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Targeting MYC-driven lymphoma: lessons learned and future directions. 靶向MYC驱动的淋巴瘤:经验教训和未来方向。
IF 4.6 Q1 ONCOLOGY Pub Date : 2023-04-12 eCollection Date: 2023-01-01 DOI: 10.20517/cdr.2022.127
Sandra Martínez-Martín, Marie-Eve Beaulieu, Laura Soucek

MYC plays a central role in tumorigenesis by orchestrating cell proliferation, growth and survival, among other transformation mechanisms. In particular, MYC has often been associated with lymphomagenesis. In fact, MYC overexpressing lymphomas such as high-grade B-cell lymphoma (HGBL) and double expressor diffuse large B-cell lymphomas (DLBCL), are considered addicted to MYC. In such a context, MYC targeting therapies are of special interest, as MYC withdrawal is expected to result in tumor regression. However, whether high MYC levels are always predictive of increased sensitivity to these approaches is not clear yet. Even though no MYC inhibitor has received regulatory approval to date, substantial efforts have been made to investigate avenues to render MYC a druggable target. Here, we summarize the different classes of molecules currently under development, which mostly target MYC indirectly in aggressive B-cell lymphomas, paying special attention to subtypes with MYC/BCL2 or BCL6 translocations or overexpression.

MYC通过协调细胞增殖、生长和存活等转化机制在肿瘤发生中发挥核心作用。特别是,MYC经常与淋巴肿瘤有关。事实上,MYC过表达淋巴瘤,如高级别B细胞淋巴瘤(HGBL)和双表达弥漫性大B细胞淋巴瘤,被认为对MYC上瘾。在这种情况下,MYC靶向治疗特别令人感兴趣,因为MYC退出有望导致肿瘤消退。然而,高MYC水平是否总是预测对这些方法的敏感性增加,目前尚不清楚。尽管迄今为止还没有MYC抑制剂获得监管部门的批准,但已经做出了大量努力来研究使MYC成为药物靶点的途径。在这里,我们总结了目前正在开发的不同类别的分子,它们主要间接靶向侵袭性B细胞淋巴瘤中的MYC,特别关注MYC/BCL2或BCL6易位或过表达的亚型。
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引用次数: 0
Heterotypic signaling of cancer-associated fibroblasts in shaping the cancer cell drug resistance. 癌症相关成纤维细胞的异型信号形成了癌细胞的抗药性。
IF 4.6 Q1 ONCOLOGY Pub Date : 2023-03-27 eCollection Date: 2023-01-01 DOI: 10.20517/cdr.2022.72
Ramesh Butti, Ashwini Khaladkar, Priya Bhardwaj, Gopinath Prakasam

The context-dependent reciprocal interaction between the cancer cells and surrounding fibroblasts is imperative for regulating malignant potential, metabolic reprogramming, immunosuppression, and ECM deposition. However, recent evidence also suggests that cancer-associated fibroblasts induce chemoresistance in cancer cells to various anticancer regimens. Because of the protumorigenic function of cancer-associated fibroblasts, these stromal cell types have emerged as fascinating therapeutic targets for cancer. However, this notion was recently challenged by studies that targeted cancer-associated fibroblasts and highlighted the underlying heterogeneity by identifying a subset of these cells with tumor-restricting functions. Hence, it is imperative to understand the heterogeneity and heterotypic signaling of cancer-associated fibroblasts to target tumor-promoting signaling processes by sparing tumor-restricting ones. In this review, we discuss the heterogeneity and heterotypic signaling of cancer-associated fibroblasts in shaping drug resistance and also list the cancer-associated fibroblast-targeting therapeutics.

癌细胞与周围成纤维细胞之间的相互影响是调节恶性潜能、代谢重编程、免疫抑制和 ECM 沉积的必要条件。然而,最近的证据也表明,癌症相关成纤维细胞会诱导癌细胞对各种抗癌方案产生化疗抵抗。由于癌症相关成纤维细胞具有原发性致癌功能,这些基质细胞类型已成为令人着迷的癌症治疗靶点。然而,最近一些针对癌症相关成纤维细胞的研究对这一观点提出了挑战,这些研究通过鉴定这些细胞中具有肿瘤抑制功能的亚群,突出了潜在的异质性。因此,当务之急是了解癌症相关成纤维细胞的异质性和异型信号转导,以针对促进肿瘤的信号转导过程,同时避免抑制肿瘤的信号转导过程。在这篇综述中,我们将讨论癌症相关成纤维细胞在形成耐药性方面的异质性和异型信号转导,并列举癌症相关成纤维细胞靶向疗法。
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引用次数: 0
Targeting regulated cell death pathways in acute myeloid leukemia. 以急性髓性白血病中受调控的细胞死亡途径为靶点。
Pub Date : 2023-03-15 eCollection Date: 2023-01-01 DOI: 10.20517/cdr.2022.108
Sylvain Garciaz, Thomas Miller, Yves Collette, Norbert Vey

The use of the BCL2 inhibitor venetoclax has transformed the management of patients with acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy. By triggering intrinsic apoptosis, the drug is an excellent illustration of how our greater understanding of molecular cell death pathways can be translated into the clinic. Nevertheless, most venetoclax-treated patients will relapse, suggesting the need to target additional regulated cell death pathways. To highlight advances in this strategy, we review the recognized regulated cell death pathways, including apoptosis, necroptosis, ferroptosis and autophagy. Next, we detail the therapeutic opportunities to trigger regulated cell death in AML. Finally, we describe the main drug discovery challenges for regulated cell death inducers and their translation into clinical trials. A better knowledge of the molecular pathways regulating cell death represents a promising strategy to develop new drugs to cure resistant or refractory AML patients, particularly those resistant to intrinsic apoptosis.

BCL2 抑制剂 venetoclax 的使用改变了对不符合强化化疗条件的急性髓性白血病(AML)患者的治疗。该药物通过触发细胞内在凋亡,很好地诠释了我们如何将对细胞分子死亡途径的更深入了解应用于临床。尽管如此,大多数接受过 venetoclax 治疗的患者仍会复发,这表明有必要针对其他受调控的细胞死亡途径进行治疗。为了强调这一策略的进展,我们回顾了公认的调控细胞死亡途径,包括细胞凋亡、坏死、铁变性和自噬。接下来,我们将详细介绍在急性髓细胞性白血病中引发调节性细胞死亡的治疗机会。最后,我们介绍了调节性细胞死亡诱导剂的主要药物发现挑战及其转化为临床试验的情况。更好地了解调控细胞死亡的分子通路是开发治疗耐药或难治性急性髓细胞性白血病患者(尤其是对内在凋亡耐药的患者)新药的大有可为的策略。
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引用次数: 0
Cancer stem cells in drug resistance: an introduction to the e-book covering the special issue on the "Cancer Stem Cells and Drug Resistance". 癌症干细胞的耐药性:介绍电子书覆盖的特刊“癌症干细胞和耐药性”。
Pub Date : 2023-01-01 DOI: 10.20517/cdr.2023.23
Balázs Sarkadi
© The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
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引用次数: 0
Multimodal 4-arylchromene derivatives with microtubule-destabilizing, anti-angiogenic, and MYB-inhibitory activities. 具有微管不稳定、抗血管生成和myb抑制活性的多模态4-芳基铬衍生物。
Pub Date : 2023-01-01 DOI: 10.20517/cdr.2022.90
Leonhard H F Köhler, Sebastian Reich, Maria Yusenko, Karl-Heinz Klempnauer, Gerrit Begemann, Rainer Schobert, Bernhard Biersack

Aim: Efficient and readily available anticancer drugs are sought as treatment options. For this reason, chromene derivatives were prepared using the one-pot reaction and tested for their anticancer and anti-angiogenic properties. Methods: 2-Amino-3-cyano-4-(aryl)-7-methoxy-4H-chromene compounds (2A-R) were repurposed or newly synthesized via a three-component reaction of 3-methoxyphenol, various aryl aldehydes, and malononitrile. We performed assays to study the inhibition of tumor cell growth [3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromid (MTT) assay], effects on microtubules (immunofluorescence), cell cycle (flow-activated cell sorting analysis), angiogenesis (zebrafish model), and MYB activity (luciferase reporter assay). Fluorescence microscopy was applied for localization studies via copper-catalyzed azide-alkyne click reaction of an alkyne-tagged drug derivative. Results: Compounds 2A-C and 2F exhibited robust antiproliferative activities against several human cancer cell lines (50% inhibitory concentrations in the low nanomolar range) and showed potent MYB inhibition. The alkyne derivative 3 was localized in the cytoplasm after only 10 min of incubation. Substantial microtubule disruption and G2/M cell-cycle arrest were observed, where compound 2F stood out as a promising microtubule-disrupting agent. The study of anti-angiogenic properties showed that 2A was the only candidate with a high potential to inhibit blood vessel formation in vivo. Conclusion: The close interplay of various mechanisms, including cell-cycle arrest, MYB inhibition, and anti-angiogenic activity, led to identifying promising multimodal anticancer drug candidates.

目的:寻求有效和容易获得的抗癌药物作为治疗选择。为此,采用一锅反应法制备了铬胺衍生物,并对其抗癌和抗血管生成性能进行了测试。方法:以3-甲氧基苯酚、各种芳基醛和丙二腈为原料,经三组分反应,重新利用或合成2-氨基-3-氰-4-(芳基)-7-甲氧基- 4h -铬化合物(2A-R)。我们进行了实验来研究肿瘤细胞生长的抑制[3-(4,5 -二甲基噻唑-2-基)- 2,5 -二苯基溴化四唑(MTT)试验],对微管(免疫荧光)、细胞周期(流动激活细胞分选分析)、血管生成(斑马鱼模型)和MYB活性(荧光素酶报告细胞试验)的影响。利用荧光显微镜对一种炔标记药物衍生物的铜催化叠氮-炔咔嗒反应进行了定位研究。结果:化合物2A-C和2F对几种人类癌细胞系表现出强大的抗增殖活性(在低纳摩尔范围内抑制浓度为50%),并表现出有效的MYB抑制作用。10分钟后,炔衍生物3在细胞质中定位。观察到大量的微管破坏和G2/M细胞周期阻滞,其中化合物2F作为一种有前途的微管破坏剂而突出。抗血管生成特性的研究表明,2A是体内唯一具有高抑制血管形成潜力的候选药物。结论:多种机制的密切相互作用,包括细胞周期阻滞、MYB抑制和抗血管生成活性,导致了有希望的多模式抗癌候选药物的确定。
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引用次数: 1
How acute myeloid leukemia (AML) escapes from FMS-related tyrosine kinase 3 (FLT3) inhibitors? Still an overrated complication? 急性髓性白血病(AML)如何从fms相关酪氨酸激酶3 (FLT3)抑制剂中逃脱?还是一个被高估的并发症?
Pub Date : 2023-01-01 DOI: 10.20517/cdr.2022.130
Salvatore Perrone, Tiziana Ottone, Nadezda Zhdanovskaya, Matteo Molica

FMS-related tyrosine kinase 3 (FLT3) mutations, present in about 25%-30% of acute myeloid leukemia (AML) patients, constitute one of the most frequently detected mutations in these patients. The binding of FLT3L to FLT3 activates the phosphatidylinositol 3-kinase (PI3K) and RAS pathways, producing increased cell proliferation and the inhibition of apoptosis. Two types of FLT3 mutations exist: FLT3-ITD and FLT3-TKD (point mutations in D835 and I836 or deletion of codon I836). A class of drugs, tyrosine-kinase inhibitors (TKI), targeting mutated FLT3, is already available with 1st and 2nd generation molecules, but only midostaurin and gilteritinib are currently approved. However, the emergence of resistance or the selection of clones not responding to FLT3 inhibitors has become an important clinical dilemma, as the duration of clinical responses is generally limited to a few months. This review analyzes the insights into mechanisms of resistance to TKI and poses a particular view on the clinical relevance of this phenomenon. Has resistance been overlooked? Indeed, FLT3 inhibitors have significantly contributed to reducing the negative impact of FLT3 mutations on the prognosis of AML patients who are no longer considered at high risk by the European LeukemiaNet (ELN) 2022. Finally, several ongoing efforts to overcome resistance to FLT3-inhibitors will be presented: new generation FLT3 inhibitors in monotherapy or combined with standard chemotherapy, hypomethylating drugs, or IDH1/2 inhibitors, Bcl2 inhibitors; novel anti-human FLT3 monoclonal antibodies (e.g., FLT3/CD3 bispecific antibodies); FLT3-CAR T-cells; CDK4/6 kinase inhibitor (e.g., palbociclib).

fms相关酪氨酸激酶3 (FLT3)突变存在于约25%-30%的急性髓性白血病(AML)患者中,是这些患者中最常检测到的突变之一。FLT3L与FLT3结合可激活磷脂酰肌醇3-激酶(PI3K)和RAS通路,促进细胞增殖,抑制细胞凋亡。FLT3存在两种类型的突变:FLT3- itd和FLT3- tkd (D835和I836点突变或密码子I836缺失)。一类靶向突变FLT3的药物酪氨酸激酶抑制剂(TKI)已经有了第一代和第二代分子,但目前只有米多舒林和吉特替尼获得批准。然而,耐药的出现或对FLT3抑制剂无反应的克隆的选择已成为一个重要的临床难题,因为临床反应的持续时间通常限于几个月。这篇综述分析了对TKI耐药机制的见解,并对这一现象的临床相关性提出了特别的看法。抗药性被忽视了吗?事实上,FLT3抑制剂显著有助于减少FLT3突变对AML患者预后的负面影响,这些患者不再被欧洲白血病网(ELN) 2022视为高风险。最后,将介绍一些正在进行的克服FLT3抑制剂耐药的努力:新一代FLT3抑制剂单药或与标准化疗、低甲基化药物或IDH1/2抑制剂、Bcl2抑制剂联合使用;新型抗人FLT3单克隆抗体(如FLT3/CD3双特异性抗体);FLT3-CAR t细胞;CDK4/6激酶抑制剂(如帕博西尼)。
{"title":"How acute myeloid leukemia (AML) escapes from FMS-related tyrosine kinase 3 (FLT3) inhibitors? Still an overrated complication?","authors":"Salvatore Perrone,&nbsp;Tiziana Ottone,&nbsp;Nadezda Zhdanovskaya,&nbsp;Matteo Molica","doi":"10.20517/cdr.2022.130","DOIUrl":"https://doi.org/10.20517/cdr.2022.130","url":null,"abstract":"<p><p>FMS-related tyrosine kinase 3 (FLT3) mutations, present in about 25%-30% of acute myeloid leukemia (AML) patients, constitute one of the most frequently detected mutations in these patients. The binding of FLT3L to FLT3 activates the phosphatidylinositol 3-kinase (PI3K) and RAS pathways, producing increased cell proliferation and the inhibition of apoptosis. Two types of FLT3 mutations exist: FLT3-ITD and FLT3-TKD (point mutations in D835 and I836 or deletion of codon I836). A class of drugs, tyrosine-kinase inhibitors (TKI), targeting mutated FLT3, is already available with 1<sup>st</sup> and 2<sup>nd</sup> generation molecules, but only midostaurin and gilteritinib are currently approved. However, the emergence of resistance or the selection of clones not responding to FLT3 inhibitors has become an important clinical dilemma, as the duration of clinical responses is generally limited to a few months. This review analyzes the insights into mechanisms of resistance to TKI and poses a particular view on the clinical relevance of this phenomenon. Has resistance been overlooked? Indeed, FLT3 inhibitors have significantly contributed to reducing the negative impact of FLT3 mutations on the prognosis of AML patients who are no longer considered at high risk by the European LeukemiaNet (ELN) 2022. Finally, several ongoing efforts to overcome resistance to FLT3-inhibitors will be presented: new generation FLT3 inhibitors in monotherapy or combined with standard chemotherapy, hypomethylating drugs, or IDH1/2 inhibitors, Bcl2 inhibitors; novel anti-human FLT3 monoclonal antibodies (e.g., FLT3/CD3 bispecific antibodies); FLT3-CAR T-cells; CDK4/6 kinase inhibitor (e.g., palbociclib).</p>","PeriodicalId":70759,"journal":{"name":"癌症耐药(英文)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10344728/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9826410","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 2
Importance of ROS1 gene fusions in non-small cell lung cancer. ROS1基因融合在非小细胞肺癌中的重要性。
Pub Date : 2023-01-01 DOI: 10.20517/cdr.2022.105
Meri Muminovic, Carlos Rodrigo Carracedo Uribe, Andres Alvarez-Pinzon, Khine Shan, Luis E Raez
Targeted therapy has become one of the standards of care for advanced lung cancer. More than 10 genetic aberrations have been discovered that are actionable and several tyrosine kinase inhibitors (TKIs) have been approved to target each of them. Among several genetic aberrations that are actionable in non-small cell lung cancer (NSCLC), ROS1 translocations also known as gene fusion proteins, are found in only 1%-2% of the patient population. ROS1 mutations can usually be detected using a combination of techniques such as immunohistochemistry (IHC), Fluorescence in-situ testing (FISH), polymerase chain reaction (PCR), and next-generation sequencing (NGS). However, RNA NGS and ctDNA NGS (liquid biopsies) also contribute to the diagnosis. There are currently numerous FDA-approved agents for these tumors, including crizotinib and entrectinib; however, there is in-vitro sensitivity data and clinical data documenting responses to ceritinib and lorlatinib. Clinical responses and survival rates with these agents are frequently among the best compared to other TKIs with genetic aberrations; however, intrinsic or extrinsic mechanisms of resistance may develop, necessitating research for alternative treatment modalities. To combat the mechanisms of resistance, novel agents such as repotrectenib, cabozantinib, talotrectinib, and others are being developed. In this article, we examine the literature pertaining to patients with ROS1 tumors, including epidemiology, clinical outcomes, resistance mechanisms, and treatment options.
靶向治疗已成为晚期肺癌治疗的标准之一。已经发现了10多种可治疗的遗传畸变,并且已经批准了几种酪氨酸激酶抑制剂(TKIs)来针对每种畸变。在非小细胞肺癌(NSCLC)中可操作的几种遗传畸变中,ROS1易位也称为基因融合蛋白,仅在1%-2%的患者群体中发现。ROS1突变通常可以通过免疫组织化学(IHC)、荧光原位检测(FISH)、聚合酶链反应(PCR)和下一代测序(NGS)等技术的组合来检测。然而,RNA NGS和ctDNA NGS(液体活检)也有助于诊断。目前有许多fda批准的药物用于治疗这些肿瘤,包括克唑替尼和恩替尼;然而,有体外敏感性数据和临床数据记录了对ceritinib和lorlatinib的反应。与其他具有遗传畸变的tki相比,这些药物的临床反应和生存率通常是最好的;然而,内在或外在的耐药机制可能会发展,需要研究替代治疗方式。为了对抗耐药机制,正在开发诸如repotrectenib、cabozantinib、talotrectinib等新型药物。在这篇文章中,我们研究了与ROS1肿瘤患者有关的文献,包括流行病学、临床结果、耐药机制和治疗方案。
{"title":"Importance of <i>ROS1</i> gene fusions in non-small cell lung cancer.","authors":"Meri Muminovic,&nbsp;Carlos Rodrigo Carracedo Uribe,&nbsp;Andres Alvarez-Pinzon,&nbsp;Khine Shan,&nbsp;Luis E Raez","doi":"10.20517/cdr.2022.105","DOIUrl":"https://doi.org/10.20517/cdr.2022.105","url":null,"abstract":"Targeted therapy has become one of the standards of care for advanced lung cancer. More than 10 genetic aberrations have been discovered that are actionable and several tyrosine kinase inhibitors (TKIs) have been approved to target each of them. Among several genetic aberrations that are actionable in non-small cell lung cancer (NSCLC), ROS1 translocations also known as gene fusion proteins, are found in only 1%-2% of the patient population. ROS1 mutations can usually be detected using a combination of techniques such as immunohistochemistry (IHC), Fluorescence in-situ testing (FISH), polymerase chain reaction (PCR), and next-generation sequencing (NGS). However, RNA NGS and ctDNA NGS (liquid biopsies) also contribute to the diagnosis. There are currently numerous FDA-approved agents for these tumors, including crizotinib and entrectinib; however, there is in-vitro sensitivity data and clinical data documenting responses to ceritinib and lorlatinib. Clinical responses and survival rates with these agents are frequently among the best compared to other TKIs with genetic aberrations; however, intrinsic or extrinsic mechanisms of resistance may develop, necessitating research for alternative treatment modalities. To combat the mechanisms of resistance, novel agents such as repotrectenib, cabozantinib, talotrectinib, and others are being developed. In this article, we examine the literature pertaining to patients with ROS1 tumors, including epidemiology, clinical outcomes, resistance mechanisms, and treatment options.","PeriodicalId":70759,"journal":{"name":"癌症耐药(英文)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10344718/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9826411","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 1
miR-16-5p enhances sensitivity to RG7388 through targeting PPM1D expression (WIP1) in Childhood Acute Lymphoblastic Leukemia. miR-16-5p通过靶向儿童急性淋巴细胞白血病中PPM1D表达(WIP1)增强对RG7388的敏感性。
Pub Date : 2023-01-01 DOI: 10.20517/cdr.2022.113
Maryam Zanjirband, Soheila Rahgozar, Narges Aberuyi

Aim: Given the encouraging results of the p53-Mdm2 inhibitor RG7388 in clinical trials and the vital function of miR-16-5p in suppressing cell proliferation, the aim of the present study was to investigate the combined impact of RG7388 and miR-16-5p overexpression on the childhood acute lymphoblastic leukemia (chALL). Methods: miRTarBase and miRDB, along with KEGG and STRING databases, were used to predict miR-16-5p target genes and explore protein-protein interaction networks, respectively. B- and T-lymphoblastic cell lines, in addition to patient primary cells, were treated with RG7388. Ectopic overexpression of miR-16-5p in Nalm6 cell line was induced through cell electroporation and transfection of microRNA mimics was confirmed by qRT-PCR. Cell viability was evaluated using the MTT assay. Western blot analyses were performed to evaluate the effects of RG7388 and miR-16-5p upregulation on the protein levels of p53 and its downstream target genes in chALL cells. Paired sample t-test was employed for statistical analyses. Results: MTT assay showed RG7388-induced cytotoxicity in wild-type p53 Nalm6 cell line and p53 functional patient primary cells. However, CCRF-CEM and p53 non-functional leukemic cells indicated drug resistance. Western blot analyses validated the bioinformatics results, confirming the downregulation of WIP1, p53 stabilization, as well as overexpression of p21WAF1 and Mdm2 proteins in Nalm6 cells transfected with miR-16-5p. Moreover, enhanced sensitivity to RG7388 was observed in the transfected cells. Conclusion: This is the first study indicating the mechanistic importance of miR-16-5p overexpression in chALL and its inhibitory role in leukemia treatment when combined with the p53-Mdm2 antagonist, RG7388. These findings might be useful for researchers and clinicians to pave the way for better management of chALL.

目的:鉴于p53-Mdm2抑制剂RG7388在临床试验中的令人鼓舞的结果和miR-16-5p在抑制细胞增殖方面的重要功能,本研究的目的是探讨RG7388和miR-16-5p过表达对儿童急性淋巴细胞白血病(chALL)的联合影响。方法:分别使用miRTarBase和miRDB以及KEGG和STRING数据库预测miR-16-5p靶基因并探索蛋白-蛋白相互作用网络。除了患者原代细胞外,还使用RG7388处理B淋巴母细胞和t淋巴母细胞。通过细胞电穿孔诱导Nalm6细胞株中miR-16-5p异位过表达,并通过qRT-PCR证实转染了microRNA模拟物。采用MTT法测定细胞活力。Western blot分析RG7388和miR-16-5p上调对chALL细胞中p53及其下游靶基因蛋白水平的影响。采用配对样本t检验进行统计分析。结果:MTT实验显示rg7388对野生型p53 Nalm6细胞系和p53功能性患者原代细胞均有诱导细胞毒性作用。然而,CCRF-CEM和p53无功能白血病细胞显示耐药。Western blot分析验证了生物信息学结果,证实了转染miR-16-5p的Nalm6细胞中WIP1下调,p53稳定,p21WAF1和Mdm2蛋白过表达。此外,转染的细胞对RG7388的敏感性增强。结论:这是首次研究表明miR-16-5p过表达在chALL中的机制重要性,以及miR-16-5p与p53-Mdm2拮抗剂RG7388联合在白血病治疗中的抑制作用。这些发现可能对研究人员和临床医生为更好地管理chALL铺平道路有用。
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引用次数: 1
Fungal mycobiome-mediated immune response: a non-negligible promoter in pancreatic oncogenesis and chemoresistance. 真菌菌群介导的免疫反应:胰腺肿瘤发生和化疗耐药的不可忽视的启动子。
Pub Date : 2023-01-01 DOI: 10.20517/cdr.2023.06
Yaling Jiang, Valentina Donati, Godefridus J Peters, Elisa Giovannetti, Dong Mei Deng

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers in humans due to late diagnosis and poor response to treatments. The tumor microenvironment (TME) of PDAC is characterized by a distinctive, suppressive immune profile, which inhibits the protective functions of anti-tumor immunity and thereby contributes to PDAC progression. Recently, the study of Alam et al. discovered for the first time that the intratumoral fungal mycobiome could contribute to the recruitment and activation of type 2 immune cells in the TME of PDAC via enhancing the secretion of a chemoattractant, interleukin (IL-) 33. In this article, we reviewed the important findings of this study. Together with our findings, we synthetically discussed the role of the fungal mycobiome in orchestrating the immune response and thereby modulating tumor progression.

胰腺导管腺癌(Pancreatic ductal adenocarcinoma, PDAC)是人类最致命的癌症之一,因其诊断较晚且对治疗反应较差。PDAC的肿瘤微环境(tumor microenvironment, TME)具有独特的抑制免疫特征,抑制抗肿瘤免疫的保护功能,从而促进PDAC的进展。最近,Alam等人的研究首次发现肿瘤内真菌菌群可通过增强一种趋化剂白细胞介素(IL-) 33的分泌,参与PDAC TME中2型免疫细胞的募集和激活。在本文中,我们回顾了本研究的重要发现。结合我们的研究结果,我们综合讨论了真菌菌群在协调免疫反应从而调节肿瘤进展中的作用。
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引用次数: 0
Targeting hormone-resistant breast cancer cells with docetaxel: a look inside the resistance. 用多西紫杉醇靶向激素抗性乳腺癌细胞:抗性内部观察。
Pub Date : 2023-01-01 DOI: 10.20517/cdr.2022.96
Alexander M Scherbakov, Anna A Basharina, Danila V Sorokin, Ekaterina I Mikhaevich, Iman E Mizaeva, Alexandra L Mikhaylova, Tatiana A Bogush, Mikhail A Krasil'nikov

Aim: The study aims to analyze the effect of long-term incubation of ERα-positive MCF7 breast cancer cells with 4-hydroxytamoxifen (HT) on their sensitivity to tubulin polymerization inhibitor docetaxel. Methods: The analysis of cell viability was performed by the MTT method. The expression of signaling proteins was analyzed by immunoblotting and flow cytometry. ERα activity was evaluated by gene reporter assay. To establish hormone-resistant subline MCF7, breast cancer cells were treated with 4-hydroxytamoxifen for 12 months. Results: The developed MCF7/HT subline has lost sensitivity to 4-hydroxytamoxifen, and the resistance index was 2. Increased Akt activity (2.2-fold) and decreased ERα expression (1.5-fold) were revealed in MCF7/HT cells. The activity of the estrogen receptor α was reduced (1.5-fold) in MCF7/HT. Evaluation of class III β-tubulin expression (TUBB3), a marker associated with metastasis, revealed the following trends: higher expression of TUBB3 was detected in triple-negative breast cancer MDA-MB-231 cells compared to hormone-responsive MCF7 cells (P < 0.05). The lowest expression of TUBB3 was found in hormone-resistant MCF7/HT cells (MCF7/HT < MCF7 < MDA-MB-231, approximately 1:2:4). High TUBB3 expression strongly correlated with docetaxel resistance: IC50 value of docetaxel for MDA-MB-231 cells was greater than that for MCF7 cells, whereas resistant MCF7/HT cells were the most sensitive to the drug. The accumulation of cleaved PARP (a 1.6-fold increase) and Bcl-2 downregulation (1.8-fold) were more pronounced in docetaxel-treated resistant cells (P < 0.05). The expression of cyclin D1 decreased (2.8-fold) only in resistant cells after 4 nM docetaxel treatment, while this marker was unchanged in parental MCF7 breast cancer cells. Conclusion: Further development of taxane-based chemotherapy for hormone-resistant cancer looks highly promising, especially for cancers with low TUBB3 expression.

目的:分析er α阳性MCF7乳腺癌细胞与4-羟他莫昔芬(HT)长期孵育对微管蛋白聚合抑制剂多西他赛(docetaxel)敏感性的影响。方法:采用MTT法测定细胞活力。通过免疫印迹和流式细胞术分析信号蛋白的表达。采用基因报告法测定ERα活性。为了建立激素耐药亚群MCF7,用4-羟他莫昔芬治疗乳腺癌细胞12个月。结果:建立的MCF7/HT亚群对4-羟他莫昔芬失去敏感性,耐药指数为2。MCF7/HT细胞中Akt活性升高(2.2倍),ERα表达降低(1.5倍)。MCF7/HT中雌激素受体α活性降低1.5倍。ⅲ类β-微管蛋白(class III β-tubulin,一种与转移相关的标志物)表达的评估显示:与激素应答的MCF7细胞相比,三阴性乳腺癌MDA-MB-231细胞中TUBB3的表达更高(P < 0.05)。TUBB3在激素抗性MCF7/HT细胞中表达最低(MCF7/HT < MCF7 < MDA-MB-231,约1:2:4)。TUBB3高表达与多西他赛耐药密切相关:MDA-MB-231细胞对多西他赛的IC50值大于MCF7细胞,而耐药的MCF7/HT细胞对多西他赛最敏感。在多西他赛处理的耐药细胞中,cleaved PARP的积累(增加1.6倍)和Bcl-2的下调(增加1.8倍)更为明显(P < 0.05)。在多西紫杉醇治疗4 nM后,cyclin D1的表达仅在耐药细胞中下降(2.8倍),而该标志物在亲代MCF7乳腺癌细胞中保持不变。结论:紫杉烷为基础的激素耐药化疗的进一步发展前景广阔,特别是对于低TUBB3表达的癌症。
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引用次数: 2
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癌症耐药(英文)
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