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Overcoming immuno-resistance by rescheduling anti-VEGF/cytotoxics/anti-PD-1 combination in lung cancer model. 在肺癌模型中重新安排抗血管内皮生长因子/细胞毒素/抗-PD-1联合疗法,克服免疫耐受。
Q1 ONCOLOGY Pub Date : 2024-03-14 eCollection Date: 2024-01-01 DOI: 10.20517/cdr.2023.146
Guillaume Sicard, Dorian Protzenko, Sarah Giacometti, Fabrice Barlési, Joseph Ciccolini, Raphaelle Fanciullino

Background: Many tumors are refractory to immune checkpoint inhibitors, but their combination with cytotoxics is expected to improve sensitivity. Understanding how and when cytotoxics best re-stimulate tumor immunity could help overcome resistance to immune checkpoint inhibitors. Methods: In vivo studies were performed in C57BL/6 mice grafted with immune-refractory LL/2 lung cancer model. A longitudinal immunomonitoring study on tumor, spleen, and blood after multiple treatments including Cisplatin, Pemetrexed, and anti-VEGF, either alone or in combination, was performed, spanning a period of up to 21 days, to determine the optimal time window during which immune checkpoint inhibitors should be added. Finally, an efficacy study was conducted comparing the antiproliferative performance of various schedules of anti-VEGF, Pemetrexed-Cisplatin doublet, plus anti-PD-1 (i.e., immunomonitoring-guided scheduling, concurrent dosing or a random sequence), as well as single agent anti-PD1. Results: Immunomonitoring showed marked differences between treatments, organs, and time points. However, harnessing tumor immunity (i.e., promoting CD8 T cells or increasing the T CD8/Treg ratio) started on D7 and peaked on D14 with the anti-VEGF followed by cytotoxics combination. Therefore, a 14-day delay between anti-VEGF/cytotoxic and anti-PD1 administration was considered the best sequence to test. Efficacy studies then confirmed that this sequence achieved higher antiproliferative efficacy compared to other treatment modalities (i.e., -71% in tumor volume compared to control). Conclusions: Anti-VEGF and cytotoxic agents show time-dependent immunomodulatory effects, suggesting that sequencing is a critical feature when combining these agents with immune checkpoint inhibitors. An efficacy study confirmed that sequencing treatments further enhance antiproliferative effects in lung cancer models compared to concurrent dosing and partly reverse the resistance to cytotoxics and anti-PD1.

背景:许多肿瘤对免疫检查点抑制剂难治,但将其与细胞毒性药物联合使用有望提高敏感性。了解细胞毒素如何以及何时最有效地重新刺激肿瘤免疫有助于克服对免疫检查点抑制剂的耐药性。研究方法在移植了免疫难治性LL/2肺癌模型的C57BL/6小鼠中进行体内研究。在包括顺铂、培美曲塞和抗血管内皮生长因子(单独或联合)在内的多种治疗后,对肿瘤、脾脏和血液进行了长达 21 天的纵向免疫监测研究,以确定添加免疫检查点抑制剂的最佳时间窗。最后,还进行了一项疗效研究,比较了抗血管内皮生长因子、培美曲塞-顺铂双药加抗PD-1(即免疫监测指导下的排期、同时给药或随机排期)以及单药抗PD-1的抗增殖性能。结果显示免疫监测显示不同治疗、器官和时间点之间存在明显差异。然而,利用肿瘤免疫(即促进 CD8 T 细胞或增加 T CD8/Treg 比率)始于第 7 天,在抗血管内皮生长因子和细胞毒联合治疗的第 14 天达到高峰。因此,抗血管内皮生长因子/细胞毒素和抗 PD1 的给药间隔 14 天被认为是最佳的试验顺序。随后进行的疗效研究证实,与其他治疗方式相比,这种顺序能取得更高的抗增殖疗效(即与对照组相比,肿瘤体积减少 71%)。结论抗血管内皮生长因子和细胞毒性药物显示出时间依赖性免疫调节效应,这表明在将这些药物与免疫检查点抑制剂联合使用时,排序是一个关键特征。一项疗效研究证实,与同时给药相比,序贯疗法能进一步增强肺癌模型的抗增殖效果,并能部分逆转对细胞毒性药物和抗 PD1 的耐药性。
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引用次数: 0
Circular RNA circNCOA3 promotes tumor progression and anti-PD-1 resistance in colorectal cancer. 环状 RNA circNCOA3 促进结直肠癌的肿瘤进展和抗 PD-1 抗性。
Q1 ONCOLOGY Pub Date : 2024-03-13 eCollection Date: 2024-01-01 DOI: 10.20517/cdr.2023.151
Dong-Liang Chen, Nuo Chen, Hui Sheng, Dong-Sheng Zhang

Aim: Circular RNAs (circRNAs) have been found to be involved in tumor progression, but their role in colorectal cancer (CRC) immune escape remains to be elucidated. Methods: circRNAs differentially expressed in responsive and resistant CRC tissues to programmed cell death 1 (PD-1) antibody therapy were identified by microarray analysis. The clinical and pathological significance of circNCOA3 was validated in a separate cohort of CRC samples. The function of circNCOA3 was explored experimentally. RNA immunoprecipitation and luciferase activity assays were conducted to identify downstream targets of circNCOA3. Results: The circNCOA3 was markedly overexpressed in CRC samples resistant to PD-1 blockade. circNCOA3 expression was significantly correlated with adverse tumor phenotypes and poor outcomes in CRC patients. Knockdown of circNCOA3 expression markedly suppressed the proliferative and invasive capability of CRC cells. Moreover, knockdown of circNCOA3 increased the proportion of CD8+ T cells while decreasing the proportion of myeloid-derived suppressor cells (MDSCs). Knockdown of circNCOA3 inhibited tumor growth and increased the sensitivity to PD-1 antibody treatment in mouse tumor models. Further studies revealed that circNCOA3 acted as a competing endogenous RNA (ceRNA) for miR-203a-3p.1 to influence the level of CXCL1. Conclusion: Our findings indicate that circNCOA3 might be useful as a potential biomarker to predict the efficacy and prognosis of CRC patients treated with anti-PD-1 therapy.

目的:已发现环状 RNA(circRNA)参与肿瘤进展,但它们在结直肠癌(CRC)免疫逃逸中的作用仍有待阐明。方法:通过芯片分析确定了对程序性细胞死亡1(PD-1)抗体治疗有反应和无反应的CRC组织中表达不同的circRNA。在一组单独的 CRC 样本中验证了 circNCOA3 的临床和病理意义。实验探索了 circNCOA3 的功能。进行了 RNA 免疫沉淀和荧光素酶活性测定,以确定 circNCOA3 的下游靶点。结果发现circNCOA3的表达与CRC患者的不良肿瘤表型和不良预后显著相关。敲除 circNCOA3 表达可明显抑制 CRC 细胞的增殖和侵袭能力。此外,敲除 circNCOA3 还能增加 CD8+ T 细胞的比例,同时降低髓源性抑制细胞(MDSCs)的比例。在小鼠肿瘤模型中,敲除 circNCOA3 可抑制肿瘤生长并提高对 PD-1 抗体治疗的敏感性。进一步研究发现,circNCOA3 是 miR-203a-3p.1 的竞争性内源性 RNA(ceRNA),可影响 CXCL1 的水平。结论我们的研究结果表明,circNCOA3 可作为一种潜在的生物标记物,用于预测接受抗 PD-1 治疗的 CRC 患者的疗效和预后。
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引用次数: 0
Regulation of Nrf2/Keap1 signaling pathway in cancer drug resistance by galectin-1: cellular and molecular implications. galectin-1在癌症耐药性中对Nrf2/Keap1信号通路的调控:细胞和分子意义。
Q1 ONCOLOGY Pub Date : 2024-02-29 eCollection Date: 2024-01-01 DOI: 10.20517/cdr.2023.79
İlhan Yaylim, Melek Aru, Ammad Ahmad Farooqi, Mehmet Tolgahan Hakan, Brigitta Buttari, Marzia Arese, Luciano Saso

Oxidative stress is characterized by the deregulation of the redox state in the cells, which plays a role in the initiation of various types of cancers. The activity of galectin-1 (Gal-1) depends on the cell redox state and the redox state of the microenvironment. Gal-1 expression has been related to many different tumor types, as it plays important roles in several processes involved in cancer progression, such as apoptosis, cell migration, adhesion, and immune response. The erythroid-2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1) signaling pathway is a crucial mechanism involved in both cell survival and cell defense against oxidative stress. In this review, we delve into the cellular and molecular roles played by Gal-1 in the context of oxidative stress onset in cancer cells, particularly focusing on its involvement in activating the Nrf2/Keap1 signaling pathway. The emerging evidence concerning the anti-apoptotic effect of Gal-1, together with its ability to sustain the activation of the Nrf2 pathway in counteracting oxidative stress, supports the role of Gal-1 in the promotion of tumor cells proliferation, immuno-suppression, and anti-tumor drug resistance, thus highlighting that the inhibition of Gal-1 emerges as a potential strategy for the restraint and regression of tumor progression. Overall, a deeper understanding of the multi-functionality and disease-specific expression profiling of Gal-1 will be crucial for the design and development of novel Gal-1 inhibitors as anticancer agents. Excitingly, although it is still understudied, the ever-growing knowledge of the sophisticated interplay between Gal-1 and Nrf2/Keap1 will enable researchers to gain valuable insights into the underlying causes of carcinogenesis and metastasis.

氧化应激的特征是细胞内氧化还原状态的失调,它在各种癌症的诱发过程中起着重要作用。Galectin-1(Gal-1)的活性取决于细胞的氧化还原状态和微环境的氧化还原状态。Gal-1 的表达与许多不同类型的肿瘤有关,因为它在涉及癌症进展的几个过程中起着重要作用,如细胞凋亡、细胞迁移、粘附和免疫反应。红细胞-2相关因子2(Nrf2)/Kelch样ECH相关蛋白1(Keap1)信号通路是参与细胞存活和细胞防御氧化应激的重要机制。在这篇综述中,我们将深入探讨 Gal-1 在癌细胞氧化应激发生过程中发挥的细胞和分子作用,尤其是它在激活 Nrf2/Keap1 信号通路中的参与。有关 Gal-1 抗凋亡作用的新证据,以及 Gal-1 在对抗氧化应激过程中维持 Nrf2 通路激活的能力,支持了 Gal-1 在促进肿瘤细胞增殖、免疫抑制和抗肿瘤药物耐药性方面的作用,从而强调了抑制 Gal-1 成为抑制和抑制肿瘤发展的潜在策略。总之,深入了解 Gal-1 的多功能性和疾病特异性表达谱对于设计和开发新型 Gal-1 抑制剂作为抗癌药物至关重要。令人兴奋的是,尽管对 Gal-1 和 Nrf2/Keap1 之间复杂的相互作用的研究仍然不足,但不断增长的知识将使研究人员能够对致癌和转移的根本原因获得有价值的见解。
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引用次数: 0
Novel players in the development of chemoresistance in ovarian cancer: ovarian cancer stem cells, non-coding RNA and nuclear receptors. 卵巢癌化疗耐药性发展过程中的新角色:卵巢癌干细胞、非编码 RNA 和核受体。
Q1 ONCOLOGY Pub Date : 2024-02-28 eCollection Date: 2024-01-01 DOI: 10.20517/cdr.2023.152
Shahil Alam, Pankaj Kumar Giri

Ovarian cancer (OC) ranks as the fifth leading factor for female mortality globally, with a substantial burden of new cases and mortality recorded annually. Survival rates vary significantly based on the stage of diagnosis, with advanced stages posing significant challenges to treatment. OC is primarily categorized as epithelial, constituting approximately 90% of cases, and correct staging is essential for tailored treatment. The debulking followed by chemotherapy is the prevailing treatment, involving platinum-based drugs in combination with taxanes. However, the efficacy of chemotherapy is hindered by the development of chemoresistance, both acquired during treatment (acquired chemoresistance) and intrinsic to the patient (intrinsic chemoresistance). The emergence of chemoresistance leads to increased mortality rates, with many advanced patients experiencing disease relapse shortly after initial treatment. This review delves into the multifactorial nature of chemoresistance in OC, addressing mechanisms involving transport systems, apoptosis, DNA repair, and ovarian cancer stem cells (OCSCs). While previous research has identified genes associated with these mechanisms, the regulatory roles of non-coding RNA (ncRNA) and nuclear receptors in modulating gene expression to confer chemoresistance have remained poorly understood and underexplored. This comprehensive review aims to shed light on the genes linked to different chemoresistance mechanisms in OC and their intricate regulation by ncRNA and nuclear receptors. Specifically, we examine how these molecular players influence the chemoresistance mechanism. By exploring the interplay between these factors and gene expression regulation, this review seeks to provide a comprehensive mechanism driving chemoresistance in OC.

卵巢癌(OC)是导致全球女性死亡的第五大因素,每年新增病例和死亡率都很高。根据诊断阶段的不同,存活率也大不相同,晚期卵巢癌给治疗带来了巨大挑战。卵巢癌主要分为上皮性,约占病例的 90%,正确的分期对于针对性治疗至关重要。目前最常用的治疗方法是切除肿瘤,然后进行化疗,其中包括铂类药物和类固醇类药物。然而,化疗的疗效因化疗耐药性的产生而受到阻碍,化疗耐药性既有治疗过程中获得的(获得性化疗耐药性),也有患者自身固有的(固有化疗耐药性)。化疗耐药性的出现导致死亡率上升,许多晚期患者在接受初始治疗后不久就会复发。本综述深入探讨了卵巢癌化疗耐药性的多因素性质,探讨了涉及转运系统、细胞凋亡、DNA修复和卵巢癌干细胞(OCSCs)的机制。虽然以往的研究已经确定了与这些机制相关的基因,但人们对非编码 RNA(ncRNA)和核受体在调节基因表达以产生化疗抗性方面的调控作用仍然知之甚少,探索不足。本综述旨在阐明与 OC 中不同化疗抗性机制相关的基因及其受 ncRNA 和核受体的复杂调控。具体而言,我们将研究这些分子角色如何影响化疗耐药机制。通过探讨这些因素与基因表达调控之间的相互作用,本综述旨在提供一种全面的 OC 化疗抗性驱动机制。
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引用次数: 0
Leveraging genomics, transcriptomics and epigenomics to understand chemoimmunotherapy resistance in chronic lymphocytic leukemia. 利用基因组学、转录组学和表观基因组学了解慢性淋巴细胞白血病的化疗免疫治疗耐药性。
Q1 ONCOLOGY Pub Date : 2024-02-28 eCollection Date: 2024-01-01 DOI: 10.20517/cdr.2023.98
Shin Yeu Ong, Lili Wang

Patients with chronic lymphocytic leukemia (CLL) have differing clinical outcomes. Recent advances integrating multi-omic data have uncovered molecular subtypes in CLL with different prognostic implications and may allow better prediction of therapy response. While finite-duration chemoimmunotherapy (CIT) has enabled deep responses and prolonged duration of responses in the past, the advent of novel targeted therapy for the treatment of CLL has dramatically changed the therapeutic landscape. In this review, we discuss the latest genomic, transcriptomic, and epigenetic alterations regarded as major drivers of resistance to CIT in CLL. Further advances in genomic medicine will allow for better prediction of response to therapy and provide the basis for rational selection of therapy for long-term remissions with minimal toxicity.

慢性淋巴细胞白血病(CLL)患者的临床预后各不相同。整合多组学数据的最新进展发现了具有不同预后影响的慢性淋巴细胞白血病分子亚型,从而可以更好地预测治疗反应。过去,有限时间化疗免疫疗法(CIT)能够产生深度反应并延长反应持续时间,而治疗 CLL 的新型靶向疗法的出现则极大地改变了治疗格局。在这篇综述中,我们将讨论被视为CLL对CIT产生耐药性的主要驱动因素的最新基因组、转录组和表观遗传学改变。基因组医学的进一步发展将能更好地预测对治疗的反应,并为合理选择治疗方法提供依据,以实现毒性最小的长期缓解。
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引用次数: 0
Reactive oxygen species and its role in pathogenesis and resistance to therapy in acute myeloid leukemia. 活性氧及其在急性髓性白血病发病机制和抗药性中的作用。
Q1 ONCOLOGY Pub Date : 2024-02-22 eCollection Date: 2024-01-01 DOI: 10.20517/cdr.2023.125
Jamshid Sorouri Khorashad, Sian Rizzo, Alex Tonks

Relapse following a short clinical response to therapy is the major challenge for the management of acute myeloid leukemia (AML) patients. Leukemic stem cells (LSC), as the source of relapse, have been investigated for their metabolic preferences and their alterations at the time of relapse. As LSC rely on oxidative phosphorylation (OXPHOS) for energy requirement, reactive oxygen species (ROS), as by-products of OXPHOS, have been investigated for their role in the effectiveness of the standard AML therapy. Increased levels of non-mitochondrial ROS, generated by nicotinamide adenine dinucleotide phosphate oxidase, in a subgroup of AML patients add to the complexity of studying ROS. Although there are various studies presenting the contribution of ROS to AML pathogenesis, resistance, and its inhibition or activation as a target, a model that can clearly explain its role in AML has not been conceptualized. This is due to the heterogeneity of AML, the dynamics of ROS production, which is influenced by factors such as the type of treatment, cell differentiation state, mitochondrial activity, and also the heterogeneous generation of non-mitochondrial ROS and limited available data on their interaction with the microenvironment. This review summarizes these challenges and the recent progress in this field.

急性髓性白血病(AML)患者在短期临床治疗反应后复发是治疗面临的主要挑战。白血病干细胞(LSC)是复发的来源,人们一直在研究它们的代谢偏好及其在复发时的变化。由于白血病干细胞依赖氧化磷酸化(OXPHOS)来获取能量,活性氧(ROS)作为 OXPHOS 的副产物,已被用于研究其在急性髓细胞性白血病标准疗法有效性中的作用。在一部分急性髓细胞性白血病患者中,由烟酰胺腺嘌呤二核苷酸磷酸氧化酶产生的非线粒体 ROS 水平升高,增加了研究 ROS 的复杂性。尽管有各种研究介绍了 ROS 对急性髓细胞性白血病发病机制的贡献、抗药性及其作为靶点的抑制或激活,但尚未形成一个能清楚解释其在急性髓细胞性白血病中作用的模型。这是由于急性髓细胞性白血病的异质性、ROS产生的动态性(受治疗类型、细胞分化状态、线粒体活性等因素的影响)、非线粒体ROS产生的异质性以及它们与微环境相互作用的现有数据有限。本综述总结了这些挑战以及该领域的最新进展。
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引用次数: 0
Glycogen synthase kinase 3β: the nexus of chemoresistance, invasive capacity, and cancer stemness in pancreatic cancer. 糖原合成酶激酶 3β:胰腺癌化疗抗药性、侵袭能力和癌症干细胞的纽带。
Q1 ONCOLOGY Pub Date : 2024-01-31 eCollection Date: 2024-01-01 DOI: 10.20517/cdr.2023.84
Masahiro Uehara, Takahiro Domoto, Satoshi Takenaka, Osamu Takeuchi, Takeo Shimasaki, Tomoharu Miyashita, Toshinari Minamoto

The treatment of pancreatic cancer remains a significant clinical challenge due to the limited number of patients eligible for curative (R0) surgery, failures in the clinical development of targeted and immune therapies, and the pervasive acquisition of chemotherapeutic resistance. Refractory pancreatic cancer is typified by high invasiveness and resistance to therapy, with both attributes related to tumor cell stemness. These malignant characteristics mutually enhance each other, leading to rapid cancer progression. Over the past two decades, numerous studies have produced evidence of the pivotal role of glycogen synthase kinase (GSK)3β in the progression of over 25 different cancer types, including pancreatic cancer. In this review, we synthesize the current knowledge on the pathological roles of aberrant GSK3β in supporting tumor cell proliferation and invasion, as well as its contribution to gemcitabine resistance in pancreatic cancer. Importantly, we discuss the central role of GSK3β as a molecular hub that mechanistically connects chemoresistance, tumor cell invasion, and stemness in pancreatic cancer. We also discuss the involvement of GSK3β in the formation of desmoplastic tumor stroma and in promoting anti-cancer immune evasion, both of which constitute major obstacles to successful cancer treatment. Overall, GSK3β has characteristics of a promising therapeutic target to overcome chemoresistance in pancreatic cancer.

由于符合治愈性(R0)手术条件的患者人数有限、靶向疗法和免疫疗法的临床开发失败以及化疗耐药性的普遍存在,胰腺癌的治疗仍然是一项重大的临床挑战。难治性胰腺癌具有高侵袭性和耐药性,这两种特性都与肿瘤细胞的干性有关。这些恶性特征相互促进,导致癌症迅速发展。在过去二十年中,大量研究证明糖原合酶激酶(GSK)3β在包括胰腺癌在内的超过 25 种不同癌症类型的进展过程中起着关键作用。在这篇综述中,我们总结了目前关于异常 GSK3β 在支持肿瘤细胞增殖和侵袭中的病理作用及其对胰腺癌吉西他滨耐药性的贡献的知识。重要的是,我们讨论了 GSK3β 作为分子枢纽的核心作用,它从机理上将胰腺癌的化疗耐药性、肿瘤细胞侵袭和干性联系在一起。我们还讨论了 GSK3β 参与脱鳞肿瘤基质的形成和促进抗癌免疫逃避的情况,这两者都是成功治疗癌症的主要障碍。总之,GSK3β具有克服胰腺癌化疗耐药性的治疗靶点的特征。
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引用次数: 0
Ritonavir reverses resistance to docetaxel and cabazitaxel in prostate cancer cells with acquired resistance to docetaxel. 利托那韦能逆转前列腺癌细胞对多西他赛和卡巴他赛的耐药性。
Q1 ONCOLOGY Pub Date : 2024-01-31 eCollection Date: 2024-01-01 DOI: 10.20517/cdr.2023.136
Eric van der Putten, Katja Wosikowski, Jos H Beijnen, Gábor Imre, Colin R Freund

Aim: Docetaxel is a microtubule-stabilizing drug used for the treatment of several cancers, including prostate cancer. Resistance to docetaxel can either occur through intrinsic resistance or develop under therapeutic pressure, i.e., acquired resistance. A possible explanation for the occurrence of acquired resistance to docetaxel is increased drug efflux via P-glycoprotein (P-gp) drug transporters. Methods: We have generated docetaxel-resistant cell lines DU-145DOC10 and 22Rv1DOC8 by exposing parental cell lines DU-145DOC and 22Rv1 to increasing levels of docetaxel. Gene expression levels between DU-145DOC10 and 22Rv1DOC8 were compared with those of their respective originator cell lines. Both parental and resistant cell lines were treated with the taxane drugs docetaxel and cabazitaxel in combination with the P-gp/CYP3A4 inhibitor ritonavir and the P-gp inhibitor elacridar. Results: In the docetaxel-resistant cell lines DU-145DOC10 and 22Rv1DOC8, the ABCB1 (P-gp) gene was highly up-regulated. Expression of the P-gp protein was also significantly increased in the docetaxel-resistant cell lines in a Western blotting assay. The addition of ritonavir to docetaxel resulted in a return of the sensitivity to docetaxel in the DU-145DOC10 and 22Rv1DOC8 to a level similar to the sensitivity in the originator cells. We found that these docetaxel-resistant cell lines could also be re-sensitized to cabazitaxel in a similar manner. In a Caco-2 P-gp transporter assay, functional inhibition of P-gp-mediated transport of docetaxel with ritonavir was demonstrated. Conclusion: Our results demonstrate that ritonavir restores sensitivity to both docetaxel and cabazitaxel in docetaxel-resistant cell lines, most likely by inhibiting P-gp-mediated drug efflux.

目的:多西他赛是一种微管稳定药物,用于治疗包括前列腺癌在内的多种癌症。对多西他赛的耐药性可以通过内在耐药性产生,也可以在治疗压力下产生,即获得性耐药性。对多西他赛产生获得性耐药性的一个可能解释是,通过 P 糖蛋白(P-gp)药物转运体的药物外流增加。方法:我们将亲本细胞株 DU-145DOC 和 22Rv1 暴露于不断增加的多西他赛水平,生成了多西他赛耐药细胞株 DU-145DOC10 和 22Rv1DOC8。将 DU-145DOC10 和 22Rv1DOC8 的基因表达水平与其各自的原代细胞系的基因表达水平进行了比较。亲代细胞系和耐药细胞系都接受了多西他赛和卡巴齐他赛与 P-gp/CYP3A4 抑制剂利托那韦和 P-gp 抑制剂艾拉克瑞达联合治疗。研究结果在多西他赛耐药细胞系 DU-145DOC10 和 22Rv1DOC8 中,ABCB1(P-gp)基因高度上调。在 Western 印迹检测中,多西他赛耐药细胞系的 P-gp 蛋白表达也明显增加。在多西他赛中加入利托那韦后,DU-145DOC10和22Rv1DOC8对多西他赛的敏感性恢复到与原代细胞相似的水平。我们发现,这些对多西他赛耐药的细胞系也能以类似的方式重新对卡巴他赛敏感。在 Caco-2 P-gp 转运试验中,利托那韦对 P-gp 介导的多西他赛转运起到了功能性抑制作用。结论我们的研究结果表明,利托那韦很可能通过抑制 P-gp 介导的药物外流,恢复了多西他赛耐药细胞株对多西他赛和卡巴他赛的敏感性。
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引用次数: 0
Supramolecular host-guest nanosystems for overcoming cancer drug resistance. 用于克服癌症抗药性的超分子主客体纳米系统。
IF 4.6 Q1 ONCOLOGY Pub Date : 2023-11-22 eCollection Date: 2023-01-01 DOI: 10.20517/cdr.2023.77
Sha Wu, Miaomiao Yan, Minghao Liang, Wenzhi Yang, Jingyu Chen, Jiong Zhou

Cancer drug resistance has become one of the main challenges for the failure of chemotherapy, greatly limiting the selection and use of anticancer drugs and dashing the hopes of cancer patients. The emergence of supramolecular host-guest nanosystems has brought the field of supramolecular chemistry into the nanoworld, providing a potential solution to this challenge. Compared with conventional chemotherapeutic platforms, supramolecular host-guest nanosystems can reverse cancer drug resistance by increasing drug uptake, reducing drug efflux, activating drugs, and inhibiting DNA repair. Herein, we summarize the research progress of supramolecular host-guest nanosystems for overcoming cancer drug resistance and discuss the future research direction in this field. It is hoped that this review will provide more positive references for overcoming cancer drug resistance and promoting the development of supramolecular host-guest nanosystems.

癌症耐药性已成为化疗失败的主要挑战之一,极大地限制了抗癌药物的选择和使用,使癌症患者的希望破灭。超分子主客体纳米系统的出现将超分子化学领域带入了纳米世界,为解决这一难题提供了可能。与传统的化疗平台相比,超分子主客体纳米系统可以通过增加药物吸收、减少药物外流、激活药物和抑制DNA修复来逆转癌症耐药性。在此,我们总结了超分子主客体纳米系统克服癌症耐药性的研究进展,并探讨了该领域未来的研究方向。希望本综述能为克服癌症耐药性、促进超分子主客体纳米系统的发展提供更多积极的参考。
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引用次数: 0
Unveiling T cell evasion mechanisms to immune checkpoint inhibitors in acute myeloid leukemia. 揭示急性髓系白血病免疫检查点抑制剂的T细胞逃避机制。
Q1 ONCOLOGY Pub Date : 2023-09-26 eCollection Date: 2023-01-01 DOI: 10.20517/cdr.2023.39
Lindsay Gurska, Kira Gritsman

Acute myeloid leukemia (AML) is a heterogeneous and aggressive hematologic malignancy that is associated with a high relapse rate and poor prognosis. Despite advances in immunotherapies in solid tumors and other hematologic malignancies, AML has been particularly difficult to treat with immunotherapies, as their efficacy is limited by the ability of leukemic cells to evade T cell recognition. In this review, we discuss the common mechanisms of T cell evasion in AML: (1) increased expression of immune checkpoint molecules; (2) downregulation of antigen presentation molecules; (3) induction of T cell exhaustion; and (4) creation of an immunosuppressive environment through the increased frequency of regulatory T cells. We also review the clinical investigation of immune checkpoint inhibitors (ICIs) in AML. We discuss the limitations of ICIs, particularly in the context of T cell evasion mechanisms in AML, and we describe emerging strategies to overcome T cell evasion, including combination therapies. Finally, we provide an outlook on the future directions of immunotherapy research in AML, highlighting the need for a more comprehensive understanding of the complex interplay between AML cells and the immune system.

急性髓细胞白血病(AML)是一种异质性和侵袭性血液系统恶性肿瘤,复发率高,预后差。尽管在实体瘤和其他血液系统恶性肿瘤的免疫疗法方面取得了进展,但AML特别难以用免疫疗法治疗,因为其疗效受到白血病细胞逃避T细胞识别能力的限制。在这篇综述中,我们讨论了AML中T细胞逃避的常见机制:(1)免疫检查点分子表达增加;(2) 抗原呈递分子的下调;(3) 诱导T细胞耗竭;以及(4)通过增加调节性T细胞的频率来创造免疫抑制环境。我们还回顾了免疫检查点抑制剂(ICIs)在AML中的临床研究。我们讨论了ICIs的局限性,特别是在AML中T细胞逃避机制的背景下,并描述了克服T细胞逃避的新策略,包括联合疗法。最后,我们展望了AML免疫治疗研究的未来方向,强调需要更全面地了解AML细胞和免疫系统之间的复杂相互作用。
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癌症耐药(英文)
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