with structure-activity relationship concerning anti-cancer potential.

在最致命的疾病中,癌症的特征是肿瘤或因有丝分裂过程中分裂失控而导致的特定类型细胞数量增加。由于传统的细胞毒性药物具有很大的毒性,当代的研究人员集中精力开发高选择性的抗癌药物。一些已上市的药物分子通过与某些靶点/生长因子/酶(如端粒酶、组蛋白去乙酰化酶(HDAC)、蛋氨酸氨肽酶(MetAP II))相互作用,产生抗癌作用、胸苷酸合成酶(TS)、糖原合成酶激酶-3(GSK)、表皮生长因子(EGF)、血管内皮生长因子(VEGF)、病灶粘附激酶(FAK)、STAT3、胸苷磷酸化酶和碱性磷酸酶。这些药物分子的分子结构中含有各种杂环分子,可发挥药效。最近,1,3,4-噁二唑(五元杂环分子)及其衍生物吸引了研究人员的目光,因为有报道称它们具有广泛的药理活性,包括抗癌活性。1,3,4-噁二唑通过作用于上述任何靶点而显示出抗癌潜力。本研究重点介绍了 1,3,4-噁二唑类抗癌化合物的合成、与靶点的相互作用机制以及与抗癌潜力有关的结构-活性关系。
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引用次数: 0
Ribosome-inactivating Protein MAP30 Isolated from Momordica Charantia L. Induces Apoptosis in Hepatocellular Carcinoma Cells. 从 Momordica Charantia L. 中分离出的核糖体失活蛋白 MAP30 能诱导肝细胞癌细胞凋亡。
IF 2.8 4区 医学 Q3 ONCOLOGY Pub Date : 2024-01-01 DOI: 10.2174/1574892818666221103114649
Yiping Zhou, Di Yang, Zihao Qiang, Yanfa Meng, Ruigang Li, Xiang Fan, Wei Zhao, Yao Meng

Background: Ribosome-inactivating proteins (RIPs) have been reported to exert antitumor and anti-virus activities. A recent patent CN202011568116.7 has developed a new method to prepare Momordica anti-HIV protein of 30 kDa (MAP30). MAP30 is a type I RIP, which kills various tumor cells through the N-glycosidase activity and irreversibly inhibits protein synthesis.

Objective: To assess the potential role of MAP30 in inducing apoptosis of human hepatocellular carcinoma HCC-LM3 cells and elucidate the molecular mechanism of MAP30.

Methods: CCK-8 assay was used to assess the proliferation of HCC-LM3 cells. Flow cytometry was used to measure the cycle, the level of ROS and apoptosis in HCC-LM3 cells. Western blots was used to measure protein levels.

Results: Treatment with MAP30 reduced survival and proliferation of human liver cancer HCCLM3 cells in a dose-dependent manner. PI staining showed cell cycle arrest in G0/G1 phase. Furthermore, MAP30 increased the level of ROS in HCC-LM3 cells in 24 h treatment. To further confirm the role of MAP30 in inducing cell apoptosis, immunoblotting was carried out to detect the change of apoptosis-related proteins including PARP poly (ADP-ribose) polymerase (PARP- 1), Casepase3 and Cleaved-Caspase9. We found that PARP-1 and Caspase-3 were downregulated, whereas Cleaved-Caspase9 was up-regulated in HCC-LM3 cells treated with MAP30.

Conclusion: This study indicated that MAP30 has the potential to be a novel therapeutic agent for human hepatocellular carcinoma.

背景:据报道,核糖体失活蛋白(RIPs)具有抗肿瘤和抗病毒活性。最近的一项专利 CN202011568116.7 开发了一种制备 30 kDa Momordica 抗艾滋病毒蛋白(MAP30)的新方法。MAP30 是一种 I 型 RIP,通过 N-糖苷酶活性杀死各种肿瘤细胞,并不可逆地抑制蛋白质合成:评估 MAP30 在诱导人肝癌 HCC-LM3 细胞凋亡中的潜在作用,并阐明 MAP30 的分子机制:采用 CCK-8 检测法评估 HCC-LM3 细胞的增殖情况。流式细胞术用于测量 HCC-LM3 细胞的周期、ROS 水平和凋亡。用 Western 印迹法测定蛋白质水平:结果:用 MAP30 处理人肝癌 HCCLM3 细胞可降低其存活率和增殖率,且呈剂量依赖性。PI 染色显示细胞周期停滞在 G0/G1 期。此外,MAP30 还能提高 HCC-LM3 细胞在 24 小时处理过程中的 ROS 水平。为了进一步证实 MAP30 在诱导细胞凋亡中的作用,我们采用免疫印迹法检测了 PARP 多(ADP-核糖)聚合酶(PARP-1)、Casepase3 和裂解-Caspase9 等细胞凋亡相关蛋白的变化。我们发现,在用MAP30处理的HCC-LM3细胞中,PARP-1和Caspase-3下调,而Cleaved-Caspase9上调:结论:这项研究表明,MAP30 有可能成为治疗人类肝细胞癌的新型药物。
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引用次数: 0
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Recent patents on anti-cancer drug discovery
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