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Cellular and molecular mechanisms of gastrointestinal cancer liver metastases and drug resistance 胃肠癌肝转移和耐药性的细胞和分子机制
IF 15.8 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-06 DOI: 10.1016/j.drup.2024.101125
Daosong Dong , Xue Yu , Jingjing Xu , Na Yu , Zhe Liu , Yanbin Sun

Distant metastases and drug resistance account for poor survival of patients with gastrointestinal (GI) malignancies such as gastric cancer, pancreatic cancer, and colorectal cancer. GI cancers most commonly metastasize to the liver, which provides a unique immunosuppressive tumour microenvironment to support the development of a premetastatic niche for tumor cell colonization and metastatic outgrowth. Metastatic tumors often exhibit greater resistance to drugs than primary tumors, posing extra challenges in treatment. The liver metastases and drug resistance of GI cancers are regulated by complex, intertwined, and tumor-dependent cellular and molecular mechanisms that influence tumor cell behavior (e.g. epithelial-to-mesenchymal transition, or EMT), tumor microenvironment (TME) (e.g. the extracellular matrix, cancer-associated fibroblasts, and tumor-infiltrating immune cells), tumor cell-TME interactions (e.g. through cytokines and exosomes), liver microenvironment (e.g. hepatic stellate cells and macrophages), and the route and mechanism of tumor cell dissemination (e.g. circulating tumor cells). This review provides an overview of recent advances in the research on cellular and molecular mechanisms that regulate liver metastases and drug resistance of GI cancers. We also discuss recent advances in the development of mechanism-based therapy for these GI cancers. Targeting these cellular and molecular mechanisms, either alone or in combination, may potentially provide novel approaches to treat metastatic GI malignancies.

胃癌、胰腺癌和结肠直肠癌等消化道恶性肿瘤患者生存率低的原因是远处转移和耐药性。消化道癌症最常转移到肝脏,肝脏提供了独特的免疫抑制肿瘤微环境,支持肿瘤细胞定植和转移生长的转移前生态位的形成。与原发肿瘤相比,转移性肿瘤往往表现出更强的耐药性,这给治疗带来了额外的挑战。消化道癌症的肝转移和耐药性受复杂、交织、依赖肿瘤的细胞和分子机制调控,这些机制影响着肿瘤细胞的行为(如上皮细胞向间质转化(EMT))、肿瘤微环境(TME)(如细胞外基质、癌抗原等)、肿瘤细胞的生长和转移。细胞外基质、癌症相关成纤维细胞和肿瘤浸润免疫细胞)、肿瘤细胞-TME 相互作用(如通过细胞因子和外泌体)、肝脏微环境(如肝星状细胞和巨噬细胞)以及肿瘤细胞扩散的途径和机制(如循环肿瘤细胞)。本综述概述了调控消化道癌症肝转移和耐药性的细胞和分子机制研究的最新进展。我们还讨论了针对这些消化道癌症开发基于机制的疗法的最新进展。针对这些细胞和分子机制,无论是单独还是联合治疗,都有可能为治疗转移性消化道恶性肿瘤提供新的方法。
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引用次数: 0
crVDAC3 alleviates ferroptosis by impeding HSPB1 ubiquitination and confers trastuzumab deruxtecan resistance in HER2-low breast cancer crVDAC3通过阻碍HSPB1泛素化减轻铁变态反应,并使HER2低下的乳腺癌产生曲妥珠单抗德鲁司坦抗性。
IF 15.8 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-06 DOI: 10.1016/j.drup.2024.101126
Yutian Zou , Anli Yang , Bo Chen , Xinpei Deng , Jindong Xie , Danian Dai , Jinhui Zhang , Hailin Tang , Tao Wu , Zhigang Zhou , Xiaoming Xie , Jin Wang

Aims

With the wide application of trastuzumab deruxtecan (T-DXd), the survival of HER2-low breast cancer patients is dramatically improved. However, resistance to T-DXd still exists in a subset of patients, and the molecular mechanism remains unclear.

Methods

An in vivo shRNA lentiviral library functional screening was performed to identify potential circular RNA (crRNA) that mediates T-DXd resistance. RNA pull-down, mass spectrometry, RNA immunoprecipitation, and co-immunoprecipitation assays were conducted to investigate the molecular mechanism. Ferroptosis was detected using C11-BODIPY, Liperfluo, FerroOrange staining, glutathione quantification, malondialdehyde quantification, and transmission electron microscopy. Molecular docking, virtual screening, and patient-derived xenograft (PDX) models were used to validate therapeutic agents.

Results

VDAC3-derived crRNA (crVDAC3) ranked first in functional shRNA library screening. Knockdown of crVDAC3 increased the sensitivity of HER2-low breast cancer cells to T-DXd treatment. Further mechanistic research revealed that crVDAC3 specifically binds to HSPB1 protein and inhibits its ubiquitination degradation, leading to intracellular accumulation and increased levels of HSPB1 protein. Notably, suppression of crVDAC3 dramatically increases excessive ROS levels and labile iron pool accumulation. Inhibition of crVDAC3 induces ferroptosis in breast cancer cells by reducing HSPB1 expression, thereby mediating T-DXd resistance. Through virtual screening and experimental validation, we identified that paritaprevir could effectively bind to crVDAC3 and prevent its interaction with HSPB1 protein, thereby increasing ubiquitination degradation of HSPB1 protein to overcome T-DXd resistance. Finally, we validated the enhanced therapeutic efficacy of T-DXd by paritaprevir in a HER2-low PDX model.

Conclusion

This finding reveals the molecular mechanisms underlying T-DXd resistance in HER2-low breast cancer. Our study provides a new strategy to overcome T-DXd resistance by inhibiting the interaction between crVDAC3 and HSPB1 protein.

目的:随着曲妥珠单抗德鲁司康(T-DXd)的广泛应用,HER2低下乳腺癌患者的生存率得到了显著提高。然而,仍有一部分患者对 T-DXd 存在耐药性,其分子机制仍不清楚:方法:进行了体内 shRNA 慢病毒库功能筛选,以确定介导 T-DXd 耐药性的潜在环状 RNA(crRNA)。为研究其分子机制,进行了 RNA 拉取、质谱分析、RNA 免疫沉淀和共免疫沉淀试验。利用 C11-BODIPY、Liperfluo、FerroOrange 染色、谷胱甘肽定量、丙二醛定量和透射电子显微镜检测铁中毒。分子对接、虚拟筛选和患者异种移植(PDX)模型被用来验证治疗药物:结果:VDAC3衍生的crRNA(crVDAC3)在功能性shRNA文库筛选中排名第一。敲除crVDAC3可提高HER2低的乳腺癌细胞对T-DXd治疗的敏感性。进一步的机理研究发现,crVDAC3 能特异性地与 HSPB1 蛋白结合并抑制其泛素化降解,从而导致 HSPB1 蛋白在细胞内的积累和水平升高。值得注意的是,抑制crVDAC3会显著增加过量的ROS水平和易损铁池的积累。抑制crVDAC3可通过降低HSPB1的表达诱导乳腺癌细胞的铁变态反应,从而介导T-DXd耐药性。通过虚拟筛选和实验验证,我们发现帕立替韦能有效结合crVDAC3,阻止其与HSPB1蛋白的相互作用,从而增加HSPB1蛋白的泛素化降解,克服T-DXd耐药性。最后,我们在HER2-low PDX模型中验证了帕立特韦增强T-DXd疗效的作用:结论:这一发现揭示了HER2-low乳腺癌T-DXd耐药的分子机制。我们的研究通过抑制crVDAC3和HSPB1蛋白之间的相互作用,为克服T-DXd耐药性提供了一种新策略。
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引用次数: 0
An increased prevalence of carbapenem-resistant hypervirulent Klebsiella pneumoniae associated with the COVID-19 pandemic 与 COVID-19 大流行有关的耐碳青霉烯类高病毒性肺炎克雷伯菌发病率增加
IF 15.8 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-02 DOI: 10.1016/j.drup.2024.101124
Chao Liu , Jun Guo , Shuaihua Fan , Wei Guo , Huaiqing Qi , Stephen Baker , Pengcheng Du , Bin Cao

Background

Klebsiella pneumoniae (Kp) is a common community-acquired and nosocomial pathogen. Carbapenem-resistant and hypervirulent (CR-hvKp) variants can emerge rapidly within healthcare facilities and impacted by other infectious agents such as COVID-19 virus.

Methods

To understand the impact of COVID-19 virus on the prevalence of CR-hvKp, we accessed Kp genomes with corresponding metadata from GenBank. Sequence types (STs), antimicrobial resistance genes, and virulence genes, and those scores and CR-hvKp were identified. We analyzed population diversity and phylogenetic characteristics of five most common STs, measured the prevalence of CR-hvKp, identified CR-hvKp subtypes, and determined associations between carbapenem resistance gene subtypes with STs and plasmid types. These variables were compared pre- and during the COVID-19 pandemic.

Findings

The proportion of CR-hvKp isolates increased within multiple STs in different continents during the COVID-19 pandemic and persistent CR-hvKp subtypes were found in common STs. blaKPC was dominant in CG258, blaKPC-2 was detected in 97 % of the ST11 CR-hvKp, blaNDM subtypes were prominent in ST147 (87.4 %) and ST307 (70.8 %); blaOXA-48 and its subtypes were prevalent in ST15 (80.5 %). The possession of carbapenemase genes was different among subclades from different origins in different periods of time within each ST. IncFIB/IncHI1B hybrid plasmids contained virulence genes and carbapenemase genes and were predominant in ST147 (67.37 %) and ST307 (56.25 %).

Interpretation

The prevalence of CR-hvKp increased during the COVID-19 pandemic, which was evident by an increase in local endemic clones. This process was facilitated by the convergence of plasmids containing carbapenemase genes and virulence genes. These findings have implications for the appropriate use of antimicrobials and infection prevention and control during outbreaks of respiratory viruses and pandemic management.

(Kp)是一种常见的社区获得性和医院内病原体。耐碳青霉烯类和高病毒性(CR-hvKp)变种可在医疗机构内迅速出现,并受到 COVID-19 病毒等其他传染源的影响。为了了解 COVID-19 病毒对 CR-hvKp 流行的影响,我们从 GenBank 获取了 Kp 基因组及相应的元数据。我们确定了序列类型(ST)、抗菌药耐药性基因和毒力基因,以及这些得分和 CR-hvKp。我们分析了五种最常见 ST 的种群多样性和系统发育特征,测量了 CR-hvKp 的流行率,确定了 CR-hvKp 亚型,并确定了碳青霉烯耐药基因亚型与 ST 和质粒类型之间的关联。这些变量在 COVID-19 大流行之前和期间进行了比较。在 COVID-19 大流行期间,各大洲多个 ST 中的 CR-hvKp 分离物比例增加,在常见的 ST 中发现了持续的 CR-hvKp 亚型。CG258 中 CR-hvKp 占主导地位,97% 的 ST11 中检测到 CR-hvKp,其亚型在 ST147(87.4%)和 ST307(70.8%)中表现突出;其亚型在 ST15(80.5%)中普遍存在。碳青霉烯酶基因的拥有情况在每个 ST 的不同时期不同来源的亚支系中有所不同。IncFIB/IncHI1B杂交质粒含有毒力基因和碳青霉烯酶基因,主要存在于ST147(67.37%)和ST307(56.25%)中。在 COVID-19 大流行期间,CR-hvKp 的流行率有所上升,当地流行克隆的增加就是明证。含有碳青霉烯酶基因和毒力基因的质粒的融合促进了这一过程。这些发现对在呼吸道病毒爆发和大流行管理期间适当使用抗菌药物、预防和控制感染具有重要意义。
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引用次数: 0
Emergence of silent NDM-1 carbapenemase gene in carbapenem-susceptible Klebsiella pneumoniae: Clinical implications and epidemiological insights 碳青霉烯类易感肺炎克雷伯菌中出现沉默的 NDM-1 碳青霉烯酶基因:临床意义和流行病学见解。
IF 15.8 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-07-29 DOI: 10.1016/j.drup.2024.101123
Juanxiu Qin , Yuan Zhu , Yiwei Zhu , Qianqian Gao , Haomin Zhang , Min Li , Zhen Shen

The global dissemination of carbapenemase genes, particularly blaNDM-1, poses a significant threat to public health. While research has mainly focused on strains with phenotypic resistance, the impact of silent resistance genes has been largely overlooked. This study documents the first instance of silent blaNDM-1 in a cluster of clonally related carbapenem-susceptible K. pneumoniae strains from a single patient. Despite initial effectiveness of carbapenem therapy, the patient experienced four recurrent lung infections over five months, indicating persistent K. pneumoniae infection. Genomic sequencing revealed all strains harbored blaNDM-1 on the epidemic IncX3 plasmid. A deletion within the upstream promoter region (PISAba125) of blaNDM-1 hindered its expression, resulting in phenotypic susceptibility to carbapenems. However, in vitro bactericidal assays and a mouse infection model showed that K. pneumoniae strains with silent blaNDM-1 exhibited significant tolerance to carbapenem-mediated killing. These findings demonstrate that silent blaNDM-1 can mediate both phenotypic susceptibility and antibiotic tolerance. In silico analysis of 1986 blaNDM sequences showed that 1956 (98.5%) retained the original promoter PISAba125. Given that previous genomic sequencing typically targets carbapenem-resistant strains, accurately assessing the prevalence of silent blaNDM remains challenging. This study highlights the hidden threat of silent resistance genes to clinical antimicrobial therapy and calls for enhanced clinical awareness and laboratory detection.

碳青霉烯酶基因(尤其是 blaNDM-1)在全球的传播对公共卫生构成了重大威胁。虽然研究主要集中在具有表型耐药性的菌株上,但沉默耐药基因的影响在很大程度上被忽视了。本研究首次记录了来自一名患者的一组克隆相关的碳青霉烯类耐药肺炎克氏菌中的沉默blaNDM-1基因。尽管碳青霉烯类疗法最初有效,但该患者在五个月内经历了四次复发性肺部感染,表明肺炎克氏菌感染持续存在。基因组测序显示,所有菌株都在流行病 IncX3 质粒上携带 blaNDM-1。blaNDM-1 上游启动子区域(PISAba125)的缺失阻碍了其表达,导致表型上对碳青霉烯类敏感。然而,体外杀菌试验和小鼠感染模型表明,具有沉默 blaNDM-1 的肺炎克雷伯菌株对碳青霉烯类药物介导的杀灭表现出明显的耐受性。这些发现表明,沉默的 blaNDM-1 可介导表型易感性和抗生素耐受性。对 1986 个 blaNDM 序列的硅分析表明,1956 个(98.5%)序列保留了原始启动子 PISAba125。鉴于以前的基因组测序通常以耐碳青霉烯菌株为目标,因此准确评估沉默 blaNDM 的流行率仍具有挑战性。这项研究强调了沉默耐药基因对临床抗菌治疗的隐性威胁,并呼吁加强临床意识和实验室检测。
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引用次数: 0
Framework nucleic acid-based nanoparticles enhance temozolomide sensitivity in glioblastoma 基于框架核酸的纳米粒子可提高替莫唑胺对胶质母细胞瘤的敏感性
IF 15.8 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-07-27 DOI: 10.1016/j.drup.2024.101122
Yufei Lan , Xiaodie Li , Boyang Liu , Jiankun Lu , Boming Zuo , Yue Wang , Shuting Cao , Xin Fu , Qu Yue , Xin Luo , Xiangyang Zhong , Yaoyuan Dong , Zhao Wang , Tao Yang , Xinyun Xie , Tianci Zeng , Manqing Zhang , Yuankai Wang , Yixiong Shen , Huaqin Zuo , Hongbo Guo

O6-methylguanine DNA methyltransferase (MGMT) is a crucial determinant of temozolomide (TMZ) sensitivity in patients with glioblastoma (GBM). The therapeutic potential of small interfering RNA (siRNA) targeting MGMT to enhance TMZ sensitivity has been hampered by serum nuclease degradation, off-target effects, poor accumulation at tumor sites, and low circulation in blood stream. In this study, we developed a framework nucleic acid-based nanoparticles (FNN), which is constructed from a six-helix DNA bundle, to encapsulate and protect siMGMT for improving TMZ sensitivity in GBM treatment. For better blood-brain barrier (BBB) penetration and GBM targeting, we conjugated Angiopep-2 (ANG) targeting modules to each end of the FNN. Nucleolin (NCL)-responsive locks were engineered along the sides of the six-helix DNA bundle, which safeguard siMGMT before tumor entry. Upon interaction with tumor-overexpressed NCL, these locks unlock, exposing siMGMT, this allows for effective suppression of MGMT, resulting in a significant improvement of TMZ therapeutic efficacy in GBM. This innovative strategy has the potential to transform the current treatment landscape for GBM.

O6-甲基鸟嘌呤 DNA 甲基转移酶(MGMT)是决定胶质母细胞瘤(GBM)患者对替莫唑胺(TMZ)敏感性的关键因素。以 MGMT 为靶点的小干扰 RNA(siRNA)在提高 TMZ 敏感性方面的治疗潜力一直受到血清核酸酶降解、脱靶效应、肿瘤部位蓄积不良和血流循环低等因素的阻碍。在这项研究中,我们开发了一种基于核酸的框架纳米颗粒(FNN),它由六螺旋 DNA 束构建而成,可包裹并保护 siMGMT,以提高 TMZ 治疗 GBM 的敏感性。为了实现更好的血脑屏障(BBB)穿透和 GBM 靶向,我们在 FNN 的两端连接了 Angiopep-2 (ANG) 靶向模块。沿着六螺旋 DNA 束的两侧设计了核胶质蛋白(NCL)响应锁,在 siMGMT 进入肿瘤前对其进行保护。当与肿瘤高表达的 NCL 相互作用时,这些锁会解锁,使 siMGMT 暴露,从而有效抑制 MGMT,显著提高 TMZ 对 GBM 的疗效。这一创新策略有可能改变目前GBM的治疗格局。
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引用次数: 0
BCL7A inhibits the progression and drug-resistance in acute myeloid leukemia BCL7A 可抑制急性髓性白血病的进展和耐药性。
IF 15.8 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-07-22 DOI: 10.1016/j.drup.2024.101120
Tushuai Li , Renjie Gao , Kaiwen Xu , Pengpeng Pan , Congcong Chen , Daokuan Wang , Keyi Zhang , Jilei Qiao , Yue Gu

Aims

This study aimed to elucidate the biological roles and regulatory mechanisms of B-cell lymphoma 7 protein family member A (BCL7A) in acute myeloid leukemia (AML), particularly its interaction with polypyrimidine tract binding protein 1 (PTBP1) and the effects on cancer progression and drug resistance.

Methods

BCL7A expression levels were analyzed in AML tissues and cell lines, focusing on associations with promoter hypermethylation. Interaction with PTBP1 and effects of differential expression of BCL7A were examined in vitro and in vivo. The impacts on cell proliferation, cycle progression, apoptosis, and differentiation were studied. Additionally, the regulatory roles of BCL7A on interferon regulatory factor 7 (IRF7) and 3-hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1) were assessed.

Results

BCL7A was downregulated in AML due to promoter hypermethylation and negatively regulated by PTBP1. Upregulation of BCL7A impeded AML cell growth, induced apoptosis, promoted cell differentiation, and decreased cell infiltration into lymph nodes, enhancing survival in mouse models. Overexpression of BCL7A upregulated IRF7 and downregulated HMGCS1, linking to reduced AML cell malignancy and decreased resistance to cytarabine.

Conclusions

BCL7A acts as a tumor suppressor in AML, inhibiting malignant progression and enhancing drug sensitivity through the IRF7/HMGCS1 pathway. These findings suggest potential therapeutic targets for improving AML treatment outcomes.

目的:本研究旨在阐明B细胞淋巴瘤7蛋白家族成员A(BCL7A)在急性髓性白血病(AML)中的生物学作用和调控机制,特别是它与多嘧啶束结合蛋白1(PTBP1)的相互作用及其对癌症进展和耐药性的影响:方法:分析AML组织和细胞系中BCL7A的表达水平,重点研究其与启动子超甲基化的关系。在体外和体内研究了BCL7A与PTBP1的相互作用以及不同表达的影响。研究了其对细胞增殖、周期进展、凋亡和分化的影响。此外,还评估了 BCL7A 对干扰素调节因子 7(IRF7)和 3-hydroxy-3-methylglutaryl-CoA synthase 1(HMGCS1)的调节作用:结果:BCL7A在急性髓细胞性白血病中因启动子超甲基化而下调,并受到PTBP1的负调控。BCL7A的上调阻碍了AML细胞的生长,诱导细胞凋亡,促进细胞分化,减少细胞向淋巴结的浸润,提高了小鼠模型的存活率。BCL7A的过表达上调了IRF7,下调了HMGCS1,从而降低了AML细胞的恶性程度和对阿糖胞苷的耐药性:结论:BCL7A在急性髓细胞性白血病中是一种肿瘤抑制因子,通过IRF7/HMGCS1通路抑制恶性进展并提高药物敏感性。这些发现为改善急性髓细胞性白血病的治疗效果提供了潜在的治疗靶点。
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引用次数: 0
Intersecting pathways: The role of hybrid E/M cells and circulating tumor cells in cancer metastasis and drug resistance 交叉途径:混合 E/M 细胞和循环肿瘤细胞在癌症转移和耐药性中的作用
IF 15.8 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-07-14 DOI: 10.1016/j.drup.2024.101119
Amirali Hariri , Mina Mirian , Arezoo Khosravi , Atefeh Zarepour , Siavash Iravani , Ali Zarrabi

Cancer metastasis and therapy resistance are intricately linked with the dynamics of Epithelial-Mesenchymal Transition (EMT) and Circulating Tumor Cells (CTCs). EMT hybrid cells, characterized by a blend of epithelial and mesenchymal traits, have emerged as pivotal in metastasis and demonstrate remarkable plasticity, enabling transitions across cellular states crucial for intravasation, survival in circulation, and extravasation at distal sites. Concurrently, CTCs, which are detached from primary tumors and travel through the bloodstream, are crucial as potential biomarkers for cancer prognosis and therapeutic response. There is a significant interplay between EMT hybrid cells and CTCs, revealing a complex, bidirectional relationship that significantly influences metastatic progression and has a critical role in cancer drug resistance. This resistance is further influenced by the tumor microenvironment, with factors such as tumor-associated macrophages, cancer-associated fibroblasts, and hypoxic conditions driving EMT and contributing to therapeutic resistance. It is important to understand the molecular mechanisms of EMT, characteristics of EMT hybrid cells and CTCs, and their roles in both metastasis and drug resistance. This comprehensive understanding sheds light on the complexities of cancer metastasis and opens avenues for novel diagnostic approaches and targeted therapies and has significant advancements in combating cancer metastasis and overcoming drug resistance.

癌症转移和耐药性与上皮-间质转化(EMT)和循环肿瘤细胞(CTC)的动态密切相关。EMT混合细胞具有上皮细胞和间质细胞的混合特征,在肿瘤转移过程中起着关键作用,并表现出显著的可塑性,可在细胞状态之间进行转换,这对肿瘤的内侵、循环中的存活和远端部位的外侵至关重要。同时,从原发肿瘤中分离出来并通过血液循环的 CTCs 是癌症预后和治疗反应的潜在生物标志物,具有至关重要的作用。EMT 混合细胞和 CTC 之间存在着重要的相互作用,揭示了一种复杂的双向关系,这种关系对转移进展产生了重大影响,并在癌症耐药性中发挥着关键作用。这种耐药性还受到肿瘤微环境的进一步影响,肿瘤相关巨噬细胞、癌症相关成纤维细胞和缺氧条件等因素会驱动 EMT 并导致耐药性。了解 EMT 的分子机制、EMT 杂交细胞和 CTCs 的特征及其在转移和耐药性中的作用非常重要。这种全面的认识揭示了癌症转移的复杂性,为新型诊断方法和靶向治疗开辟了途径,并在抗击癌症转移和克服耐药性方面取得了重大进展。
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引用次数: 0
Point mutation P174L of the penA gene endowing ceftazidime resistance to Burkholderia pseudomallei in China 中国假丝酵母伯克霍尔德菌对头孢唑肟耐药性的 PenA 基因点突变 P174L
IF 15.8 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-07-14 DOI: 10.1016/j.drup.2024.101121
Shen Tian , Xingyong Wu , Lin Liu , Anyang Li , Xuemiao Li , Hua Pei , Yanshuang Wang , David A.B. Dance , Hai Chen , Qianfeng Xia

In a clinical isolate of Burkholderia pseudomallei from Hainan, the association between the emergence of ceftazidime resistance and a novel PenA P174L allele was identified for the first time, providing an understanding of one mechanism by which ceftazidime resistance arises in B. pseudomallei.

在海南的一个临床分离的假马来伯克霍尔德氏菌中,首次发现了头孢他啶耐药性的出现与新型PenA P174L等位基因之间的关联,从而了解了头孢他啶耐药性在假马来伯克霍尔德氏菌中产生的一种机制。
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引用次数: 0
Targeting undruggable phosphatase overcomes trastuzumab resistance by inhibiting multi-oncogenic kinases 以不可药用磷酸酶为靶点,通过抑制多种致癌激酶克服曲妥珠单抗抗药性
IF 15.8 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-07-14 DOI: 10.1016/j.drup.2024.101118
Lu Wang , Yusheng Lin , Zhimeng Yao , Nipun Babu , Wan Lin , Chaoying Chen , Liang Du , Songwang Cai , Yunlong Pan , Xiao Xiong , Qiantao Ye , Hongzheng Ren , Dianzheng Zhang , Yexi Chen , Sai-Ching Jim Yeung , Edwin Bremer , Hao Zhang

Aims

Resistance to targeted therapy is one of the critical obstacles in cancer management. Resistance to trastuzumab frequently develops in the treatment for HER2+ cancers. The role of protein tyrosine phosphatases (PTPs) in trastuzumab resistance is not well understood. In this study, we aim to identify pivotal PTPs affecting trastuzumab resistance and devise a novel counteracting strategy.

Methods

Four public datasets were used to screen PTP candidates in relation to trastuzumab responsiveness in HER2+ breast cancer. Tyrosine kinase (TK) arrays were used to identify kinases that linked to protein tyrosine phosphate receptor type O (PTPRO)-enhanced trastuzumab sensitivity. The efficacy of small activating RNA (saRNA) in trastuzumab-conjugated silica nanoparticles was tested for PTPRO upregulation and resistance mitigation in cell models, a transgenic mouse model, and human cancer cell line-derived xenograft models.

Results

PTPRO was identified as the key PTP which influences trastuzumab responsiveness and patient survival. PTPRO de-phosphorated several TKs, including the previously overlooked substrate ERBB3, thereby inhibiting multiple oncogenic pathways associated with drug resistance. Notably, PTPRO, previously deemed “undruggable,” was effectively upregulated by saRNA-loaded nanoparticles. The upregulated PTPRO simultaneously inhibited ERBB3, ERBB2, and downstream SRC signaling pathways, thereby counteracting trastuzumab resistance.

Conclusions

Antibody-conjugated saRNA represents an innovative approach for targeting “undruggable” PTPs.

目的靶向治疗的抗药性是癌症治疗的关键障碍之一。在治疗 HER2+ 癌症的过程中,曲妥珠单抗经常会产生抗药性。蛋白酪氨酸磷酸酶(PTPs)在曲妥珠单抗耐药中的作用尚不十分清楚。在这项研究中,我们旨在找出影响曲妥珠单抗耐药性的关键 PTPs,并设计出一种新的应对策略。方法利用四个公开数据集筛选与 HER2+ 乳腺癌中曲妥珠单抗反应性相关的 PTP 候选者。酪氨酸激酶(TK)阵列用于鉴定与蛋白酪氨酸磷酸受体O型(PTPRO)增强曲妥珠单抗敏感性相关的激酶。在细胞模型、转基因小鼠模型和人类癌细胞系衍生的异种移植模型中,测试了曲妥珠单抗共轭硅纳米粒子中的小激活 RNA(saRNA)对 PTPRO 的上调和抗药性缓解的功效。PTPRO 可使多个 TK(包括以前被忽视的底物 ERBB3)去磷酸化,从而抑制与耐药性相关的多种致癌通路。值得注意的是,以前被认为 "不可药用 "的 PTPRO 被载入 saRNA 的纳米颗粒有效上调。上调的 PTPRO 同时抑制了 ERBB3、ERBB2 和下游 SRC 信号通路,从而抵消了曲妥珠单抗的耐药性。
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引用次数: 0
Increased oxygen stimulation promotes chemoresistance and phenotype shifting through PLCB1 in gliomas 增氧刺激通过 PLCB1 促进胶质瘤的抗药性和表型转移
IF 15.8 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-07-10 DOI: 10.1016/j.drup.2024.101113
Kang Ma , Shi Wang , Yingjie Ma , Lan Zeng , Kai Xu , Ning Mu , Ying Lai , Yaning Shi , Chuanyan Yang , Beike Chen , Yulian Quan , Lan Li , Yongling Lu , Yang Yang , Yan Liu , Rong Hu , Xiaoming Wang , Yujie Chen , Xiuwu Bian , Hua Feng , Tunan Chen

Gliomas, the most common CNS (central nerve system) tumors, face poor survival due to severe chemoresistance exacerbated by hypoxia. However, studies on whether altered hypoxic conditions benefit for chemo-sensitivity and how gliomas react to increased oxygen stimulation are limited. In this study, we demonstrated that increased oxygen stimulation promotes glioma growth and chemoresistance. Mechanically, increased oxygen stimulation upregulates miR-1290 levels. miR-1290, in turn, downregulates PLCB1, while PLCB1 facilitates the proteasomal degradation of β-catenin and active-β-catenin by increasing the proportion of ubiquitinated β-catenin in a destruction complex-independent mechanism. This process inhibits PLCB1 expression, leads to the accumulation of active-β-catenin, boosting Wnt signaling through an independent mechanism and ultimately promoting chemoresistance in glioma cells. Pharmacological inhibition of Wnt by WNT974 could partially inhibit glioma volume growth and prolong the shortened survival caused by increased oxygen stimulation in a glioma-bearing mouse model. Moreover, PLCB1, a key molecule regulated by increased oxygen stimulation, shows promising predictive power in survival analysis and has great potential to be a biomarker for grading and prognosis in glioma patients. These results provide preliminary insights into clinical scenarios associated with altered hypoxic conditions in gliomas, and introduce a novel perspective on the role of the hypoxic microenvironment in glioma progression. Furthermore, the outcomes reveal the potential risks of utilizing hyperbaric oxygen treatment (HBOT) in glioma patients, particularly when considering HBOT as a standalone option to ameliorate neuro-dysfunctions or when combining HBOT with a single chemotherapy agent without radiotherapy.

胶质瘤是最常见的中枢神经系统(CNS)肿瘤,由于缺氧加剧了严重的化疗耐药性,因此生存率很低。然而,关于改变低氧条件是否有利于化疗敏感性以及胶质瘤如何对增加的氧刺激做出反应的研究十分有限。在这项研究中,我们证明了氧刺激的增加会促进胶质瘤的生长和化疗耐药性。miR-1290反过来又会下调PLCB1,而PLCB1则通过增加泛素化β-catenin的比例,在一种与破坏复合体无关的机制中促进β-catenin和活性-β-catenin的蛋白酶体降解。这一过程会抑制 PLCB1 的表达,导致活性-β-catenin 的积累,通过独立机制增强 Wnt 信号转导,最终促进胶质瘤细胞的化疗抗性。在胶质瘤小鼠模型中,WNT974对Wnt的药理抑制可部分抑制胶质瘤体积的增长,并延长因氧刺激增加而导致的生存期缩短。此外,受氧刺激增加调控的关键分子 PLCB1 在生存分析中显示出良好的预测能力,极有可能成为胶质瘤患者分级和预后的生物标志物。这些结果提供了与胶质瘤缺氧条件改变相关的临床情景的初步见解,并为缺氧微环境在胶质瘤进展中的作用引入了一个新的视角。此外,研究结果还揭示了胶质瘤患者使用高压氧治疗(HBOT)的潜在风险,尤其是在考虑将高压氧治疗作为改善神经功能障碍的一种独立选择,或将高压氧治疗与单一化疗药物结合使用而不进行放疗时。
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引用次数: 0
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Drug Resistance Updates
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