更新于：2024-11-01

MCT4 x MCT1

更新于：2024-11-01

基本信息

关联

项与 MCT4 x MCT1 相关的药物

NGT-008

靶点

MCT1 x MCT4

作用机制

MCT1抑制剂 [+1]

在研机构

Nirogyone Therapeutics, LLC

原研机构

Nirogyone Therapeutics, LLC

在研适应症

乳腺癌

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

18F-FACH (Helmholtz-Zentrum Dresden-Rossendorf)

靶点

MCT1 x MCT4

作用机制

MCT1抑制剂 [+1]

在研机构

Helmholtz-Zentrum Dresden-Rossendorf e. V.

原研机构

Helmholtz-Zentrum Dresden-Rossendorf e. V.

在研适应症

肿瘤

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 MCT4 x MCT1 相关的临床结果

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100 项与 MCT4 x MCT1 相关的转化医学

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0 项与 MCT4 x MCT1 相关的专利（医药）

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586

项与 MCT4 x MCT1 相关的文献（医药）

2024-10-01·Molecular Nutrition & Food Research

The Inhibitory Effects of the Natural Stilbene Piceatannol on Lactate Transport In Vitro Mediated by Monocarboxylate Transporters

Article

作者: Schüller, Andreas ; Ibacache‐Chía, Andrés P. ; Sierralta, Jimena A.

ScopeLactate, a signaling molecule and energy source, crosses membranes through monocarboxylate transporters (MCTs). MCT1 and MCT4 are potential cancer drug targets due to their role in metabolic reprogramming of cancer cells. Stilbenes, plant secondary metabolites found in several food sources, have anticancer effects, though their mechanisms of action are not well understood. This study links the anticancer activity of natural stilbenes to tumor cell lactate metabolism.Methods and resultsThe impact of resveratrol, pinostilbene, pterostilbene, rhapontigenin, and piceatannol on lactate transport is studied using a fluorescence resonance energy transfer (FRET)‐based lactate sensor. The viability and migration of cells expressing MCT1 or MCT4 are also evaluated. Piceatannol inhibits MCT1 effectively at low micromolar concentrations, with less effect on MCT4. All stilbenes significantly reduce cell viability and migration.ConclusionsThese findings indicate that both MCTs are stilbene targets, with piceatannol highlighted as a cost‐effective, low‐toxicity compound for studying MCTs in cancer, providing a new mechanism of action of the therapeutic and nutraceutical effects of natural polyphenols. This enriches the understanding of dietary polyphenols in cancer prevention and therapy.

2024-09-01·Placenta

Immunohistochemical localization of HCA1 receptor in placenta in presence of fetal growth restriction

Article

作者: Matsumoto, Koichi ; Kozai, Ayumi ; Murakami, Ryuta ; Kanenishi, Kenji ; Ueno, Masaki ; Chiba, Yoichi ; Miyai, Yumi

INTRODUCTIONGlucose metabolism produces lactate and hydrogen ions in an anaerobic environment. Fetuses with intrauterine growth restriction are considered to become progressively lactacidemic as well as hypoxic. Roles of lactate in the placenta in the presence of fetal growth restriction (FGR) remain to be clarified.METHODSImmunohistochemical localization of lactate-related substances, such as a receptor for lactate (hydroxy-carboxylic acid 1 receptor (HCA1 receptor/GPR81)), monocarboxylate transporters (MCTs) for lactate, lactate dehydrogenases (LDHs), and proteins expressed in syncytiotrophoblasts or cytotrophoblasts was examined in placentas of appropriate weight for gestational age (AGA) fetus and those showing FGR.RESULTSImmunoreactivity for the HCA1 receptor was present in the cytoplasm of some trophoblasts, predominantly localized to their basal (fetus-facing) side, and was frequently colocalized with that for E-cadherin or serine peptidase inhibitor, Kunitz type 1 (SPINT1), a marker protein of cytotrophoblasts. Immunoreactivity for MCT1 and MCT4 was present on the basal and the microvillous (maternal-facing) membranes of trophoblasts in both groups, respectively. Clear immunoreactivity for LDHA and LDHB was also observed in the cytoplasm of trophoblasts, mainly localized to their basal side. However, there were no significant differences in immunohistochemically stained areas of lactate-related substances between AGA and late-onset FGR groups. On the other hand, there were correlations between coefficients of the presence of chorioamnionitis and the values of LDHB and E-cadherin.DISCUSSIONImmunohistochemical localization of the HCA1 receptor was predominantly observed in the cytoplasm located on the basal side of trophoblasts, suggesting a role of lactate in human placental development, including syncytialization.

2024-08-01·iScience

Monocarboxylate transporter 4 facilitates Mycobacterium tuberculosis survival through NF-κB p65-mediated interleukin-10 production

Article

作者: Zhou, Chaoying ; Chen, Shuo ; Wen, Qian ; Li, Qianna ; Zhou, Xinying ; Han, Zhenyu ; Liang, Yao ; Liang, Yun ; Lin, Lingming ; Li, Rong ; Huang, Yingqi ; Ma, Li ; Wang, Qi

Tuberculosis (TB) is a chronic infectious disease caused by Mycobacterium tuberculosis (Mtb) infection, with the highest single-cause mortality. Monocarboxylate transporter 4 (Mct4) transports intracellular lactate outside, but its role in regulating host immune response against Mtb infection remains unknown. Mct4 expression was upregulated in Mtb-infected macrophages and in patients with TB. Mct4 silencing/deficiency significantly decreased Mtb survival in macrophages and in lungs and spleens of mice, while Mct4 overexpression facilitated Mtb survival in macrophages. Furthermore, Mct4 promoted intracellular lactate transport, nuclear factor κB (NF-κB) p65 activation, and interleukin-10 (IL-10) production upon Mtb infection. Mechanistically, IL-10 silencing and IL-10-neutralizing antibody blocked Mct4 overexpressing increased Mtb survival. Replenishing lactate and NF-κB p65 inhibitor JSH23 treatment could inhibit Mct4 overexpressing increased NF-κB p65 activation, IL-10 production, and Mtb survival in macrophages. This study demonstrates that Mct4 promotes Mtb survival through restricting intracellular lactate accumulation to promote NF-κB p65-mediated IL-10 production and suggests Mct4-NF-κB p65-IL-10 axis a potential target for TB treatment.

项与 MCT4 x MCT1 相关的新闻（医药）

2024-06-20

·今日头条

联合治疗！天津医科大学发文：揭示非小细胞肺癌治疗新策略

本文为转化医学网原创，转载请注明出处作者：Jerry 导读：由于非小细胞肺癌（NSCLC）的五年生存率较低，这给全球健康带来了挑战，因此需要开发新的治疗策略。 6月19日，天津医科大学研究团队在期刊《cell Death&Disease》上发表了研究论文，题为“Syrosingopine and UK5099 synergistically suppress non-small cell lung cancer by activating the integrated stress response”，本研究提出了一种有前途的治疗方法，即联合昔洛舍平和UK-5099激活ISR，显著抑制NSCLC的生长和增殖。 https://www.nature.com/articles/s41419-024-06821-4 研究背景 01 非小细胞肺癌（NSCLC）是全球最常见的癌症之一，具有高发病率和死亡率。由于其异质性和侵袭性，NSCLC通常在晚期被诊断出来，这导致其生存率极低。由于对传统疗法的抵抗和高复发率，NSCLC带来了各种挑战。这种日益流行的趋势以及随之而来的医疗负担凸显了迫切需要更有效的治疗策略。整合应激反应（ISR）是一种细胞防御机制，在应对多种应激条件（如氧化应激、内质网应激、营养缺乏或毒性损伤）时被激活，旨在通过减少蛋白质合成和增强应激修复途径来恢复细胞稳态。然而，过度应激也可能导致细胞凋亡。由于其对细胞生存和细胞死亡的双向影响，ISR已成为治疗多种癌症的潜在治疗靶点，并因此备受关注。例如，ONC201/TIC10通过激活ATF4激活ISR，导致实体瘤细胞死亡，并对广泛的肿瘤显示出抗增殖作用。研究表明，如吲哚瑞林-3'-单氧化物、GSK2606414和特拉唑嗪等化合物可以通过抑制ISR来促进癌细胞死亡。这表明靶向ISR可能是治疗NSCLC的一种新型策略。昔洛舍平和UK-5099已经成为癌症研究中感兴趣的化合物。昔洛舍平因其靶向单羧酸转运体1（MCT1）和单羧酸转运体4（MCT4）而为人所知，它在破坏癌细胞代谢方面显示出了潜力。它在调节沃伯格效应方面的作用，使其成为癌症治疗中具有潜力的治疗方法。UK-5099最初被认为是线粒体丙酮酸载体（MPC）的抑制剂，它改变了癌细胞的代谢状态，从而诱导应激反应。先前的研究强调了这些化合物在诱导癌细胞毒性方面的潜力，表明它们在靶向癌细胞代谢和克服耐药方面的应用。它们独特的机制为癌症治疗提供了一种新的视角，特别是在肺癌等代谢在癌症中起关键作用的癌症中。研究进展 02 体外实验证明昔洛舍平与UK-5099在抑制NSCLC细胞增殖方面具有协同作用。首先，研究人员使用CCK-8法测定昔洛舍平和UK-5099对H661和PC-9细胞系的亚细胞毒浓度。如图1A中的IC50值所示，观察到的抗增殖作用是浓度依赖性的。研究人员采用SynergyFinder软件中的ZIP药物协同作用模型，通过精细化浓度梯度分析进一步研究这些药物的协同作用。该分析显示，H661细胞的平均和最大药物相互作用贡献分别为11.31%和16.97%，PC-9细胞的平均和最大药物相互作用贡献分别为12.73%和19.04%，见图1B。值得注意的是，这些ZIP协同得分超过10%的阈值，突出了药物联合的有效协同影响。CCK-8实验结果进一步证实昔洛舍平 (5 μM)和UK-5099 (20 μM)降低细胞活力的有效性，表明随着时间的推移，细胞活力显著降低。集落形成实验显示，两种细胞系的克隆生长都明显减少，证实了H661和PC-9细胞的集落形成能力受到抑制。此外，EdU染色实验提供了细胞增殖减少的目视确认。这些体外结果一致表明昔洛舍平和UK-5099显著阻碍NSCLC细胞的增殖，为潜在的治疗策略提供了有希望的见解。图1：昔洛舍平与UK-5099的组合在体外显示出对NSCLC细胞增殖的协同抑制作用研究结论 03 总之，本研究结果表明，昔洛舍平与UK-5099的联合治疗在NSCLC中显示出显著的抗肿瘤活性。此外，研究人员揭示了抗肿瘤作用的机制是通过氧化应激和代谢紊乱来持续激活ISR。昔洛舍平与UK-5099的联合治疗可能为NSCLC的治疗提供新的见解。参考资料： https://www.nature.com/articles/s41419-024-06821-4 注：本文旨在介绍医学研究进展，不能作为治疗方案参考。如需获得健康指导，请至正规医院就诊。【关于投稿】转化医学网（360zhyx.com）是转化医学核心门户，旨在推动基础研究、临床诊疗和产业的发展，核心内容涵盖组学、检验、免疫、肿瘤、心血管、糖尿病等。如您有最新的研究内容发表，欢迎联系我们进行免费报道（公众号菜单栏-在线客服联系），我们的理念：内容创造价值，转化铸就未来！转化医学网（360zhyx.com）发布的文章旨在介绍前沿医学研究进展，不能作为治疗方案使用；如需获得健康指导，请至正规医院就诊。热门·直播/活动 🕓 上海｜06月20日 ▶ 【日程公布】合成生物学前沿技术与临床应用研讨会 🕓 北京｜09月20日-21日 ▶ 第五届单细胞技术应用研讨会暨空间组学前沿研讨会欢迎您的参与！点击对应文字查看详情

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