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LncRNA DYNLRB2-AS1 promotes gemcitabine resistance of nasopharyngeal carcinoma by inhibiting the ubiquitination degradation of DHX9 protein LncRNA DYNLRB2-AS1 通过抑制 DHX9 蛋白的泛素化降解促进吉西他滨对鼻咽癌的耐药性
IF 15.8 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-06-14 DOI: 10.1016/j.drup.2024.101111
Kai-Lin Chen , Sai-Wei Huang , Ji-Jin Yao , Shi-Wei He , Sha Gong , Xi-Rong Tan , Ye-Lin Liang , Jun-Yan Li , Sheng-Yan Huang , Ying-Qin Li , Yin Zhao , Han Qiao , Sha Xu , Shengbing Zang , Jun Ma , Na Liu

Gemcitabine (GEM) based induction chemotherapy is a standard treatment for locoregionally advanced nasopharyngeal carcinoma (NPC). However, approximately 15 % of patients are still resistant to GEM-containing chemotherapy, which leads to treatment failure. Nevertheless, the underlying mechanisms of GEM resistance remain poorly understood. Herein, based on a microarray analysis, we identified 221 dysregulated lncRNAs, of which, DYNLRB2-AS1 was one of the most upregulated lncRNAs in GEM-resistance NPC cell lines. DYNLRB2-AS1 was shown to function as contain an oncogenic lncRNA that promoted NPC GEM resistance, cell proliferation, but inhibited cell apoptosis. Mechanistically, DYNLRB2-AS1 could directly bind to the DHX9 protein and prevent its interaction with the E3 ubiquitin ligase PRPF19, and thus blocking PRPF19-mediated DHX9 degradation, which ultimately facilitated the repair of DNA damage in the presence of GEM. Clinically, higher DYNLRB2-AS1 expression indicated an unfavourable overall survival of NPC patients who received induction chemotherapy. Overall, this study identified the oncogenic lncRNA DYNLRB2-AS1 as an independent prognostic biomarker for patients with locally advanced NPC and as a potential therapeutic target for overcoming GEM chemoresistance in NPC.

以吉西他滨(GEM)为基础的诱导化疗是局部区域晚期鼻咽癌(NPC)的标准治疗方法。然而,仍有约15%的患者对含吉西他滨的化疗产生耐药性,导致治疗失败。然而,人们对GEM耐药的内在机制仍然知之甚少。在此,我们基于微阵列分析鉴定了221个调控失调的lncRNA,其中DYNLRB2-AS1是GEM耐药NPC细胞系中上调最多的lncRNA之一。研究表明,DYNLRB2-AS1含有致癌lncRNA,它能促进鼻咽癌GEM耐药、细胞增殖,但抑制细胞凋亡。从机理上讲,DYNLRB2-AS1可直接与DHX9蛋白结合,阻止其与E3泛素连接酶PRPF19的相互作用,从而阻断PRPF19介导的DHX9降解,最终在GEM存在的情况下促进DNA损伤的修复。在临床上,DYNLRB2-AS1表达较高表明接受诱导化疗的鼻咽癌患者总生存率较低。总之,本研究发现致癌 lncRNA DYNLRB2-AS1 是局部晚期鼻咽癌患者的独立预后生物标志物,也是克服鼻咽癌 GEM 化疗耐药性的潜在治疗靶点。
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引用次数: 0
Lansoprazole (LPZ) reverses multidrug resistance (MDR) in cancer through impeding ATP-binding cassette (ABC) transporter-mediated chemotherapeutic drug efflux and lysosomal sequestration 兰索拉唑(LPZ)通过阻碍ATP结合盒(ABC)转运体介导的化疗药物外流和溶酶体螯合,逆转癌症的多药耐药性(MDR)。
IF 24.3 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-06-04 DOI: 10.1016/j.drup.2024.101100
Ning Ji , Hui Li , Yixuan Zhang , Yuelin Li , Peiyu Wang , Xin Chen , Yi-Nan Liu , Jing-Quan Wang , Yuqi Yang , Zhe-Sheng Chen , Yueguo Li , Ran Wang , Dexin Kong

Aims

Lansoprazole is one of the many proton pump inhibitors (PPIs) that acts more strongly with ABCB1 and ABCG2. The present study is to investigate the potential of lansoprazole on reversal of ABCB1/G2-mediated MDR in cancer, in vitro and in vivo.

Methods

Reversal studies and combination evaluation were conducted to determine the synergistic anti-MDR effects on lansoprazole. Lysosomal staining was used to determination of lansoprazole on ABCB1-mediated lysosomal sequestration. Substrate accumulation and efflux assays, ATPase activity, and molecular docking were conducted to evaluate lansoprazole on ABCB1/G2 functions. Western blot and immunofluorescence were used to detect lansoprazole on ABCB1/G2 expression and subcellular localization. MDR nude mice models were established to evaluate the effects of lansoprazole on MDR in vivo.

Results

Lansoprazole attenuated ABCB1/G2-mediated MDR and exhibited synergistic effects with substrate drugs in MDR cells. In vivo experiments demonstrated that lansoprazole attenuated ABCB1/G2-mediated MDR and exhibited synergistic effects that augmented the sensitivity of substrate anticancer drugs in ABCB1/G2-mediated settings without obvious toxicity. Lansoprazole impeded lysosomal sequestration mediated by ABCB1, leading to a substantial increase in intracellular accumulation of substrate drugs. The effects of lansoprazole were not attributable to downregulation or alterations in subcellular localization of ABCB1/G2. Lansoprazole promoted the ATPase activity of ABCB1/G2 and competitively bound to the substrate-binding region of ABCB1/G2.

Conclusions

These findings present novel therapeutic avenues whereby the combination of lansoprazole and chemotherapeutic agents mitigates MDR mediated by ABCB1/G2 overexpression.

目的兰索拉唑是众多质子泵抑制剂(PPI)中与ABCB1和ABCG2作用较强的一种。本研究旨在探讨兰索拉唑在体外和体内逆转 ABCB1/G2 介导的癌症 MDR 的潜力。溶酶体染色用于确定兰索拉唑对 ABCB1 介导的溶酶体螯合作用的影响。通过底物蓄积和外流试验、ATP酶活性和分子对接来评估兰索拉唑对ABCB1/G2功能的影响。利用Western印迹和免疫荧光检测兰索拉唑对ABCB1/G2表达和亚细胞定位的影响。结果兰索拉唑可减轻ABCB1/G2-介导的MDR,并在MDR细胞中与底物药物协同作用。体内实验表明,兰索拉唑减轻了 ABCB1/G2 介导的 MDR,并表现出协同效应,在 ABCB1/G2 介导的环境中提高了底物抗癌药物的敏感性,且无明显毒性。兰索拉唑阻碍了 ABCB1 介导的溶酶体螯合作用,导致底物药物在细胞内的蓄积大幅增加。兰索拉唑的作用并不归因于ABCB1/G2的下调或亚细胞定位的改变。兰索拉唑促进了ABCB1/G2的ATP酶活性,并与ABCB1/G2的底物结合区竞争性结合。结论这些发现提供了新的治疗途径,即兰索拉唑与化疗药物联合使用可减轻ABCB1/G2过表达介导的MDR。
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引用次数: 0
Targeting anoikis resistance as a strategy for cancer therapy 以抗药性为靶点的癌症治疗策略
IF 24.3 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-06-01 DOI: 10.1016/j.drup.2024.101099
Yumin Wang , Sihang Cheng , Joshua S. Fleishman , Jichao Chen , Hailin Tang , Zhe-Sheng Chen , Wenkuan Chen , Mingchao Ding

Anoikis, known as matrix detachment-induced apoptosis or detachment-induced cell death, is crucial for tissue development and homeostasis. Cancer cells develop means to evade anoikis, e.g. anoikis resistance, thereby allowing for cells to survive under anchorage-independent conditions. Uncovering the mechanisms of anoikis resistance will provide details about cancer metastasis, and potential strategies against cancer cell dissemination and metastasis. Here, we summarize the principal elements and core molecular mechanisms of anoikis and anoikis resistance. We discuss the latest progress of how anoikis and anoikis resistance are regulated in cancers. Furthermore, we summarize emerging data on selective compounds and nanomedicines, explaining how inhibiting anoikis resistance can serve as a meaningful treatment modality against cancers. Finally, we discuss the key limitations of this therapeutic paradigm and possible strategies to overcome them. In this review, we suggest that pharmacological modulation of anoikis and anoikis resistance by bioactive compounds could surmount anoikis resistance, highlighting a promising therapeutic regimen that could be used to overcome anoikis resistance in cancers.

Anoikis被称为基质脱落诱导的细胞凋亡或脱落诱导的细胞死亡,对于组织的发育和平衡至关重要。癌细胞发展出逃避anoikis的方法,如anoikis抗性,从而使细胞在不依赖锚的条件下存活。揭示anoikis抗性的机制将提供有关癌症转移的详细信息,以及应对癌细胞扩散和转移的潜在策略。在此,我们总结了anoikis和anoikis抗性的主要因素和核心分子机制。我们还将讨论癌症中嗜酸酶和嗜酸酶抗性调控的最新进展。此外,我们还总结了有关选择性化合物和纳米药物的新兴数据,解释了抑制 anoikis 抗性如何成为一种有意义的癌症治疗方式。最后,我们讨论了这种治疗模式的主要局限性以及克服这些局限性的可能策略。在这篇综述中,我们认为通过生物活性化合物对anoikis和anoikis抗性进行药理调节可以克服anoikis抗性,并强调了一种可用于克服癌症中anoikis抗性的有前途的治疗方案。
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引用次数: 0
Application of biomimetic nanovaccines in cancer immunotherapy: A useful strategy to help combat immunotherapy resistance 生物仿生纳米疫苗在癌症免疫疗法中的应用:帮助对抗免疫疗法耐药性的有效策略
IF 24.3 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-06-01 DOI: 10.1016/j.drup.2024.101098
Zhijie Xu , Haiyan Zhou , Tongfei Li , Qiaoli Yi , Abhimanyu Thakur , Kui Zhang , Xuelei Ma , Jiang-Jiang Qin , Yuanliang Yan

Breakthroughs in actual clinical applications have begun through vaccine-based cancer immunotherapy, which uses the body's immune system, both humoral and cellular, to attack malignant cells and fight diseases. However, conventional vaccine approaches still face multiple challenges eliciting effective antigen-specific immune responses, resulting in immunotherapy resistance. In recent years, biomimetic nanovaccines have emerged as a promising alternative to conventional vaccine approaches by incorporating the natural structure of various biological entities, such as cells, viruses, and bacteria. Biomimetic nanovaccines offer the benefit of targeted antigen-presenting cell (APC) delivery, improved antigen/adjuvant loading, and biocompatibility, thereby improving the sensitivity of immunotherapy. This review presents a comprehensive overview of several kinds of biomimetic nanovaccines in anticancer immune response, including cell membrane-coated nanovaccines, self-assembling protein-based nanovaccines, extracellular vesicle-based nanovaccines, natural ligand-modified nanovaccines, artificial antigen-presenting cells-based nanovaccines and liposome-based nanovaccines. We also discuss the perspectives and challenges associated with the clinical translation of emerging biomimetic nanovaccine platforms for sensitizing cancer cells to immunotherapy.

以疫苗为基础的癌症免疫疗法利用人体的体液免疫和细胞免疫系统来攻击恶性细胞和对抗疾病,在实际临床应用中取得了突破性进展。然而,传统疫苗方法在激发有效的抗原特异性免疫反应方面仍面临多重挑战,导致免疫疗法产生抗药性。近年来,生物仿生纳米疫苗结合了各种生物实体(如细胞、病毒和细菌)的天然结构,成为替代传统疫苗方法的一种很有前景的方法。生物仿生纳米疫苗具有靶向抗原递呈细胞(APC)递送、改善抗原/佐剂负载和生物相容性等优点,从而提高了免疫疗法的灵敏度。本综述全面概述了抗癌免疫反应中的几种仿生纳米疫苗,包括细胞膜包被纳米疫苗、自组装蛋白纳米疫苗、细胞外囊基纳米疫苗、天然配体修饰纳米疫苗、人工抗原递呈细胞纳米疫苗和脂质体纳米疫苗。我们还讨论了与新兴生物仿生纳米疫苗平台的临床转化相关的前景和挑战,以提高癌细胞对免疫疗法的敏感性。
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引用次数: 0
CircPDIA3/miR-449a/XBP1 feedback loop curbs pyroptosis by inhibiting palmitoylation of the GSDME-C domain to induce chemoresistance of colorectal cancer CircPDIA3/miR-449a/XBP1反馈环路通过抑制GSDME-C结构域的棕榈酰化来抑制热蛋白沉积,从而诱导结直肠癌的化疗耐药性
IF 24.3 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-05-28 DOI: 10.1016/j.drup.2024.101097
Jiatong Lin , Zejian Lyu , Huolun Feng , Huajie Xie , Jingwen Peng , Weifu Zhang , Jun Zheng , Jiabin Zheng , Zihao Pan , Yong Li

Although oxaliplatin (OXA) is widely used in the frontline treatment of colorectal cancer (CRC), CRC recurrence is commonly observed due to OXA resistance. OXA resistance is associated with a number of factors, including abnormal regulation of pyroptosis. It is therefore important to elucidate the abnormal regulatory mechanism underlying pyroptosis. Here, we identified that the circular RNA circPDIA3 played an important role in chemoresistance in CRC. CircPDIA3 could induce chemoresistance in CRC by inhibiting pyroptosis both in vitro and in vivo. Mechanistically, RIP, RNA pull-down and co-IP assays revealed that circPDIA3 directly bonded to the GSDME-C domain, subsequently enhanced the autoinhibitory effect of the GSDME-C domain through blocking the GSDME-C domain palmitoylation by ZDHHC3 and ZDHHC17, thereby restraining pyroptosis. Additionally, it was found that the circPDIA3/miR-449a/XBP1 positive feedback loop increased the expression of circPDIA3 to induce chemoresistance. Furthermore, our clinical data and patient-derived tumor xenograft (PDX) models supported the positive association of circPDIA3 with development of chemoresistance in CRC patients. Taken together, our findings demonstrated that circPDIA3 could promote chemoresistance by amplifying the autoinhibitory effect of the GSDME-C domain through inhibition of the GSDME-C domain palmitoylation in CRC. This study provides novel insights into the mechanism of circRNA in regulating pyroptosis and providing a potential therapeutic target for reversing chemoresistance of CRC.

尽管奥沙利铂(OXA)被广泛应用于结直肠癌(CRC)的一线治疗,但由于对 OXA 产生耐药性,CRC 复发现象十分常见。OXA 耐药性与多种因素有关,包括热蛋白沉积的异常调控。因此,阐明热蛋白沉积的异常调控机制非常重要。在这里,我们发现环状 RNA circPDIA3 在 CRC 的化疗耐药性中发挥了重要作用。循环RNA circPDIA3可通过抑制体外和体内的热凋亡诱导CRC的化疗耐药性。从机理上讲,RIP、RNA pull-down和co-IP实验发现,circPDIA3直接与GSDME-C结构域结合,然后通过阻断ZDHHC3和ZDHHC17对GSDME-C结构域棕榈酰化,增强GSDME-C结构域的自身抑制作用,从而抑制热凋亡。此外,研究还发现,circPDIA3/miR-449a/XBP1正反馈回路增加了circPDIA3的表达,从而诱导化疗耐药。此外,我们的临床数据和患者来源的肿瘤异种移植(PDX)模型也支持 circPDIA3 与 CRC 患者化疗耐药性的发生呈正相关。综上所述,我们的研究结果表明,circPDIA3可通过抑制GSDME-C结构域棕榈酰化,放大GSDME-C结构域的自身抑制作用,从而促进CRC的化疗耐药性。这项研究为我们揭示circRNA调控化脓过程的机制提供了新的视角,并为逆转CRC的化疗耐药性提供了潜在的治疗靶点。
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引用次数: 0
KLF12 interacts with TRIM27 to affect cisplatin resistance and cancer metastasis in esophageal squamous cell carcinoma by regulating L1CAM expression KLF12与TRIM27相互作用,通过调节L1CAM的表达影响食管鳞状细胞癌的顺铂耐药性和癌症转移。
IF 15.8 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-05-27 DOI: 10.1016/j.drup.2024.101096
Hao Zhang , Yujia Zheng , Zhen Wang , Lin Dong , Liyan Xue , Xiaolin Tian , Haiteng Deng , Qi Xue , Shugeng Gao , Yibo Gao , Chunxiang Li , Jie He

Krüppel-like factor 12 (KLF12) has been characterized as a transcriptional repressor, and previous studies have unveiled its roles in angiogenesis, neural tube defect, and natural killer (NK) cell proliferation. However, the contribution of KLF12 to cancer treatment remains undefined. Here, we show that KLF12 is downregulated in various cancer types, and KLF12 downregulation promotes cisplatin resistance and cancer metastasis in esophageal squamous cell carcinoma (ESCC). Mechanistically, KLF12 binds to the promoters of L1 Cell Adhesion Molecule (L1CAM) and represses its expression. Depletion of L1CAM abrogates cisplatin resistance and cancer metastasis caused by KLF12 loss. Moreover, the E3 ubiquitin ligase tripartite motif-containing 27 (TRIM27) binds to the N-terminal region of KLF12 and ubiquitinates KLF12 at K326 via K33-linked polyubiquitination. Notably, TRIM27 depletion enhances the transcriptional activity of KLF12 and consequently inhibits L1CAM expression. Overall, our study elucidated a novel regulatory mechanism involving TRIM27, KLF12 and L1CAM, which plays a substantial role in cisplatin resistance and cancer metastasis in ESCC. Targeting these genes could be a promising approach for ESCC treatment.

Krüppel样因子12(KLF12)是一种转录抑制因子,先前的研究揭示了它在血管生成、神经管缺陷和自然杀伤(NK)细胞增殖中的作用。然而,KLF12 对癌症治疗的贡献仍未确定。在这里,我们发现 KLF12 在多种癌症类型中被下调,而 KLF12 的下调促进了食管鳞状细胞癌(ESCC)的顺铂耐药性和癌症转移。从机制上讲,KLF12 与 L1 细胞粘附分子(L1CAM)的启动子结合并抑制其表达。L1CAM的缺失会削弱顺铂抗性以及KLF12缺失导致的癌症转移。此外,E3 泛素连接酶含三方基序 27(TRIM27)与 KLF12 的 N 端区域结合,并通过 K33 链接的多泛素化在 K326 处泛素化 KLF12。值得注意的是,TRIM27 的缺失会增强 KLF12 的转录活性,从而抑制 L1CAM 的表达。总之,我们的研究阐明了一种涉及TRIM27、KLF12和L1CAM的新型调控机制,该机制在ESCC的顺铂耐药和癌症转移中发挥了重要作用。靶向这些基因可能是治疗 ESCC 的一种有前景的方法。
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引用次数: 0
FAT1 as a tumor mutation burden specific gene affects the immunotherapy effect in head and neck squamous cell cancer FAT1 作为肿瘤突变负荷特异性基因影响头颈部鳞状细胞癌的免疫治疗效果。
IF 15.8 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-05-27 DOI: 10.1016/j.drup.2024.101095
Haotian Cao , Tianjun Lan , Shijia Kuang , Liansheng Wang , Jintao Li , Qunxin Li , Yanyan Li , Qiuping Xu , Qian Chen , Shuwei Ren , Chunhong Lan , Nengtai Ouyang , Jianwei Liao , Yongsheng Huang , Jinsong Li

Background

Response to immunotherapy is the main challenge of head and neck squamous cancer (HNSCC) treatment. Previous studies have indicated that tumor mutational burden (TMB) is associated with prognosis, but it is not always a precise index. Hence, investigating specific genetic mutations and tumor microenvironment (TME) changes in TMB-high patients is essential for precision therapy of HNSCC.

Methods

A total of 33 HNSCC patients were enrolled in this study. We calculated the TMB score based on next-generation sequencing (NGS) sequencing and grouped these patients based on TMB score. Then, we examined the immune microenvironment of HNSCC using assessments of the bulk transcriptome and the single-cell RNA sequence (scRNA-seq) focusing on the molecular nature of TMB and mutations in HNSCC from our cohort. The association of the mutation pattern and TMB was analyzed in The Cancer Genome Atlas (TCGA) and validated by our cohort.

Results

33 HNSCC patients were divided into three groups (TMB-low, -medium, and -high) based on TMB score. In the result of 520-gene panel sequencing data, we found that FAT1 and LRP1B mutations were highly prevalent in TMB-high patients. FAT1 mutations are associated with resistance to immunotherapy in HNSCC patients. This involves many metabolism-related pathways like RERE, AIRE, HOMER1, etc. In the scRNA-seq data, regulatory T cells (Tregs), monocytes, and DCs were found mainly enriched in TMB-high samples.

Conclusion

Our analysis unraveled the FAT1 gene as an assistant predictor when we use TMB as a biomarker of drug resistance in HNSCC. Tregs, monocytes, and dendritic cells (DCs) were found mainly enriched in TMB-high samples.

背景:对免疫疗法的反应是头颈部鳞癌(HNSCC)治疗的主要挑战。以往的研究表明,肿瘤突变负荷(TMB)与预后相关,但它并不总是一个精确的指标。因此,研究TMB高的患者的特定基因突变和肿瘤微环境(TME)变化对于HNSCC的精准治疗至关重要:本研究共纳入 33 例 HNSCC 患者。我们根据新一代测序(NGS)计算了TMB评分,并根据TMB评分对这些患者进行了分组。然后,我们利用大体转录组和单细胞 RNA 序列(scRNA-seq)的评估来研究 HNSCC 的免疫微环境,重点是我们队列中 HNSCC 中 TMB 和突变的分子性质。在癌症基因组图谱(TCGA)中分析了突变模式与TMB的关联,并通过我们的队列进行了验证:根据 TMB 评分,33 例 HNSCC 患者被分为三组(TMB 低、中、高)。在 520 个基因的测序结果中,我们发现 FAT1 和 LRP1B 突变在 TMB 高的患者中非常普遍。FAT1 突变与 HNSCC 患者对免疫疗法的耐药性有关。这涉及许多代谢相关通路,如 RERE、AIRE、HOMER1 等。在scRNA-seq数据中,调节性T细胞(Tregs)、单核细胞和DCs主要富集在TMB高的样本中:结论:我们的分析发现,当我们使用TMB作为HNSCC耐药性的生物标记时,FAT1基因是一个辅助预测因子。TMB高的样本中主要富集了Tregs、单核细胞和树突状细胞(DCs)。
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引用次数: 0
Characterization of NMCR-3, NMCR-4 and NMCR-5, three novel non-mobile colistin resistance determinants: Implications for MCR-3, MCR-7, and MCR-5 progenitors, respectively NMCR-3、NMCR-4 和 NMCR-5 这三种新型非移动性秋水仙素抗性决定因子的特征:分别对 MCR-3、MCR-7 和 MCR-5 祖细胞的影响
IF 24.3 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-04-26 DOI: 10.1016/j.drup.2024.101088
Yating Guo , Geng Zou , Anusak Kerdsin , Constance Schultsz , Can Hu , Weicheng Bei , Huanchun Chen , Jinquan Li , Yang Zhou

In this study, the progenitors of MCR-3, MCR-7 and MCR-5, namely NMCR-3, NMCR-4 and NMCR-5, were firstly discovered and indicating Aeromonas was a natural reservoir for MCR-3 and MCR-7. Furthermore, different evolutionary models for MCR-3, MCR-7 and MCR-5 were proposed.

本研究首次发现了MCR-3、MCR-7和MCR-5的祖先,即NMCR-3、NMCR-4和NMCR-5,并指出气单胞菌是MCR-3和MCR-7的天然储库。此外,还提出了 MCR-3、MCR-7 和 MCR-5 的不同进化模式。
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引用次数: 0
Spotlight on ideal target antigens and resistance in antibody-drug conjugates: Strategies for competitive advancement 聚焦抗体药物共轭物中的理想靶抗原和抗药性:提高竞争力的策略
IF 24.3 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-04-23 DOI: 10.1016/j.drup.2024.101086
Mingxia Jiang , Qiao Li , Binghe Xu

Antibody-drug conjugates (ADCs) represent a novel and promising approach in targeted therapy, uniting the specificity of antibodies that recognize specific antigens with payloads, all connected by the stable linker. These conjugates combine the best targeted and cytotoxic therapies, offering the killing effect of precisely targeting specific antigens and the potent cell-killing power of small molecule drugs. The targeted approach minimizes the off-target toxicities associated with the payloads and broadens the therapeutic window, enhancing the efficacy and safety profile of cancer treatments. Within precision oncology, ADCs have garnered significant attention as a cutting-edge research area and have been approved to treat a range of malignant tumors. Correspondingly, the issue of resistance to ADCs has gradually come to the fore. Any dysfunction in the steps leading to the ADCs' action within tumor cells can lead to the development of resistance. A deeper understanding of resistance mechanisms may be crucial for developing novel ADCs and exploring combination therapy strategies, which could further enhance the clinical efficacy of ADCs in cancer treatment. This review outlines the brief historical development and mechanism of ADCs and discusses the impact of their key components on the activity of ADCs. Furthermore, it provides a detailed account of the application of ADCs with various target antigens in cancer therapy, the categorization of potential resistance mechanisms, and the current state of combination therapies. Looking forward, breakthroughs in overcoming technical barriers, selecting differentiated target antigens, and enhancing resistance management and combination therapy strategies will broaden the therapeutic indications for ADCs. These progresses are anticipated to advance cancer treatment and yield benefits for patients.

抗体-药物共轭物(ADCs)是靶向治疗中一种新型且前景广阔的方法,它将识别特定抗原的特异性抗体与有效载荷结合在一起,所有载荷都由稳定的连接体连接。这些共轭物结合了最佳的靶向疗法和细胞毒疗法,既有精确靶向特定抗原的杀伤效果,又有小分子药物强大的细胞杀伤力。这种靶向方法最大限度地减少了有效载荷的脱靶毒性,扩大了治疗窗口,提高了癌症治疗的有效性和安全性。在精准肿瘤学领域,ADC 作为一个前沿研究领域备受关注,已被批准用于治疗一系列恶性肿瘤。相应地,ADCs 的耐药性问题也逐渐凸显出来。ADCs在肿瘤细胞内发挥作用的任何步骤出现功能障碍,都可能导致耐药性的产生。深入了解耐药机制可能对开发新型 ADC 和探索联合治疗策略至关重要,这将进一步提高 ADC 在癌症治疗中的临床疗效。本综述概述了 ADCs 的简要历史发展和机制,并讨论了其关键成分对 ADCs 活性的影响。此外,它还详细介绍了ADCs与各种靶抗原在癌症治疗中的应用、潜在耐药机制的分类以及联合疗法的现状。展望未来,在克服技术壁垒、选择差异化靶抗原、加强耐药性管理和联合治疗策略方面取得的突破将拓宽 ADCs 的治疗适应症。预计这些进展将推动癌症治疗,为患者带来益处。
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引用次数: 0
Heterogeneity of SOS response expression in clinical isolates of Escherichia coli influences adaptation to antimicrobial stress 临床分离的大肠埃希菌中 SOS 响应表达的异质性影响了对抗菌压力的适应性
IF 24.3 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-04-23 DOI: 10.1016/j.drup.2024.101087
Sara Diaz-Diaz , Andrea Garcia-Montaner , Roberta Vanni , Marina Murillo-Torres , Esther Recacha , Marina R. Pulido , Maria Romero-Muñoz , Fernando Docobo-Pérez , Alvaro Pascual , Jose Manuel Rodriguez-Martinez

In recent years, new evidence has shown that the SOS response plays an important role in the response to antimicrobials, with involvement in the generation of clinical resistance. Here we evaluate the impact of heterogeneous expression of the SOS response in clinical isolates of Escherichia coli on response to the fluoroquinolone, ciprofloxacin. In silico analysis of whole genome sequencing data showed remarkable sequence conservation of the SOS response regulators, RecA and LexA. Despite the genetic homogeneity, our results revealed a marked differential heterogeneity in SOS response activation, both at population and single-cell level, among clinical isolates of E. coli in the presence of subinhibitory concentrations of ciprofloxacin. Four main stages of SOS response activation were identified and correlated with cell filamentation. Interestingly, there was a correlation between clinical isolates with higher expression of the SOS response and further progression to resistance. This heterogeneity in response to DNA damage repair (mediated by the SOS response) and induced by antimicrobial agents could be a new factor with implications for bacterial evolution and survival contributing to the generation of antimicrobial resistance.

近年来,新的证据表明,SOS 反应在抗菌药物反应中发挥着重要作用,并参与了临床耐药性的产生。在此,我们评估了大肠埃希菌临床分离株中 SOS 反应异质性表达对氟喹诺酮类药物环丙沙星反应的影响。对全基因组测序数据的硅学分析表明,SOS 响应调节因子 RecA 和 LexA 的序列具有显著的保守性。尽管基因具有同质性,但我们的研究结果表明,在亚抑制浓度环丙沙星的作用下,临床分离的大肠杆菌在群体和单细胞水平上的 SOS 反应激活具有明显的差异性。确定了 SOS 反应激活的四个主要阶段,并将其与细胞丝状化相关联。有趣的是,SOS 反应表达较高的临床分离株与耐药性的进一步发展之间存在相关性。这种由抗菌剂诱导的 DNA 损伤修复反应(由 SOS 反应介导)的异质性可能是对细菌进化和生存产生影响的一个新因素,有助于抗菌剂耐药性的产生。
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Drug Resistance Updates
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