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Prevalence of HPV/p16+ infection among oropharyngeal squamous cell carcinoma patients in a tertiary care centre in Southern India 在印度南部三级保健中心口咽鳞状细胞癌患者中HPV/p16+感染的患病率
Q4 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-10-10 DOI: 10.17650/2313-805x-2023-10-3-98-102
V. Jawahar, S. Banerjee, J. Kini, S. Sreeram, M. S. Athiyamaan, J. Sunny, A. Krishna, C. Srinivas, D. Lobo, B. S. Mokkapatti
Introduction. Oropharyngeal squamous cell carcinomas are often found to be associated with human papilloma virus (HPV) infection. The prevalence of HPV infection among oropharyngeal squamous cell carcinomas patients in India is comparatively lower to that of the same worldwide. Aim. To find out the prevalence of HPV infection among oropharyngeal squamous cell carcinomas patients who presented in our hospital. Settings and design . Retrospective cross-sectional study. Materials and methods . Tissue block of 60 patients with biopsy-proven oropharyngeal squamous cell carcinomas were subjected to immunohistochemistry for evaluating p16 expression. The p16 expression pattern was correlated with the demographic details. Data was entered in Microsoft Excel and Statistical Analysis was done with the help of SPSS version 22 (IBM Corp. Released, 2013. IBM SPSS Statistics for Windows, Version 22.0. Armonk, NY: IBM Corp.). Results . Prevalence of HPV infection in our study was found to be 11.7 %. 85.8 % of all p16-positive patients had moderate-well differentiated disease. 6 out of 7 p16-positive patients had higher T stage (T3–4). All the patients who were p16+ were found to have a higher Nodal stage (N2–3). 100 % of all p16+ patients were found to have stage IV disease. Conclusion. Prevalence of HPV infection was found to be similar to that of previous studies conducted in India. These patients also presented with advanced nodal disease at presentation and thereby, an advanced overall stage.
介绍。口咽鳞状细胞癌常被发现与人乳头瘤病毒(HPV)感染有关。在印度,口咽鳞状细胞癌患者中HPV感染的患病率相对较低。的目标。目的了解我院口咽鳞状细胞癌患者HPV感染的流行情况。设置和设计。回顾性横断面研究。材料和方法。对60例经活检证实的口咽鳞状细胞癌患者进行组织阻滞免疫组织化学检测p16的表达。p16表达模式与人口统计学细节相关。数据在Microsoft Excel中输入,统计分析在SPSS version 22 (IBM Corp.发布,2013)的帮助下完成。IBM SPSS Statistics for Windows, Version 22.0。纽约州阿蒙克市:IBM Corp.)。结果。在我们的研究中发现HPV感染的患病率为11.7%。所有p16阳性患者中85.8%为中度分化良好的疾病。7例p16阳性患者中有6例T分期较高(T3-4)。所有p16+患者均有较高的淋巴结分期(N2-3)。100%的p16+患者被发现为IV期疾病。结论。发现HPV感染的流行程度与以前在印度进行的研究相似。这些患者在就诊时也表现为晚期淋巴结疾病,因此总体分期较晚。
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引用次数: 0
Prognostic fine needle aspiration biopsy of uveal melanoma: Molecular and genetic factors of metastasis risk 葡萄膜黑色素瘤的预后细针穿刺活检:转移风险的分子和遗传因素
Q4 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-10-10 DOI: 10.17650/2313-805x-2023-10-3-90-97
V. A. Yarovaya, I. A. Levashov, A. R. Zaretsky, L. V. Chudakova, V. V. Nazarova, A. D. Matyaeva, L. V. Demidov, A. A. Yarovoy
Introduction. Molecular genetic testing is actively used for prognostication in patients with uveal melanoma (UM). Tissue for genetic analysis may be obtained either by surgical excision or through fine-needle aspiration biopsy (FNAB). Performing genetic testing and FNAB in each institution can differ in surgical techniques and laboratory methodologies. Aim. To present our own experience of performing FNAB-based molecular genetic testing for prognostication in patients with uveal melanoma. Materials and methods. Prognostic FNAB (n = 151) were combined with brachytherapy or stereotactic surgery. Genetic testing was performed by methods based on polymerase chain reaction ( GNAQ, GNA11, EIF1AX and SF3B1 mutations) and fluorescence in situ hybridization (copy numbers of PPARG and MYC genes); cytology of FNAB material was also assessed. Results. Fine-needle aspiration biopsy material was informative in 91 % of cases. At the median follow-up of 36 months, 12 cases of distant metastases were detected. Occurrence of the assessed mutations and copy numbers were related to other representative studies. PPARG deletion was shown to be a significant prognostic factor for metastasis-free survival (p <0,01), which was demonstrated for the first time; EIF1AX and SF3B1 mutations, MYC amplification and cytological class were not shown to be significantly associated with survival in our study. Conclusion. FNAB-based molecular genetic testing for prognostication in patients with uveal melanoma was shown to be a reliable and highly informative approach. Some of the prognostic factors need to be evaluated further with longer follow-up.
介绍。分子基因检测被积极用于葡萄膜黑色素瘤(UM)患者的预后。用于遗传分析的组织可以通过手术切除或通过细针穿刺活检(FNAB)获得。在每个机构进行基因检测和FNAB在手术技术和实验室方法上可能有所不同。的目标。介绍我们自己对葡萄膜黑色素瘤患者进行基于fnab的分子基因检测预测的经验。材料和方法。预后FNAB (n = 151)联合近距离治疗或立体定向手术。采用聚合酶链反应(GNAQ、GNA11、EIF1AX和SF3B1突变)和荧光原位杂交(PPARG和MYC基因拷贝数)方法进行基因检测;同时对FNAB材料的细胞学进行评估。结果。细针穿刺活检材料在91%的病例中是有用的。中位随访36个月,发现12例远处转移。评估突变的发生和拷贝数与其他代表性研究有关。PPARG缺失被证明是无转移生存的一个重要预后因素(p < 0.01),这是第一次被证实;在我们的研究中,EIF1AX和SF3B1突变、MYC扩增和细胞学分类未显示与生存有显著相关性。结论。基于fnab的分子基因检测用于葡萄膜黑色素瘤患者的预后被证明是一种可靠且信息丰富的方法。一些预后因素需要在更长的随访中进一步评估。
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引用次数: 0
Sexual dimorphism in cancer 癌症中的两性异形现象
Q4 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-10-09 DOI: 10.17650/2313-805x-2023-10-3-24-35
G. A. Belitsky, K. I. Kirsanov, E. A. Lesovaya, V. P. Maksimova, L. V. Krivosheeva, M. G. Yakubovskaya
The incidence and mortality of malignant neoplasms of non-reproductive organs both carcinomas and sarcomas in men is one and a half times higher than in women. This is based on genetic differences, which are superimposed by patterns of epigenetic regulation of the expression of sex chromosome genes that determine sex differences in the processes of tissue differentiation, which, in turn, mediates the formation of the hormonal status of the body. Compared to the Y chromosome, the mammalian X chromosome contains several dozen times more genes encoding major regulators of proliferation, metabolism, immunity, and tumor growth inhibitors, as well as X-linked microRNAs affecting transcription factors and cross-regulation by other non-coding RNAs. This results in a female or male gene expression profile that accounts for phenotypic differences. This peculiarity, along with the fact that in female cells on the second inactivatedX chromosome epigenetic repression of the most important genes is reversed and, accordingly, their expression level is doubled, may largely explain the sex disparity in carcinogenesis. The influence of sex hormones and disparity in the expression of antitumor immunity contribute significantly to this difference. A detailed study of the mechanisms underlying sex dimorphism in carcinogenesis will be an essential contribution to fundamental oncology and to the practice of diagnosis, prognosis and personalized treatment of malignances with regard to their gender-specific course. These studies are especially relevant in relation to insufficiently studied soft tissue sarcomas, the ratio of the frequencies of which in men and women varies greatly depending on the histological subtype of the tumor.
男性非生殖器官恶性肿瘤(包括癌和肉瘤)的发病率和死亡率比女性高1.5倍。这是基于遗传差异,而遗传差异是由性染色体基因表达的表观遗传调控模式叠加而成的,性染色体基因决定了组织分化过程中的性别差异,而组织分化过程又介导了身体激素状态的形成。与Y染色体相比,哺乳动物X染色体中编码增殖、代谢、免疫和肿瘤生长抑制剂等主要调控因子的基因,以及影响转录因子和其他非编码rna交叉调控的X连锁microrna,数量是Y染色体的几十倍。这导致了女性或男性基因表达谱,这说明了表型差异。这一特性,再加上女性细胞中第二条失活x染色体上最重要基因的表观遗传抑制被逆转,因此,它们的表达水平翻了一番,可能在很大程度上解释了致癌中的性别差异。性激素的影响和抗肿瘤免疫表达的差异是造成这种差异的重要原因。对癌变中两性异形的机制进行详细的研究,将对基础肿瘤学以及针对其性别特异性病程的恶性肿瘤的诊断、预后和个性化治疗的实践做出重要贡献。这些研究尤其与研究不足的软组织肉瘤相关,其在男性和女性中的频率比例因肿瘤的组织学亚型而有很大差异。
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引用次数: 0
The role of mycoplasmas as an infectious agent in carcinogenesis 支原体在癌变中的传染作用
Q4 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-10-09 DOI: 10.17650/2313-805x-2023-10-3-36-49
M. A. Galyamina, O. V. Pobeguts, A. Yu. Gorbachev
The review presents data on studies of the role of mycoplasmas as infectious agents in carcinogenesis, as well as their participation in cancer drug therapy and the impact on the outcome of treatment. Mycoplasmas are of particular interest because they have unique abilities to readily attach to and enter eukaryotic cells, modulate their functional state, and induce chronic inflammation while evading the host’s immune system. The review will highlight the data confirming the increased colonization of tumor tissue by mycoplasmas compared to healthy ones, describe the molecular mechanisms by which mycoplasmas activate the expression of oncogenes and growth factors, inactivate tumor suppressors, promote NF-κB-dependent migration of cancer cells and modulate apoptosis, which results in abnormal growth and transformation of host cells. The review also presents data on the effectiveness of anticancer drugs in mycoplasmal infections.
这篇综述介绍了关于支原体在致癌过程中作为传染因子的作用的研究数据,以及它们参与癌症药物治疗和对治疗结果的影响。支原体特别有趣,因为它们具有独特的能力,可以很容易地附着并进入真核细胞,调节其功能状态,并在逃避宿主免疫系统的同时诱导慢性炎症。本文将重点介绍证实支原体在肿瘤组织中的定殖比健康组织中增加的数据,并描述支原体激活癌基因和生长因子的表达,灭活肿瘤抑制因子,促进NF-κ b依赖性癌细胞迁移和调节细胞凋亡,从而导致宿主细胞异常生长和转化的分子机制。该综述还介绍了抗肿瘤药物治疗支原体感染的有效性数据。
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引用次数: 0
Mechanisms of impaired expression of p53-responsive microRNA genes in diffuse B-large cell lymphoma 弥漫性b大细胞淋巴瘤中p53反应性microRNA基因表达受损的机制
Q4 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-10-09 DOI: 10.17650/2313-805x-2023-10-3-72-81
E. N. Voropaeva, T. I. Pospelova, M. I. Churkina, A. A. Gurazheva, O. V. Berezina, V. N. Maksimov
Introduction. A more in-depth description of molecular events that disrupt the functioning of the p53 signaling pathway is important for understanding the mechanisms of formation and progression of diffuse B-large cell lymphoma (DCCL), as well as its sensitivity to treatment. The p53 protein exhibits its oncosuppressive function and mediates the antitumor effects of drugs by regulating transcription and/or maturation of a wide range of target genes, including MIR-34A, MIR34B/C, MIR-129-2 and MIR-203 . In the tumor tissue of lymphomas, in comparison with normal lymphoid tissue, a decrease in the level of microRNAs encoded by these genes is shown. Aim. The aim of this study was to conduct a comprehensive analysis of the methylation of the genes of the p53-responsive microRNAs MIR-34A, MIR-34B/C, MIR-203 and MIR-129-2 , as well as mutations in the DNA-binding domain and destruction of the polyadenylation signal of the TP53 gene in DLBCL. Materials and methods. 136 DNA samples isolated from tumor tissue of patients with DLBCL and 11 DNA samples obtained from lymph nodes with reactive B-cell follicular hyperplasia were analyzed. The methylation status of MIR-203 and MIR-129-2 genes was determined by the method of methyl-specific polymerase chain reaction, MIR-34A and MIR-34B/C genes by the method of methyl-sensitive analysis of high-resolution melting curves. In tumor samples, rs78378222 genotyping was performed by polymerase chain reaction with restriction fragment length polymorphism, resulting in the destruction of the polyadenylation signal, and the nucleotide sequence of the region of the TP53 gene encoding the DNA-binding domain was determined by capillary direct sequencing by Sanger. Results. The methylation detected in lymphoma tissue was tumor-specific. The frequency of analyzed aberrations in the TP53 gene and methylation of MIR-34A, MIR-34B/C, MIR-129-2 and MIR-203 was 21, 23, 55, 65 and 66 %, respectively. At the same time, methylation of the analyzed genes of p53-responsive microRNAs and aberrations in the TP53 gene in the tumor tissue of patients with DLBCL were independent events with a tendency to mutual exclusion. At the same time, it was shown that in the vast majority of lymphoma samples, the methylation of the MIR-34A, MIR-34B/C, MIR-129-2 and MIR-203 genes was combined. Conclusion. Along with aberrations in TP53 , methylation of MIR-34A, MIR-34B/C, MIR-129-2 and MIR-203 genes may be an important cause of decreased expression of miR-34a, miR-34b, miR-34c, miR-129 and miR-203 in DLBCL. The combined methylation of the MIR-203, MIR-129-2 and MIR-34B/C genes, as well as the MIR-34B/C and MIR-34A pairs, potentially has a more pronounced pro-tumor effect due to the presence of common targets in the microRNAs encoded by them.
介绍。更深入地描述破坏p53信号通路功能的分子事件对于理解弥漫性b大细胞淋巴瘤(DCCL)的形成和进展机制及其对治疗的敏感性非常重要。p53蛋白通过调控MIR-34A、MIR34B/C、MIR-129-2和MIR-203等多种靶基因的转录和/或成熟,显示其抑癌功能,并介导药物的抗肿瘤作用。在淋巴瘤的肿瘤组织中,与正常淋巴组织相比,这些基因编码的microrna水平下降。的目标。本研究旨在全面分析DLBCL中p53应答microrna MIR-34A、MIR-34B/C、MIR-203和MIR-129-2基因的甲基化,以及dna结合域的突变和TP53基因多腺苷化信号的破坏。材料和方法。分析了从DLBCL患者肿瘤组织中分离的136份DNA样本和从反应性b细胞滤泡增生的淋巴结中获得的11份DNA样本。采用甲基化特异性聚合酶链反应法测定MIR-203和MIR-129-2基因的甲基化状态,采用高分辨率熔融曲线甲基化敏感分析法测定MIR-34A和MIR-34B/C基因的甲基化状态。在肿瘤样本中,采用限制性片段长度多态性的聚合酶链反应对rs78378222进行基因分型,导致多聚腺苷化信号被破坏,采用Sanger毛细管直接测序法确定TP53基因编码dna结合域区域的核苷酸序列。结果。在淋巴瘤组织中检测到的甲基化是肿瘤特异性的。所分析的TP53基因畸变和MIR-34A、MIR-34B/C、MIR-129-2和MIR-203甲基化的频率分别为21%、23%、55%、65%和66%。同时,所分析的p53应答microrna基因甲基化和DLBCL患者肿瘤组织中TP53基因畸变是独立事件,有相互排斥的趋势。同时,研究表明,在绝大多数淋巴瘤样本中,MIR-34A、MIR-34B/C、MIR-129-2和MIR-203基因的甲基化是组合的。结论。随着TP53的畸变,MIR-34A、MIR-34B/C、miR-129 -2和MIR-203基因的甲基化可能是DLBCL中MIR-34A、MIR-34B、miR-34c、miR-129和MIR-203表达降低的重要原因。MIR-203、MIR-129-2和MIR-34B/C基因以及MIR-34B/C和MIR-34A对的联合甲基化可能具有更明显的促肿瘤作用,因为它们编码的microrna中存在共同的靶点。
{"title":"Mechanisms of impaired expression of p53-responsive microRNA genes in diffuse B-large cell lymphoma","authors":"E. N. Voropaeva, T. I. Pospelova, M. I. Churkina, A. A. Gurazheva, O. V. Berezina, V. N. Maksimov","doi":"10.17650/2313-805x-2023-10-3-72-81","DOIUrl":"https://doi.org/10.17650/2313-805x-2023-10-3-72-81","url":null,"abstract":"Introduction. A more in-depth description of molecular events that disrupt the functioning of the p53 signaling pathway is important for understanding the mechanisms of formation and progression of diffuse B-large cell lymphoma (DCCL), as well as its sensitivity to treatment. The p53 protein exhibits its oncosuppressive function and mediates the antitumor effects of drugs by regulating transcription and/or maturation of a wide range of target genes, including MIR-34A, MIR34B/C, MIR-129-2 and MIR-203 . In the tumor tissue of lymphomas, in comparison with normal lymphoid tissue, a decrease in the level of microRNAs encoded by these genes is shown. Aim. The aim of this study was to conduct a comprehensive analysis of the methylation of the genes of the p53-responsive microRNAs MIR-34A, MIR-34B/C, MIR-203 and MIR-129-2 , as well as mutations in the DNA-binding domain and destruction of the polyadenylation signal of the TP53 gene in DLBCL. Materials and methods. 136 DNA samples isolated from tumor tissue of patients with DLBCL and 11 DNA samples obtained from lymph nodes with reactive B-cell follicular hyperplasia were analyzed. The methylation status of MIR-203 and MIR-129-2 genes was determined by the method of methyl-specific polymerase chain reaction, MIR-34A and MIR-34B/C genes by the method of methyl-sensitive analysis of high-resolution melting curves. In tumor samples, rs78378222 genotyping was performed by polymerase chain reaction with restriction fragment length polymorphism, resulting in the destruction of the polyadenylation signal, and the nucleotide sequence of the region of the TP53 gene encoding the DNA-binding domain was determined by capillary direct sequencing by Sanger. Results. The methylation detected in lymphoma tissue was tumor-specific. The frequency of analyzed aberrations in the TP53 gene and methylation of MIR-34A, MIR-34B/C, MIR-129-2 and MIR-203 was 21, 23, 55, 65 and 66 %, respectively. At the same time, methylation of the analyzed genes of p53-responsive microRNAs and aberrations in the TP53 gene in the tumor tissue of patients with DLBCL were independent events with a tendency to mutual exclusion. At the same time, it was shown that in the vast majority of lymphoma samples, the methylation of the MIR-34A, MIR-34B/C, MIR-129-2 and MIR-203 genes was combined. Conclusion. Along with aberrations in TP53 , methylation of MIR-34A, MIR-34B/C, MIR-129-2 and MIR-203 genes may be an important cause of decreased expression of miR-34a, miR-34b, miR-34c, miR-129 and miR-203 in DLBCL. The combined methylation of the MIR-203, MIR-129-2 and MIR-34B/C genes, as well as the MIR-34B/C and MIR-34A pairs, potentially has a more pronounced pro-tumor effect due to the presence of common targets in the microRNAs encoded by them.","PeriodicalId":36087,"journal":{"name":"Uspehi Molekularnoj Onkologii","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135146384","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Continuous ultraviolet irradiation induces the development of irreversible resistance of melanoma cells to anticancer drugs 持续的紫外线照射诱导黑色素瘤细胞对抗癌药物产生不可逆的耐药性
Q4 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-10-09 DOI: 10.17650/2313-805x-2023-10-3-50-58
Yu. Yu. Shchegolev, M. A. Karpukhina, D. V. Sorokin, A. M. Scherbakov, O. E. Andreeva, V. E. Razuvaeva, T. A. Bogush, I. N. Mikhaylova, L. V. Demidov, M. V. Gudkova, M. A. Krasil’nikov
Introduction. Melanoma belongs to the group of the most malignant tumors characterized by aggressive growth and active metastasis. At the same time, the effectiveness of therapy, primarily targeted therapy, is largely limited by the rapid development of drug resistance. Aim. To study the effect of chronic ultraviolet (UV) irradiation on the formation of a population of radiation-resistant melanoma cells; to study the features of cell signaling and the sensitivity of UV-resistant melanoma cells to the antitumor drugs. Materials and methods. The experiments were carried out on in vitro cultured A375 melanoma cells. Cells were cultured in a standard DMEM + 10 % FBS medium; cell growth rate was analyzed using the MTT assay; cell survival after irradiation was analyzed using a colony-forming test. Determination of the transcriptional activity of the estrogen receptor (ER) was performed by reporter analysis upon transfection into cells of a plasmid containing the luciferase reporter gene controlled by estrogen responsive element. The immunoblotting method was used to analyze the expression of cellular proteins; comparative analysis of ERα and ERβ expression was performed by immunofluorescent method. Results. Long-term UV irradiation leads to the formation of a UV-resistant subpopulation of A375 melanoma cells, which is characterized by decreased sensitivity to targeted (vemurafenib) and hormonal (tamoxifen) drugs, increased expression of Snail, an activator of the epithelial-mesenchymal transition, and in the absence of noticeable changes in the expression of PI3K / mTOR signaling. Metformin reduces Snail expression in both parental and UV-resistant A375 cells and enhances the cytostatic effect in combination with vemurafenib or tamoxifen. Conclusion . The data obtained demonstrate a decrease in the sensitivity of melanoma cells to targeted drugs under the long-term exposure to UV. The ability of metformin to potentiate the action of targeted drugs and inhibit Snail allows us to consider metformin not only as an antitumor agent, but also as a potential inhibitor of the epithelial-mesenchymal transition.
介绍。黑色素瘤是一类恶性程度最高的肿瘤,其特征是侵袭性生长和转移活跃。与此同时,治疗(主要是靶向治疗)的有效性在很大程度上受到耐药性快速发展的限制。的目标。研究慢性紫外线照射对抗辐射黑色素瘤细胞群形成的影响;研究抗紫外线黑色素瘤细胞的信号转导特征及对抗肿瘤药物的敏感性。材料和方法。实验是在体外培养的A375黑色素瘤细胞上进行的。细胞在标准DMEM + 10% FBS培养基中培养;MTT法分析细胞生长速率;用集落形成试验分析辐照后细胞的存活情况。将含有荧光素酶报告基因的质粒转染到细胞中,通过报告基因分析来测定雌激素受体(ER)的转录活性。免疫印迹法分析细胞蛋白表达;免疫荧光法对ERα和ERβ表达进行比较分析。结果。长期紫外线照射导致A375黑色素瘤细胞形成抗紫外线亚群,其特征是对靶向(vemurafenib)和激素(他莫昔芬)药物的敏感性降低,上皮-间质转化激活剂Snail的表达增加,PI3K / mTOR信号的表达没有明显变化。二甲双胍降低亲代和抗紫外线A375细胞中的蜗牛表达,并与vemurafenib或他莫昔芬联合使用增强细胞抑制作用。结论。获得的数据表明,在长期暴露于紫外线下,黑色素瘤细胞对靶向药物的敏感性降低。二甲双胍增强靶向药物作用和抑制蜗牛的能力使我们认为二甲双胍不仅是一种抗肿瘤药物,而且是上皮-间质转化的潜在抑制剂。
{"title":"Continuous ultraviolet irradiation induces the development of irreversible resistance of melanoma cells to anticancer drugs","authors":"Yu. Yu. Shchegolev, M. A. Karpukhina, D. V. Sorokin, A. M. Scherbakov, O. E. Andreeva, V. E. Razuvaeva, T. A. Bogush, I. N. Mikhaylova, L. V. Demidov, M. V. Gudkova, M. A. Krasil’nikov","doi":"10.17650/2313-805x-2023-10-3-50-58","DOIUrl":"https://doi.org/10.17650/2313-805x-2023-10-3-50-58","url":null,"abstract":"Introduction. Melanoma belongs to the group of the most malignant tumors characterized by aggressive growth and active metastasis. At the same time, the effectiveness of therapy, primarily targeted therapy, is largely limited by the rapid development of drug resistance. Aim. To study the effect of chronic ultraviolet (UV) irradiation on the formation of a population of radiation-resistant melanoma cells; to study the features of cell signaling and the sensitivity of UV-resistant melanoma cells to the antitumor drugs. Materials and methods. The experiments were carried out on in vitro cultured A375 melanoma cells. Cells were cultured in a standard DMEM + 10 % FBS medium; cell growth rate was analyzed using the MTT assay; cell survival after irradiation was analyzed using a colony-forming test. Determination of the transcriptional activity of the estrogen receptor (ER) was performed by reporter analysis upon transfection into cells of a plasmid containing the luciferase reporter gene controlled by estrogen responsive element. The immunoblotting method was used to analyze the expression of cellular proteins; comparative analysis of ERα and ERβ expression was performed by immunofluorescent method. Results. Long-term UV irradiation leads to the formation of a UV-resistant subpopulation of A375 melanoma cells, which is characterized by decreased sensitivity to targeted (vemurafenib) and hormonal (tamoxifen) drugs, increased expression of Snail, an activator of the epithelial-mesenchymal transition, and in the absence of noticeable changes in the expression of PI3K / mTOR signaling. Metformin reduces Snail expression in both parental and UV-resistant A375 cells and enhances the cytostatic effect in combination with vemurafenib or tamoxifen. Conclusion . The data obtained demonstrate a decrease in the sensitivity of melanoma cells to targeted drugs under the long-term exposure to UV. The ability of metformin to potentiate the action of targeted drugs and inhibit Snail allows us to consider metformin not only as an antitumor agent, but also as a potential inhibitor of the epithelial-mesenchymal transition.","PeriodicalId":36087,"journal":{"name":"Uspehi Molekularnoj Onkologii","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135147279","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Expression of the cytoskeletal proteins – cytokeratins and beta-III tubulin in human melanoma cell lines from the collection of N. N. Blokhin National Medical Research Center of Oncology N. N. Blokhin国家肿瘤医学研究中心收集的人黑色素瘤细胞系中细胞骨架蛋白-细胞角蛋白和β - iii微管蛋白的表达
Q4 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-10-09 DOI: 10.17650/2313-805x-2023-10-3-82-89
T. A. Bogush, I. E. Mizaeva, A. A. Basharina, A. N. Grishanina, M. A. Baryshnikova, O. S. Burova, A. A. Rudakova, V. S. Kosorukov
Introduction. Despite advances in the treatment of melanoma, the results of therapy cannot be considered satisfactory, and the search for new drugs and effective combinations of medicine continues. The drugs are being developed aimed at reducing the metastatic tumor potential – migrastatics. The targets of the drugs can be cytoskeletal proteins of tumor cells – cytokeratin (CK) intermediate filaments and microtubule protein beta-III tubulin (TUBB3). Aim. To estimate of the CK and TUBB3 expression in melanoma cell lines to form an informative in vitro cell model for screening and studying migrastatics. Materials and methods. The molecular phenotype of 21 human melanoma cell lines from the collection of N. N. Blokhin National Medical Research Center of Oncology, and 18 of which were isolated from tumor metastases in the lymph nodes, soft tissues or subcutaneously. The level of TUBB3 expression and de novo expression of CKs in vimentin-expressing cells (CK + Vim) were assessed by an immunofluorescent method and flow cytometry. Results. Beta-III tubulin expression was detected in all cultures studied, de novo expression of CKs was found in 20 / 21 lines. The exception was primary uveal melanoma 92-1, that did not express CK + Vim. Both parameters significantly differed between the cells of the studied panel: CK + Vim co-expression – from 0 to 91 %, TUBB3 – from 18 to 86 %. No correlation was found between the expression level of TUBB3 and CK + Vim (Pearson’s correlation coefficient r = 0.11; p = 0.65). Three groups of the cell lines with different ratio of TUBB3 expression and CK + Vim co-expression were identified: 1) similar level of expression of both markers; 2) the level of co-expression of CK + Vim more or less high than the index for TUBB3; 3) the level of TUBB3 expression more or less high than the index for CK + Vim co-expression. Conclusion. A panel of 21 human melanoma cell lines was formed with quantitatively estimated expression of cytoske-letal proteins responsible for the migration activity of tumor cells – CKs and TUBB3. Groups of the lines with different expression ratio of the markers can be used for screening and preclinical evaluation potential migrastatics that reduce the metastatic potential of melanoma and may reduce resistance to taxanes.
介绍。尽管在黑素瘤的治疗方面取得了进展,但治疗的结果不能令人满意,对新药和有效药物组合的研究仍在继续。目前正在开发的药物旨在降低转移性肿瘤的可能性。药物的作用靶点可以是肿瘤细胞的细胞骨架蛋白-细胞角蛋白(CK)中间丝和微管蛋白β - iii微管蛋白(TUBB3)。的目标。估计CK和TUBB3在黑色素瘤细胞系中的表达,为筛选和研究迁移性提供体外细胞模型。材料和方法。从N. N. Blokhin国家肿瘤医学研究中心收集的21株人黑色素瘤细胞株的分子表型,其中18株来自淋巴结、软组织或皮下肿瘤转移。采用免疫荧光法和流式细胞术检测vimentin表达细胞(CK + Vim)中TUBB3的表达水平和CK的新生表达水平。结果。β - iii微管蛋白在所有培养物中均有表达,在20 / 21株培养物中有新生表达。唯一的例外是原发性葡萄膜黑色素瘤92-1,它不表达CK + Vim。这两个参数在研究小组的细胞之间有显著差异:CK + Vim共表达-从0到91%,TUBB3 -从18%到86%。TUBB3表达水平与CK + Vim无相关性(Pearson相关系数r = 0.11;P = 0.65)。对TUBB3和CK + Vim共表达比例不同的三组细胞系进行了鉴定:1)两种标记物的表达水平相近;2) CK + Vim的共表达水平高于或低于TUBB3的指数;3) TUBB3表达水平高于或低于CK + Vim共表达指数。结论。21个人类黑色素瘤细胞系组成了一个小组,定量估计了负责肿瘤细胞迁移活性的细胞骨架蛋白- ck和TUBB3的表达。标记物表达比例不同的细胞系组可用于筛选和临床前评估潜在的迁移抑制剂,降低黑色素瘤的转移潜力,并可能降低对紫杉烷类药物的耐药性。
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引用次数: 0
Mechanisms of cytotoxic activity of pyrrole-carboxamides against multidrug-resistant tumor cell sublines 吡咯-羧酰胺对多药耐药肿瘤细胞亚系的细胞毒活性机制
Q4 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-10-09 DOI: 10.17650/2313-805x-2023-10-3-59-71
A. R. Galembikova, P. D. Dunaev, F. F. Bikinieva, I. G. Mustafin, P. B. Kopnin, S. S. Zykova, F. I. Mukhutdinova, E. A. Sarbazyan, S. V. Boichuk
Introduction . Mitotic poisoning agents (MPAs) affecting the dynamic state of the microtubules, are the well-known and effective chemotherapeutic agents. Mitotic poisoning agents are binding to the microtubules, and thereby interfere with tubulin polymerization or depolymerization dynamic state, resulting in the cell cycle arrest in M-phase (mitotic catastrophe) and subsequent apoptotic cell death. We reported previously about potent cytotoxic activities against the pyrrole-carboxamides (PCs) (PC-61 and PC-84) against broad spectrum of cancer cell lines, including triple negative breast cancer, lung and prostate cancer. Aim. To examine the cytotoxic activities of PC-61 and PC-84 against multidrug-resistant cancer cell lines indicated above. Materials and methods. Studу was performed on the triple-negative paclitaxel-resistant breast cancer cell line HCC1806 Tx-R and doxorubicin-resistant osteosarcoma SaOS-2 Dox-R cell line. Results. The cytotoxic activity of PCs was due to the inhibition of tubulin polymerization. Immunofluorescence staining data revealed PC’s ability to interfere with tubulin’s assembly in multidrug-resistant cancer cell lines. As an outcome of inhibition of tubulin polymerization, PCs induced cell cycle arrest in M-phase, and further led to apoptotic cell death of cancer cells. Conclusion . Collectively, we demonstrated potent cytotoxic activity of PCs against cancer cell lines with multidrug-resistant phenotype, which arising the possibilities to develop novel and effective anti-tumor agents that belongs to mitotic poisoning agents
介绍。有丝分裂中毒剂(MPAs)影响微管的动态状态,是公认的有效的化疗药物。有丝分裂中毒剂与微管结合,从而干扰微管蛋白聚合或解聚的动态状态,导致细胞周期停滞于m期(有丝分裂突变),进而导致细胞凋亡死亡。我们之前报道了吡咯-羧酰胺(PCs) (PC-61和PC-84)对广泛的癌症细胞系(包括三阴性乳腺癌、肺癌和前列腺癌)的有效细胞毒活性。的目标。目的:研究PC-61和PC-84对上述多药耐药癌细胞的细胞毒活性。材料和方法。对三阴性紫杉醇耐药乳腺癌细胞株HCC1806 Tx-R和阿霉素耐药骨肉瘤细胞株SaOS-2 Dox-R进行了研究。结果。pc的细胞毒活性是由于抑制微管蛋白聚合。免疫荧光染色数据显示,PC能够干扰多药耐药癌细胞系中微管蛋白的组装。PCs作为抑制微管蛋白聚合的结果,诱导细胞周期阻滞于m期,进而导致癌细胞凋亡死亡。结论。总的来说,我们证明了pc对具有多药耐药表型的癌细胞系的有效细胞毒活性,这为开发新型有效的抗肿瘤药物(属于有丝分裂中毒药物)提供了可能性
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引用次数: 0
Modern understanding of risk factors and mechanisms of breast cancer development 乳腺癌发展的危险因素和机制的现代认识
Q4 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-10-08 DOI: 10.17650/2313-805x-2023-10-3-15-23
N. P. Pavlova, S. S. Dyomin, M. I. Churnosov, I. V. Ponomarenko
The article presents current data on the etiopathogenesis and risk factors of breast cancer (BC). The search for the sources was carried out in the PubMed, Medline, Cochrane Library, eLIBRARY, NHGRI-EBI Catalog of GWAS systems, publications from January 2000 to December 2022 were included. The interaction of definite risk factors, endocrine stimuli and genetic disorders causes activation / inactivation of various signaling pathways that directly or indirectly affect carcinogenesis. According to modern genetic evaluations, the contribution of the hereditary component to the formation of BC reaches 40 %. Interactiones between various risk factors form several molecular subtypes of breast carcinomas, differing in receptor status and clinical course, as well as therapeutic approaches. The details of the interaction of etiopathogenetic factors of BC are not clear, and often have a multidirectional character. Matrix metalloproteinases (MMPs) regulate the mechanisms of proliferation and apoptosis, invasion and metastasis, formation of the tumor microenvironment, neoangiogenesis, as well as intergenic signaling interactions, being an important link in the pathogenesis of BC.
本文介绍了乳腺癌(BC)的发病机制和危险因素的最新数据。在PubMed, Medline, Cochrane Library, eLIBRARY, NHGRI-EBI GWAS系统目录中搜索来源,包括2000年1月至2022年12月的出版物。确定的危险因素、内分泌刺激和遗传疾病的相互作用导致直接或间接影响癌变的各种信号通路的激活/失活。根据现代遗传学评估,遗传成分对BC形成的贡献达到40%。各种危险因素之间的相互作用形成了乳腺癌的几种分子亚型,在受体状态和临床病程以及治疗方法上都有所不同。BC的发病因素相互作用的细节尚不清楚,往往具有多向性。基质金属蛋白酶(Matrix metalloproteinases, MMPs)调节肿瘤细胞增殖与凋亡、侵袭转移、肿瘤微环境形成、新生血管生成以及基因间信号相互作用等机制,是BC发病的重要环节。
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引用次数: 0
Current approaches to systemic treatment of <i>BRCA</i>-associated triple-negative breast cancer BRCA&lt /i&gt相关三阴性乳腺癌的目前全身治疗方法
Q4 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-10-07 DOI: 10.17650/2313-805x-2023-10-3-8-14
D. A. Enaldieva, P. V. Krivorotko, E. N. Imyanitov, E. K. Zhiltsova, R. V. Donskikh, L. F. Shaikhelislamova, L. P. Gigolaeva, V. F. Semiglazov
BRCA -associated triple-negative breast cancer (TNBC) is characterized by high sensitivity to DNA-damaging cytotoxic drugs. The use of well-known BRCA1/2 -specific antitumor agents – platinum derivatives and PARP inhibitors – has been discussed for a long time in the context of the treatment of metastatic BRCA -associated TNBC. Neoadjuvant regimens based on the use of anthracyclines and taxanes are the standard of drug therapy for primary BRCA -associated breast cancer. At present, there are few data regarding the addition of platinum drugs to anthracycline-taxane neoadjuvant chemotherapy in the treatment of primary BRCA -associated TNBC. This review details the various treatment options for both primary and metastatic BRCA -associated TNBC. It has been shown that the development of new strategies for the neoadjuvant chemotherapy of patients with primary BRCA -associated TNBC is an urgent clinical need to reduce the risks of recurrence and progression.
BRCA相关的三阴性乳腺癌(TNBC)的特点是对dna损伤的细胞毒性药物高度敏感。众所周知,使用BRCA1/2特异性抗肿瘤药物-铂衍生物和PARP抑制剂-在治疗转移性BRCA相关TNBC的背景下已经讨论了很长时间。基于蒽环类药物和紫杉烷类药物的新辅助治疗方案是原发性BRCA相关乳腺癌的标准药物治疗方案。目前,在蒽环类-紫杉类新辅助化疗中加入铂类药物治疗原发性BRCA相关TNBC的资料较少。这篇综述详细介绍了原发性和转移性BRCA相关TNBC的各种治疗方案。研究表明,为原发性BRCA相关TNBC患者开发新的新辅助化疗策略是降低复发和进展风险的迫切临床需要。
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引用次数: 0
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Uspehi Molekularnoj Onkologii
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