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Unraveling the complexity of drug resistance mechanisms to SINE, T cell-engaging therapies and CELMoDs in multiple myeloma: a comprehensive review. 揭示多发性骨髓瘤中SINE、T细胞激活疗法和CELMoDs耐药机制的复杂性:综述。
IF 4.6 Q1 ONCOLOGY Pub Date : 2024-06-26 eCollection Date: 2024-01-01 DOI: 10.20517/cdr.2024.39
Jacqueline Schütt, Kerstin Brinkert, Andrzej Plis, Tino Schenk, Annamaria Brioli

Despite significant advances in the understanding of multiple myeloma (MM) biology and the development of novel treatment strategies in the last two decades, MM is still an incurable disease. Novel drugs with alternative mechanisms of action, such as selective inhibitors of nuclear export (SINE), modulators of the ubiquitin pathway [cereblon E3 ligase modulatory drugs (CELMoDs)], and T cell redirecting (TCR) therapy, have led to significant improvement in patient outcomes. However, resistance still emerges, posing a major problem for the treatment of myeloma patients. This review summarizes current data on treatment with SINE, TCR therapy, and CELMoDs and explores their mechanism of resistance. Understanding these resistance mechanisms is critical for developing strategies to overcome treatment failure and improve therapeutic outcomes.

尽管在过去二十年里,人们对多发性骨髓瘤(MM)生物学的认识和新型治疗策略的开发取得了重大进展,但MM仍然是一种无法治愈的疾病。具有替代作用机制的新型药物,如核输出选择性抑制剂(SINE)、泛素通路调节剂[脑龙E3连接酶调节药物(CELMoDs)]和T细胞重定向(TCR)疗法,已使患者的预后得到显著改善。然而,耐药性依然存在,给骨髓瘤患者的治疗带来了重大问题。本综述总结了目前有关SINE、TCR疗法和CELMoDs治疗的数据,并探讨了它们的耐药机制。了解这些耐药机制对于制定克服治疗失败和改善治疗效果的策略至关重要。
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引用次数: 0
Inhibition of glutaminolysis alone and in combination with HDAC inhibitor has anti-myeloma therapeutic effects. 单独或与 HDAC 抑制剂联合抑制谷氨酰胺分解具有抗骨髓瘤治疗效果。
IF 4.6 Q1 ONCOLOGY Pub Date : 2024-06-24 eCollection Date: 2024-01-01 DOI: 10.20517/cdr.2024.35
Seiichi Okabe, Yuko Tanaka, Mitsuru Moriyama, Akihiko Gotoh

Aim: This study aimed to investigate drug candidates and their efficacy in treating refractory multiple myeloma (MM) despite significant therapeutic advances and the introduction of novel agents. Our study focused on how myeloma cells mediate the metabolic pathways essential for survival. Therefore, we examined the role of glutaminolysis in this process. Methods: We investigated the role of glutaminolysis in myeloma cell growth. In addition, we analyzed the ability of CB-839 (telaglenastat), a glutaminase (GLS) inhibitor, to suppress myeloma cell proliferation and enhance the sensitivity to histone deacetylase (HDAC) inhibitors. Results: Glutamate deprivation significantly reduced MM cell proliferation. We observed an upregulation of GLS1 expression in MM cell lines compared to that in normal controls. CB-839 inhibits MM cell proliferation in a dose-dependent manner, resulting in enhanced cytotoxicity. Additionally, intracellular α-ketoglutarate and nicotinamide adenine dinucleotide phosphate levels decreased after CB-839 administration. Combining panobinostat with CB-839 resulted in enhanced cytotoxicity and increased caspase 3/7 activity. Cells transfected with GLS shRNA exhibited reduced cell viability and elevated sub-G1 phase according to cell cycle analysis results. Compared to control cells, these cells also showed increased sensitivity to panobinostat. Conclusion: Glutaminolysis contributes to the viability of MM cells, and the GLS inhibitor CB-839 has been proven to be an effective treatment for enhancing the cytotoxic effect of HDAC inhibition. These results are clinically relevant and suggest that CB-839 is a potential therapeutic candidate for patients with MM.

目的:本研究旨在调查候选药物及其在治疗难治性多发性骨髓瘤(MM)方面的疗效,尽管在治疗方面取得了重大进展并引入了新型药物。我们的研究重点是骨髓瘤细胞如何介导生存所必需的代谢途径。因此,我们研究了谷氨酰胺溶解在这一过程中的作用。研究方法我们研究了谷氨酰胺分解在骨髓瘤细胞生长中的作用。此外,我们还分析了谷氨酰胺酶(GLS)抑制剂 CB-839(替拉格纳司他)抑制骨髓瘤细胞增殖并提高其对组蛋白去乙酰化酶(HDAC)抑制剂敏感性的能力。研究结果谷氨酸剥夺能明显减少骨髓瘤细胞的增殖。与正常对照组相比,我们在 MM 细胞系中观察到 GLS1 表达上调。CB-839 以剂量依赖的方式抑制 MM 细胞增殖,从而增强细胞毒性。此外,服用 CB-839 后,细胞内的α-酮戊二酸和烟酰胺腺嘌呤二核苷酸磷酸酯水平下降。将帕诺比诺司他(panobinostat)与 CB-839 结合使用可增强细胞毒性并提高 caspase 3/7 活性。细胞周期分析结果显示,转染 GLS shRNA 的细胞存活率降低,亚 G1 期升高。与对照细胞相比,这些细胞对泛比诺司他的敏感性也有所提高。结论谷氨酰胺溶解有助于提高 MM 细胞的活力,而 GLS 抑制剂 CB-839 已被证明是增强 HDAC 抑制的细胞毒性效果的有效治疗方法。这些结果与临床相关,表明 CB-839 是 MM 患者的潜在候选治疗药物。
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引用次数: 0
Recent advanced lipid-based nanomedicines for overcoming cancer resistance. 用于克服癌症抗药性的最新先进脂基纳米药物。
IF 4.6 Q1 ONCOLOGY Pub Date : 2024-06-21 eCollection Date: 2024-01-01 DOI: 10.20517/cdr.2024.19
Piroonrat Dechbumroong, Runjing Hu, Wisawat Keaswejjareansuk, Katawut Namdee, Xing-Jie Liang

The increasing prevalence of cancer drug resistance not only critically limits the efficiency of traditional therapies but also causes relapses or recurrences of cancer. Consequently, there remains an urgent need to address the intricate landscape of drug resistance beyond traditional cancer therapies. Recently, nanotechnology has played an important role in the field of various drug delivery systems for the treatment of cancer, especially therapy-resistant cancer. Among advanced nanomedicine technologies, lipid-based nanomaterials have emerged as effective drug carriers for cancer treatment, significantly improving therapeutic effects. Due to their biocompatibility, simplicity of preparation, and potential for functionalization, lipid-based nanomaterials are considered powerful competitors for resistant cancer. In this review, an overview of lipid-based nanomaterials for addressing cancer resistance is discussed. We summarize the recent progress in overcoming drug resistance in cancer by these lipid-based nanomaterials, and highlight their potential in future applications to reverse cancer resistance.

癌症耐药性的日益普遍不仅严重限制了传统疗法的效率,还会导致癌症复发或复发。因此,在传统癌症疗法之外,仍然迫切需要解决错综复杂的耐药性问题。最近,纳米技术在治疗癌症,尤其是耐药性癌症的各种给药系统领域发挥了重要作用。在先进的纳米医学技术中,脂基纳米材料已成为治疗癌症的有效药物载体,可显著提高治疗效果。由于脂基纳米材料具有生物相容性、制备简单、功能化潜力大等特点,被认为是抗药性癌症的有力竞争者。在这篇综述中,我们将概述用于解决癌症抗药性的脂基纳米材料。我们总结了这些脂基纳米材料在克服癌症耐药性方面的最新进展,并强调了它们在未来应用于逆转癌症耐药性方面的潜力。
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引用次数: 0
Emerging role of MYB transcription factors in cancer drug resistance. MYB 转录因子在癌症抗药性中的新作用。
Pub Date : 2024-04-30 eCollection Date: 2024-01-01 DOI: 10.20517/cdr.2023.158
Bernhard Biersack, Michael Höpfner

Decades ago, the viral myeloblastosis oncogene v-myb was identified as a gene responsible for the development of avian leukemia. However, the relevance of MYB proteins for human cancer diseases, in particular for solid tumors, remained basically unrecognized for a very long time. The human family of MYB transcription factors comprises MYB (c-MYB), MYBL2 (b-MYB), and MYBL1 (a-MYB), which are overexpressed in several cancers and are associated with cancer progression and resistance to anticancer drugs. In addition to overexpression, the presence of activated MYB-fusion proteins as tumor drivers was described in certain cancers. The identification of anticancer drug resistance mediated by MYB proteins and their underlying mechanisms are of great importance in understanding failures of current therapies and establishing new and more efficient therapy regimens. In addition, new drug candidates targeting MYB transcription factor activity and signaling have emerged as a promising class of potential anticancer therapeutics that could tackle MYB-dependent drug-resistant cancers in a more selective way. This review describes the correlation of MYB transcription factors with the formation and persistence of cancer resistance to various approved and investigational anticancer drugs.

几十年前,病毒性骨髓母细胞病致癌基因 v-myb 被确定为禽类白血病的致病基因。然而,MYB 蛋白与人类癌症疾病,尤其是实体瘤的相关性在很长一段时间内基本上仍未被认识到。人类 MYB 转录因子家族包括 MYB(c-MYB)、MYBL2(b-MYB)和 MYBL1(a-MYB)。除过表达外,某些癌症中还出现了作为肿瘤驱动因素的活化 MYB 融合蛋白。确定由 MYB 蛋白介导的抗癌药物耐药性及其内在机制,对于了解当前疗法的失败以及建立更有效的新疗法具有重要意义。此外,以 MYB 转录因子活性和信号转导为靶点的候选新药已成为一类前景广阔的潜在抗癌疗法,可以更有选择性地解决依赖 MYB 的耐药癌症问题。本综述介绍了 MYB 转录因子与癌症耐药性的形成和持续存在的相关性,以及各种已批准和正在研究的抗癌药物的耐药性。
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引用次数: 0
HER3-targeted therapy: the mechanism of drug resistance and the development of anticancer drugs. HER3靶向疗法:耐药机制与抗癌药物的开发。
Pub Date : 2024-04-29 eCollection Date: 2024-01-01 DOI: 10.20517/cdr.2024.11
Huilan Zeng, Wei Wang, Lin Zhang, Zhenghong Lin

Human epidermal growth factor receptor 3 (HER3), which is part of the HER family, is aberrantly expressed in various human cancers. Since HER3 only has weak tyrosine kinase activity, when HER3 ligand neuregulin 1 (NRG1) or neuregulin 2 (NRG2) appears, activated HER3 contributes to cancer development and drug resistance by forming heterodimers with other receptors, mainly including epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2). Inhibition of HER3 and its downstream signaling, including PI3K/AKT, MEK/MAPK, JAK/STAT, and Src kinase, is believed to be necessary to conquer drug resistance and improve treatment efficiency. Until now, despite multiple anti-HER3 antibodies undergoing preclinical and clinical studies, none of the HER3-targeted therapies are licensed for utilization in clinical cancer treatment because of their safety and efficacy. Therefore, the development of HER3-targeted drugs possessing safety, tolerability, and sensitivity is crucial for clinical cancer treatment. This review summarizes the progress of the mechanism of HER3 in drug resistance, the HER3-targeted therapies that are conducted in preclinical and clinical trials, and some emerging molecules that could be used as future designed drugs for HER3, aiming to provide insights for future research and development of anticancer drugs targeting HER3.

人类表皮生长因子受体 3(HER3)属于 HER 家族,在各种人类癌症中异常表达。由于 HER3 只具有微弱的酪氨酸激酶活性,当 HER3 配体神经胶质蛋白 1(NRG1)或神经胶质蛋白 2(NRG2)出现时,活化的 HER3 会与其他受体(主要包括表皮生长因子受体(EGFR)和人表皮生长因子受体 2(HER2))形成异二聚体,从而导致癌症发展和耐药性。抑制 HER3 及其下游信号转导,包括 PI3K/AKT、MEK/MAPK、JAK/STAT 和 Src 激酶,被认为是克服耐药性和提高治疗效率的必要条件。迄今为止,尽管有多种抗 HER3 抗体正在进行临床前和临床研究,但由于其安全性和有效性问题,还没有一种 HER3 靶向疗法被授权用于临床癌症治疗。因此,开发具有安全性、耐受性和敏感性的 HER3 靶向药物对于临床癌症治疗至关重要。本综述总结了HER3耐药机制的研究进展、已开展临床前和临床试验的HER3靶向疗法,以及一些可作为未来HER3设计药物的新兴分子,旨在为未来靶向HER3的抗癌药物研发提供启示。
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引用次数: 0
Dysregulation of calcium homeostasis in cancer and its role in chemoresistance. 癌症中的钙平衡失调及其在化疗抗药性中的作用。
Pub Date : 2024-03-15 eCollection Date: 2024-01-01 DOI: 10.20517/cdr.2023.145
Neema Kumari, Narasimha Pullaguri, Subha Narayan Rath, Ashish Bajaj, Vikas Sahu, Kranti Kiran Reddy Ealla

Globally, cancer, as a major public health concern, poses a severe threat to people's well-being. Advanced and specialized therapies can now cure the majority of people with early-stage cancer. However, emerging resistance to traditional and novel chemotherapeutic drugs remains a serious issue in clinical medicine. Chemoresistance often leads to cancer recurrence, metastasis, and increased mortality, accounting for 90% of chemotherapy failures. Thus, it is important to understand the molecular mechanisms of chemoresistance and find novel therapeutic approaches for cancer treatment. Among the several factors responsible for chemoresistance, calcium (Ca2+) dysregulation plays a significant role in cancer progression and chemoresistance. Therefore, targeting this derailed Ca2+ signalling for cancer therapy has become an emerging research area. Of note, the Ca2+ signal and its proteins are a multifaceted and potent tool by which cells achieve specific outcomes. Depending on cell survival needs, Ca2+ is either upregulated or downregulated in both chemosensitive and chemoresistant cancer cells. Consequently, the appropriate treatment should be selected based on Ca2+ signalling dysregulation. This review discusses the role of Ca2+ in cancer cells and the targeting of Ca2+ channels, pumps, and exchangers. Furthermore, we have emphasised the role of Ca2+ in chemoresistance and therapeutic strategies. In conclusion, targeting Ca2+ signalling is a multifaceted process. Methods such as site-specific drug delivery, target-based drug-designing, and targeting two or more Ca2+ proteins simultaneously may be explored; however, further clinical studies are essential to validate Ca2+ blockers' anti-cancer efficacy.

在全球范围内,癌症作为一种主要的公共健康问题,对人们的福祉构成了严重威胁。目前,先进的专业疗法可以治愈大多数早期癌症患者。然而,对传统和新型化疗药物产生的抗药性仍然是临床医学的一个严重问题。耐药性往往导致癌症复发、转移和死亡率上升,占化疗失败的 90%。因此,了解化疗耐药性的分子机制并找到新的癌症治疗方法非常重要。在导致化疗耐药性的几个因素中,钙(Ca2+)失调在癌症进展和化疗耐药性中起着重要作用。因此,针对这种脱轨的 Ca2+ 信号进行癌症治疗已成为一个新兴的研究领域。值得注意的是,Ca2+ 信号及其蛋白质是一种多方面的有效工具,细胞可通过它获得特定的结果。根据细胞生存的需要,Ca2+ 在化疗敏感和化疗耐药癌细胞中都会上调或下调。因此,应根据 Ca2+ 信号失调情况选择适当的治疗方法。本综述讨论了 Ca2+ 在癌细胞中的作用以及 Ca2+ 通道、泵和交换器的靶向作用。此外,我们还强调了 Ca2+ 在化疗耐药性和治疗策略中的作用。总之,靶向 Ca2+ 信号是一个多方面的过程。可探索的方法包括:特定部位给药、基于靶点的药物设计以及同时靶向两种或两种以上 Ca2+ 蛋白质;然而,进一步的临床研究对于验证 Ca2+ 阻滞剂的抗癌疗效至关重要。
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引用次数: 0
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。
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。
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。
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。
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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癌症耐药(英文)
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