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Wip1 phosphatase activator QGC-8–52 specifically sensitizes p53-negative cancer cells to chemotherapy while protecting normal cells Wip1磷酸酶激活剂QGC-8-52特异性地使p53阴性癌细胞对化疗增敏,同时保护正常细胞。
IF 15.8 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-12-24 DOI: 10.1016/j.drup.2024.101196
Ke Wu , Xiao-xiao Ge , Xiao-fan Duan , Jie-qing Li , Kun Wang , Qiao-Hong Chen , Zhi-min Huang , Wei-yan Zhang , Yong Wu , Qun Li
PP2C serine-threonine phosphatase Wip1 plays an important role in normal tissue homeostasis, stress signaling and pathogenesis of various human diseases. It is an attractive drug target for cancer treatment and inhibition of its expression or activity constitute a novel therapeutic intervention strategy to prevent the development of various cancers. However, previous strategies for Wip1 suppression may be ineffective in cancers lacking p53. Here, we have characterized the activity of a novel Wip1 phosphatase activator, QGC-8–52, in preclinical models of breast malignancies. QGC-8–52 significantly sensitizes the cancer cell lines with p53 deletion to chemotherapeutic agents. This effect was mediated by the Wip1-FOXO3a interaction and subsequent dephosphorylation of Thr487 that resulted, in response to anticancer treatment, in enhancing the transcription activity of FOXO3a on the proapoptotic TRAIL gene. The sensitizing effect of Wip1 activation on chemotherapeutic drugs only targeted cancer cells lacking p53. The activation of Wip1 in normal cells provided protection from anticancer drug-induced apoptosis by reducing the strength of upstream signaling to p53. Therefore, during the treatment of anticancer drugs, the activated Wip1 phosphatase boosts the apoptosis of p53-negative tumors and protects normal tissues. Our findings may represent an effective and safe therapeutic strategy for cancers with p53 deletion.
PP2C丝氨酸-苏氨酸磷酸酶Wip1在正常组织稳态、应激信号传导和多种人类疾病的发病机制中发挥重要作用。它是一种有吸引力的癌症治疗药物靶点,抑制其表达或活性是预防各种癌症发展的一种新的治疗干预策略。然而,先前的Wip1抑制策略在缺乏p53的癌症中可能无效。在这里,我们描述了一种新的Wip1磷酸酶激活剂QGC-8-52在乳腺恶性肿瘤临床前模型中的活性。QGC-8-52对p53缺失的癌细胞对化疗药物有明显的增敏作用。这种作用是由Wip1-FOXO3a相互作用和随后Thr487的去磷酸化介导的,在抗癌治疗的反应中,FOXO3a对促凋亡TRAIL基因的转录活性增强。Wip1激活对化疗药物的增敏作用仅针对缺乏p53的癌细胞。在正常细胞中,Wip1的激活通过降低p53上游信号的强度,为抗癌药物诱导的细胞凋亡提供保护。因此,在抗癌药物治疗过程中,激活的Wip1磷酸酶促进p53阴性肿瘤的凋亡,保护正常组织。我们的研究结果可能为p53缺失的癌症提供了一种有效和安全的治疗策略。
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引用次数: 0
WITHDRAWN: Low miR-224-5p in exosomes confers colorectal cancer 5-FU resistance by upregulating S100A4 外泌体中的低miR-224-5p通过上调S100A4赋予结直肠癌5-FU抗性
IF 24.3 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-12-16 DOI: 10.1016/j.drup.2024.101193
Yan-yan Yan, Zhuo-fen Deng, Xing-tao Wu, Yu Lu, Zhuang-yan Zhu, Qing Wen, Wei Zhang, Hai-yan Zhang, Xin-zhu Chen, Yu-song Wu, Xue-bing He, Zi-ang Ma, Jin-shuo Li, Hong Bi, Jian-ye Zhang
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引用次数: 0
Association of idealized amphiphiles and protease inhibitors: Conferring antimicrobial peptides with stable antibacterial activity under physiological conditions to combat multidrug-resistant bacteria 理想的两亲体和蛋白酶抑制剂的关联:赋予抗菌肽在生理条件下具有稳定的抗菌活性,以对抗多重耐药细菌。
IF 15.8 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-12-09 DOI: 10.1016/j.drup.2024.101183
Yongjie Zhu , Bowen Li , Wanying Xu, Yuanmengxue Wang, Guoyu Li, Chongpeng Bi, Anshan Shan, Changxuan Shao

Aims

The unstable antimicrobial activity of antimicrobial peptides (AMPs) under physiological conditions (especially the degradation instigated proteases) seems to be a persistent impediment for their successful implementation in clinical trials. Consequently, our objective was to devise AMP engineering frameworks that could sustain robust antibacterial efficacy within physiological environments.

Methods

In this work, we harvested AMPs with stable antimicrobial activity under the physiological barriers through the combination of idealized amphiphiles and trypsin inhibitors.

Results

We screened and identified the lead peptides IK3-A and IK3-S, which showed potent activity against Gram-negative bacteria, including multidrug-resistant (MDR) bacteria, and exhibited promising biocompatibility with mammalian cells. Remarkably, IK3-A and IK3-S maintained sustained antibacterial potency under physiological salts, serum, and protease conditions. Furthermore, both IK3-A and IK3-S kill Gram-negative bacteria by attacking the bacterial cell membrane and inducing oxidative damage (at high concentrations). Crucially, IK3-A and IK3-S have optimal safety and efficacy in mice.

Conclusions

This is the first work to compare the effects of different trypsin inhibitors on the resistance of AMPs to protease hydrolysis on the same sequence platform. In conclusion, these findings provide guidance for the molecular design of AMPs with stable antibacterial activity under physiological conditions and facilitates the process of clinical translation of AMPs as antimicrobial biomaterials against MDR bacteria. Moreover, this may stimulate a more general interest in protease inhibitors as molecular scaffolds in the creation of highly stable peptide-based biomaterials.
目的:抗菌肽(AMPs)在生理条件下不稳定的抗菌活性(尤其是降解引发的蛋白酶)似乎是其在临床试验中成功实施的持续障碍。因此,我们的目标是设计AMP工程框架,可以在生理环境中保持强大的抗菌功效。方法:通过理想的两亲体与胰蛋白酶抑制剂的结合,在生理屏障下获得具有稳定抗菌活性的抗菌肽。结果:我们筛选并鉴定了IK3-A和IK3-S先导肽,它们对革兰氏阴性菌(包括耐多药细菌)具有有效的活性,并且与哺乳动物细胞具有良好的生物相容性。值得注意的是,IK3-A和IK3-S在生理盐、血清和蛋白酶条件下保持了持续的抗菌效力。此外,IK3-A和IK3-S通过攻击细菌细胞膜并诱导氧化损伤(高浓度)杀死革兰氏阴性细菌。关键是,IK3-A和IK3-S在小鼠中具有最佳的安全性和有效性。结论:本文首次比较了不同胰蛋白酶抑制剂对AMPs在同一序列平台上的蛋白酶水解抗性的影响。综上所述,这些发现为生理条件下抗菌活性稳定的抗菌肽分子设计提供了指导,并促进了抗菌肽作为耐多药耐药细菌抗菌生物材料的临床转化过程。此外,这可能会激发人们对蛋白酶抑制剂作为制造高度稳定的肽基生物材料的分子支架的更普遍的兴趣。
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引用次数: 0
Why and how citrate may sensitize malignant tumors to immunotherapy 柠檬酸盐为何以及如何使恶性肿瘤对免疫疗法敏感
IF 15.8 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-11-26 DOI: 10.1016/j.drup.2024.101177
Philippe Icard , Mathilde Prieto , Antoine Coquerel , Ludovic Fournel , Joseph Gligorov , Johanna Noel , Adrien Mouren , Anthony Dohan , Marco Alifano , Luca Simula
Immunotherapy, either alone or in combination with chemotherapy, has demonstrated limited efficacy in a variety of solid cancers. Several factors contribute to explaining primary or secondary resistance. Among them, cancer cells, whose metabolism frequently relies on aerobic glycolysis, promote exhaustion of cytotoxic immune cells by diverting the glucose in the tumor microenvironment (TME) to their own profit, while secreting lactic acid that sustains the oxidative metabolism of immunosuppressive cells. Here, we propose to combine current treatment based on the use of immune checkpoint inhibitors (ICIs) with high doses of sodium citrate (SCT) because citrate inhibits cancer cell metabolism (by targeting both glycolysis and oxidative metabolism) and may active anti-tumor immune response. Indeed, as showed in preclinical studies, SCT reduces cancer cell growth, promoting cell death and chemotherapy effectiveness. Furthermore, since the plasma membrane citrate carrier pmCIC is mainly expressed in cancer cells and low or not expressed in immune and non-transformed cells, we argue that the inhibition of cancer cell metabolism by SCT may increase glucose availability in the TME, thus promoting functionality of anti-tumor immune cells. Concomitantly, the decrease in the amount of lactic acid in the TME may reduce the functionality of immunosuppressive cells. Preclinical studies have shown that SCT can enhance the anti-tumor immune response through an enhancement of T cell infiltration and activation, and a repolarization of macrophages towards a TAM1-like phenotype. Therefore, this simple and cheap strategy may have a major impact to increase the efficacy of current immunotherapies in human solid tumors and we encourage testing it in clinical trials.
免疫疗法,无论是单独使用还是与化疗联合使用,在多种实体癌中的疗效都很有限。原发性或继发性抗药性的产生有多种因素。其中,癌细胞的新陈代谢经常依赖有氧糖酵解,它们通过将肿瘤微环境(TME)中的葡萄糖转用于自身获利,同时分泌乳酸维持免疫抑制细胞的氧化代谢,从而促进细胞毒性免疫细胞的衰竭。在此,我们建议将目前基于使用免疫检查点抑制剂(ICIs)的治疗方法与大剂量柠檬酸钠(SCT)相结合,因为柠檬酸钠能抑制癌细胞代谢(通过靶向糖酵解和氧化代谢),并能活跃抗肿瘤免疫反应。事实上,正如临床前研究显示的那样,SCT 可减少癌细胞生长,促进细胞死亡,提高化疗效果。此外,由于质膜柠檬酸载体 pmCIC 主要在癌细胞中表达,而在免疫细胞和非转化细胞中表达较低或不表达,我们认为 SCT 对癌细胞代谢的抑制可能会增加 TME 中葡萄糖的可用性,从而促进抗肿瘤免疫细胞的功能。同时,TME 中乳酸量的减少可能会降低免疫抑制细胞的功能。临床前研究表明,SCT 可以通过增强 T 细胞的浸润和活化,以及使巨噬细胞向 TAM1 样表型的再极化来增强抗肿瘤免疫反应。因此,这种简单而廉价的策略可能会对提高当前免疫疗法在人类实体瘤中的疗效产生重大影响,我们鼓励在临床试验中进行测试。
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引用次数: 0
Blockade of purine metabolism reverses macrophage immunosuppression and enhances anti-tumor immunity in non-small cell lung cancer 阻断嘌呤代谢可逆转巨噬细胞免疫抑制,增强非小细胞肺癌的抗肿瘤免疫力
IF 15.8 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-11-23 DOI: 10.1016/j.drup.2024.101175
Li Yang , Aitian Li , Weina Yu , Huishang Wang , Lei Zhang , Dan Wang , Ying Wang , Ru Zhang , Qingyang Lei , Zhangnan Liu , Shanshan Zhen , Haiming Qin , Yaqing Liu , Yang Yang , Xian-Lu Song , Yi Zhang

Aims

Immune checkpoint blockade therapy is not effective in most patients with non-small cell lung cancer (NSCLC) due to the immunosuppressive tumor microenvironment. Macrophages are key components of tumor-infiltrating immune cells and play a critical role in immunosuppression, which can be mediated by cell-intrinsic metabolism. This study aimed to evaluate whether macrophages regulate NSCLC progression through metabolic crosstalk with cancer cells and affect immunotherapy efficacy.

Methods

The macrophage landscape of NSCLC tissues were analyzed by single-cell sequencing and verified through flow cytometry and immunofluorescence. Multiplex assay, single-cell sequencing data, ELISA, immunofluorescence, and RNA-seq et al. were used to investigate and verify the mechanism of macrophage-mediated metabolic regulation on immunosuppression. The tumor-bearing model was established in C57BL/6 J mice to explore in vivo efficacy.

Results

We found that tumor tissue-derived macrophages exhibited an anti-inflammatory phenotype and had a prognostic value for NSCLC. NSCLC cell-secreted CXCL8 recruited macrophages from peritumor tissues to tumor sites and promoted programmed death-ligand 1 (PD-L1) expression by activating purine metabolism with increasing xanthine dehydrogenase and uric acid production. Moreover, purine metabolism-mediated macrophage immunosuppression was dependent on NLRP3/caspase-1/IL-1β signaling. Blockade of purine metabolism signaling enhanced anti-tumor immunity and the efficacy of anti-PD-L1 therapy.

Conclusions

Collectively, our findings reveal a key role of purine metabolism in macrophage immunosuppression and suggest that blockade of purine metabolism combined with immune checkpoint blockade could provide synergistic effects in NSCLC treatment.
目的 由于肿瘤微环境具有免疫抑制作用,免疫检查点阻断疗法对大多数非小细胞肺癌(NSCLC)患者无效。巨噬细胞是肿瘤浸润免疫细胞的关键组成部分,在免疫抑制中发挥着关键作用,而免疫抑制可由细胞内在代谢介导。本研究旨在评估巨噬细胞是否通过与癌细胞的代谢串扰调控NSCLC的进展并影响免疫疗法的疗效。方法通过单细胞测序分析NSCLC组织的巨噬细胞情况,并通过流式细胞术和免疫荧光进行验证。采用多重检测、单细胞测序数据、ELISA、免疫荧光和RNA-seq等方法研究和验证巨噬细胞介导的代谢调控对免疫抑制的作用机制。结果我们发现,肿瘤组织来源的巨噬细胞表现出抗炎表型,对 NSCLC 有预后价值。NSCLC 细胞分泌的 CXCL8 将巨噬细胞从肿瘤周围组织招募到肿瘤部位,并通过激活嘌呤代谢,增加黄嘌呤脱氢酶和尿酸的产生,促进程序性死亡配体 1(PD-L1)的表达。此外,嘌呤代谢介导的巨噬细胞免疫抑制依赖于NLRP3/caspase-1/IL-1β信号传导。总之,我们的研究结果揭示了嘌呤代谢在巨噬细胞免疫抑制中的关键作用,并表明阻断嘌呤代谢与免疫检查点阻断相结合可在NSCLC治疗中产生协同效应。
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引用次数: 0
Post-translational modifications in drug resistance 抗药性中的翻译后修饰
IF 15.8 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-11-21 DOI: 10.1016/j.drup.2024.101173
Chenggui Miao , Yurong Huang , Cheng Zhang , Xiao Wang , Bing Wang , Xinyue Zhou , Yingqiu Song , Peng Wu , Zhe-Sheng Chen , Yibin Feng
Resistance to antitumor drugs, antimicrobial drugs, and antiviral drugs severely limits treatment effectiveness and cure rate of diseases. Protein post-translational modifications (PTMs) represented by glycosylation, ubiquitination, SUMOylation, acetylation, phosphorylation, palmitoylation, and lactylation are closely related to drug resistance. PTMs are typically achieved by adding sugar chains (glycosylation), small proteins (ubiquitination), lipids (palmitoylation), or functional groups (lactylation) to amino acid residues. These covalent additions are usually the results of signaling cascades and could be reversible, with the triggering mechanisms depending on the type of modifications. PTMs are involved in antitumor drug resistance, not only as inducers of drug resistance but also as targets for reversing drug resistance. Bacteria exhibit multiple PTMs-mediated antimicrobial drug resistance. PTMs allow viral proteins and host cell proteins to form complex interaction networks, inducing complex antiviral drug resistance. This review summarizes the important roles of PTMs in drug resistance, providing new ideas for exploring drug resistance mechanisms, developing new drug targets, and guiding treatment plans.
抗肿瘤药物、抗菌药物和抗病毒药物的抗药性严重限制了疾病的治疗效果和治愈率。以糖基化、泛素化、SUMOylation、乙酰化、磷酸化、棕榈酰化和乳酰化为代表的蛋白质翻译后修饰(PTM)与耐药性密切相关。PTM 通常是通过在氨基酸残基上添加糖链(糖基化)、小蛋白(泛素化)、脂质(棕榈酰化)或功能基团(乳化)来实现的。这些共价添加通常是信号级联的结果,可能是可逆的,触发机制取决于修饰的类型。PTMs 与抗肿瘤药物耐药性有关,不仅是耐药性的诱因,也是逆转耐药性的靶点。细菌表现出多种 PTMs 介导的抗菌药物耐药性。PTMs 使病毒蛋白质和宿主细胞蛋白质形成复杂的相互作用网络,诱导复杂的抗病毒药物耐药性。本综述总结了 PTMs 在耐药性中的重要作用,为探索耐药机制、开发新的药物靶点和指导治疗方案提供了新思路。
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引用次数: 0
AI-driven visualization tool for analyzing data and predicting drug-resistant outbreaks 人工智能驱动的可视化工具,用于分析数据和预测耐药性爆发。
IF 15.8 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-11-19 DOI: 10.1016/j.drup.2024.101174
Yoshiyasu Takefuji
A tool was developed to identify potential disease outbreaks using pathogen and serotype data. By analyzing isolate numbers and comparing them to a two-year average, the tool highlights anomalies suggestive of outbreaks. When applied to Salmonella data, it revealed potential outbreaks related to specific serotypes.
我们开发了一种工具,利用病原体和血清型数据来识别潜在的疾病爆发。通过分析分离物数量并将其与两年平均值进行比较,该工具可突出显示可能爆发疾病的异常情况。当应用于沙门氏菌数据时,它揭示了与特定血清型有关的潜在疫情爆发。
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引用次数: 0
Autophagy in cancer development, immune evasion, and drug resistance 癌症发展、免疫逃避和抗药性中的自噬作用
IF 15.8 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-11-15 DOI: 10.1016/j.drup.2024.101170
Xuegang Niu , Qi You , Kaijian Hou , Yu Tian , Penghui Wei , Yang Zhu , Bin Gao , Milad Ashrafizadeh , Amir Reza Aref , Alireza Kalbasi , Israel Cañadas , Gautam Sethi , Vinay Tergaonkar , Lingzhi Wang , Yuanxiang Lin , Dezhi Kang , Daniel J. Klionsky
Macroautophagy/autophagy is a highly conserved evolutionary mechanism involving lysosomes for the degradation of cytoplasmic components including organelles. The constitutive, basal level of autophagy is fundamental for preserving cellular homeostasis; however, alterations in autophagy can cause disease pathogenesis, including cancer. The role of autophagy in cancer is particularly complicated, since this process acts both as a tumor suppressor in precancerous stages but facilitates tumor progression during carcinogenesis and later stages of cancer progression. This shift between anti-tumor and pro-tumor roles may be influenced by genetic and environmental factors modulating key pathways such as those involving autophagy-related proteins, the PI3K-AKT-MTOR axis, and AMPK, which often show dysregulation in tumors. Autophagy regulates various cellular functions, including metabolism of glucose, glutamine, and lipids, cell proliferation, metastasis, and several types of cell death (apoptosis, ferroptosis, necroptosis and immunogenic cell death). These multifaceted roles demonstrate the potential of autophagy to affect DNA damage repair, cell death pathways, proliferation and survival, which are critical in determining cancer cells’ response to chemotherapy. Therefore, targeting autophagy pathways presents a promising strategy to combat chemoresistance, as one of the major reasons for the failure in cancer patient treatment. Furthermore, autophagy modulates immune evasion and the function of immune cells such as T cells and dendritic cells, influencing the tumor microenvironment and cancer’s biological behavior. However, the therapeutic targeting of autophagy is complex due to its dual role in promoting survival and inducing cell death in cancer cells, highlighting the need for strategies that consider both the beneficial and detrimental effects of autophagy modulation in cancer therapy. Hence, both inducers and inhibitors of autophagy have been introduced for the treatment of cancer. This review emphasizes the intricate interplay between autophagy, tumor biology, and immune responses, offering insights into potential therapeutic approaches that deploy autophagy in the cancer suppression.
大自噬/自噬是一种高度保守的进化机制,涉及溶酶体对细胞质成分(包括细胞器)的降解。自噬的组成性基础水平是维持细胞稳态的基础;然而,自噬的改变可导致疾病的发病,包括癌症。自噬在癌症中的作用尤为复杂,因为这一过程在癌前病变阶段既是肿瘤抑制因子,又在癌变和癌症后期发展阶段促进肿瘤进展。这种抗肿瘤和促肿瘤作用之间的转变可能受遗传和环境因素调节关键通路的影响,如涉及自噬相关蛋白、PI3K-AKT-MTOR 轴和 AMPK 的通路。自噬调节各种细胞功能,包括葡萄糖、谷氨酰胺和脂质的新陈代谢、细胞增殖、转移和几种类型的细胞死亡(凋亡、铁凋亡、坏死和免疫性细胞死亡)。这些多方面的作用表明,自噬有可能影响 DNA 损伤修复、细胞死亡途径、增殖和存活,而这对于决定癌细胞对化疗的反应至关重要。因此,自噬通路是抗击化疗耐药性的一种前景广阔的策略,而化疗耐药性是癌症患者治疗失败的主要原因之一。此外,自噬还能调节免疫逃避和免疫细胞(如 T 细胞和树突状细胞)的功能,影响肿瘤微环境和癌症的生物学行为。然而,由于自噬在促进癌细胞存活和诱导细胞死亡方面具有双重作用,因此针对自噬的治疗非常复杂,这突出表明在癌症治疗中需要同时考虑自噬调节的有利和不利影响。因此,自噬的诱导剂和抑制剂都被引入到癌症治疗中。这篇综述强调了自噬、肿瘤生物学和免疫反应之间错综复杂的相互作用,深入探讨了利用自噬抑制癌症的潜在治疗方法。
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引用次数: 0
Modeling the epidemiologic impact of age-targeted vaccination for drug-resistant tuberculosis 针对抗药性结核病的年龄目标疫苗接种的流行病学影响建模。
IF 15.8 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-11-13 DOI: 10.1016/j.drup.2024.101172
Pei-Yao Zhai , Zhi-Xian Chen , Ting Jiang , Jian Feng , Bin Zhang , Xiao Zang , Yan-Lin Zhao , Gang Qin
This study used a calibrated mathematical model to evaluate age-specific tuberculosis (TB) vaccination strategies, for drug-resistant (DR)-TB management in China. Prioritizing elderly vaccination significantly reduced multidrug-resistant or rifampicin-resistant TB incidence and mortality, while avoiding the need for second-line treatment, offering a promising approach to mitigate DR-TB burden by 2050.
本研究利用校准数学模型评估了针对特定年龄段的结核病(TB)疫苗接种策略,以管理中国的耐药结核病(DRTB)。优先为老年人接种疫苗可显著降低耐多药或耐利福平结核病的发病率和死亡率,同时避免二线治疗的需要,为到2050年减轻耐药结核病的负担提供了一种可行的方法。
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引用次数: 0
Zebrafish patient-derived xenograft system for predicting carboplatin resistance and metastasis of ovarian cancer 用于预测卡铂耐药性和卵巢癌转移的斑马鱼患者衍生异种移植系统
IF 15.8 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-11-09 DOI: 10.1016/j.drup.2024.101162
Feifeng Song , Xiaofen Yi , Xiaowei Zheng , Zhentao Zhang , Linqian Zhao , Yan Shen , Ye Zhi , Ting Liu , Xiaozhen Liu , Tong Xu , Xiaoping Hu , Yiwen Zhang , Huafeng Shou , Ping Huang

Aims

Ovarian cancer (OC) remains a significant challenge in oncology due to high rates of drug resistance and disease relapse following standard treatment with surgery and platinum-based chemotherapy. Despite the widespread use of these treatments, no effective biomarkers currently exist to identify which patients will respond favorably to therapy. This study introduces a zebrafish patient-derived xenograft (PDX) system, capable of replicating both the carboplatin response and metastatic behavior observed in OC patients, within a rapid 3-day assay period.

Methods

Two OC cell lines: carboplatin-sensitive (A2780) and resistant (OVCAR8) were used to assess differential responses to treatment in murine and zebrafish xenograft models. Tumor tissues from 16 OC patients were implanted into zebrafish embryos to test carboplatin responses and predict metastasis. Additionally, eight clinical OC samples were directly implanted into zebrafish embryos as part of a proof-of-concept demonstration.

Results

The zebrafish xenografts accurately reflected the carboplatin sensitivity and resistance patterns seen in in vitro and murine models. The zebrafish PDX model demonstrated a 67 % success rate for implantation and a 100 % success rate for engraftment. Notably, the model effectively distinguished between metastatic and non-metastatic disease, with an area under the ROC curve (AUC) of 0.818. Furthermore, the zebrafish PDX model showed a high concordance with patient-specific responses to carboplatin.

Conclusions

This zebrafish PDX model offers a fast, accurate, and clinically relevant platform for evaluating carboplatin response and predicting metastasis in OC patients. It holds significant potential for advancing personalized medicine, allowing for more precise therapeutic outcome predictions and individualized treatment strategies.
目的:卵巢癌(OC)在接受手术和铂类化疗的标准治疗后,耐药率和复发率很高,因此它仍然是肿瘤学领域的一项重大挑战。尽管这些治疗方法被广泛使用,但目前还没有有效的生物标志物来确定哪些患者会对治疗产生良好反应。本研究引入了一种斑马鱼患者衍生异种移植(PDX)系统,它能在 3 天的快速检测期内复制在 OC 患者身上观察到的卡铂反应和转移行为:方法:使用两种 OC 细胞系:卡铂敏感型(A2780)和耐药型(OVCAR8)来评估小鼠和斑马鱼异种移植模型对治疗的不同反应。将 16 名 OC 患者的肿瘤组织植入斑马鱼胚胎,以测试卡铂反应并预测转移。此外,作为概念验证的一部分,8 个临床 OC 样本被直接植入斑马鱼胚胎:结果:斑马鱼异种移植准确反映了体外和小鼠模型中的卡铂敏感性和耐药性模式。斑马鱼 PDX 模型的植入成功率为 67%,移植成功率为 100%。值得注意的是,该模型能有效区分转移性和非转移性疾病,ROC 曲线下面积 (AUC) 为 0.818。此外,斑马鱼 PDX 模型与患者对卡铂的特异性反应高度一致:该斑马鱼 PDX 模型为评估卡铂反应和预测 OC 患者的转移提供了一个快速、准确且与临床相关的平台。它在推进个性化医疗、实现更精确的治疗结果预测和个体化治疗策略方面具有巨大潜力。
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引用次数: 0
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Drug Resistance Updates
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