Anti-glioblastoma activity of monensin and its analogs in an organoid model of cancer.
Anti-glioblastoma activity of monensin and its analogs in an organoid model of cancer.
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DOI：
10.1016/j.biopha.2022.113440
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发表时间：
2022-09
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影响因子：
--
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胶质母细胞瘤（GBM）仍然是成人中最常诊断的原发性恶性脑癌。尽管最近在了解GBM的生物学方面取得了进展，但患者的临床结果仍然很差，诊断后的中位生存期约为一年。导致临床试验失败的一个因素是GBM药物发现中使用的传统模型很难概括患者肿瘤。先前的研究表明，莫能菌素（MON）类似物，即C-26上的酯和酰胺对各种类型的癌细胞系都是有效的。在本研究中，我们研究了这些分子在GBM类器官以及宿主：肿瘤类器官模型中的活性。使用微环细胞活力测定，我们已经鉴定了比母体MON（IC 50 = 612.6 ± 184.4 nM）更有效的七种类似物（IC 50 = 91.5 ± 54.4-291.7 ± 68.8 nM）。这些化合物中的五种在GBM类器官中诱导大量DNA片段化，提示凋亡性细胞死亡。最具活性的类似物化合物1显著减少GBM细胞迁移，诱导PARP降解，减少STAT 3、Akt和GSK 3 β的磷酸化，增加GSH 2AX信号传导并上调自噬相关标志物LC 3-II的表达。为了研究MON和化合物1在肿瘤微环境中的活性，我们从人诱导多能干细胞（iPSC）开发了人脑类器官（CO）。COs具有早期发育脑的特征，如多个神经突起，包括神经干细胞（Nestin+）、神经元（TUJ 1+）、原始脑室系统（SOX 2 +/Ki 67+）、中间区（TBR 2+）和皮质板（MAP 2+）的增殖区。为了产生宿主：肿瘤类器官，我们将RFP标记的U87 MG细胞与完全形成的CO共培养。化合物1和MON在处理4天后减小了CO中的U87 MG肿瘤大小，并诱导了PARP表达的显著降低。这些发现突出了MON类似物对GBM的治疗潜力，并支持类器官模型在抗癌药物发现中的应用。
Glioblastoma (GBM) remains the most frequently diagnosed primary malignant brain cancer in adults. Despite recent progress in understanding the biology of GBM, the clinical outcome for patients remains poor, with a median survival of approximately one year after diagnosis. One factor contributing to failure in clinical trials is the fact that traditional models used in GBM drug discovery poorly recapitulate patient tumors. Previous studies have shown that monensin (MON) analogs, namely esters and amides on C-26 were potent towards various types of cancer cell lines. In the present study we have investigated the activity of these molecules in GBM organoids, as well as in a host:tumor organoid model. Using a mini-ring cell viability assay we have identified seven analogs (IC50 = 91.5 ± 54.4–291.7 ± 68.8 nM) more potent than parent MON (IC50 = 612.6 ± 184.4 nM). Five of these compounds induced substantial DNA fragmentation in GBM organoids, suggestive of apoptotic cell death. The most active analog, compound 1, significantly reduced GBM cell migration, induced PARP degradation, diminished phosphorylation of STAT3, Akt and GSK3β, increased ɣH2AX signaling and upregulated expression of the autophagy associated marker LC3-II. To investigate the activity of MON and compound 1 in a tumor microenvironment, we developed human cerebral organoids (COs) from human induced pluripotent stem cells (iPSCs). The COs showed features of early developing brain such as multiple neural rosettes with a proliferative zone of neural stem cells (Nestin+), neurons (TUJ1 +), primitive ventricular system (SOX2 +/Ki67 +), intermediate zone (TBR2 +) and cortical plate (MAP2 +). In order to generate host:tumor organoids, we co-cultured RFP-labeled U87MG cells with fully formed COs. Compound 1 and MON reduced U87MG tumor size in the COs after four days of treatment and induced a significant reduction of PARP expression. These findings highlight the therapeutic potential of MON analogs towards GBM and support the application of organoid models in anti-cancer drug discovery.
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影响因子：
4.4
作者：
Majewska E;Szeliga M
通讯作者：
Szeliga M
影响因子：
64.8
作者：
通讯作者：
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影响因子：
4.1
作者：
Chang, Nakho;Ahn, Sun Hee;Nam, Do-Hyun
通讯作者：
Nam, Do-Hyun
影响因子：
--
作者：
Hart JR;Vogt PK
通讯作者：
Vogt PK
DOI：
10.1080/00021369.1990.10870088
发表时间：
1990-05-01
期刊：
AGRICULTURAL AND BIOLOGICAL CHEMISTRY
影响因子：
--
作者：
GABOYARD, C;DAUPHIN, G;JEMINET, G
通讯作者：
JEMINET, G