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二乙基二硫代氨基甲酸盐-氧化亚铁纳米颗粒抑制人源和小鼠胶质母细胞瘤干性：醛脱氢酶1A1抑制和铁死亡诱导

Diethyldithiocarbamate-ferrous oxide nanoparticles inhibit human and mouse glioblastoma stemness: aldehyde dehydrogenase 1A1 suppression and ferroptosis induction.

作者信息

Abu-Serie Marwa M, Osuka Satoru, Heikal Lamiaa A, Teleb Mohamed, Barakat Assem, Dudeja Vikas

机构信息

Medical Biotechnology Department, Genetic Engineering and Biotechnology Research Institute, City of Scientific Research and Technological Applications (SRTA-City), Alexandria, Egypt.

Department of Neurosurgery, School of Medicine and O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham (UAB), Birmingham, AL, United States.

出版信息

Front Pharmacol. 2024 Apr 24;15:1363511. doi: 10.3389/fphar.2024.1363511. eCollection 2024.

DOI:10.3389/fphar.2024.1363511
PMID:38720782
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11076782/
Abstract

The development of effective therapy for eradicating glioblastoma stem cells remains a major challenge due to their aggressive growth, chemoresistance and radioresistance which are mainly conferred by aldehyde dehydrogenase (ALDH)1A1. The latter is the main stemness mediator via enhancing signaling pathways of Wnt/β-catenin, phosphatidylinositol 3-kinase/AKT, and hypoxia. Furthermore, ALDH1A1 mediates therapeutic resistance by inactivating drugs, stimulating the expression of drug efflux transporters, and detoxifying reactive radical species, thereby apoptosis arresting. Recent reports disclosed the potent and broad-spectrum anticancer activities of the unique nanocomplexes of diethyldithiocarbamate (DE, ALDH1A1 inhibitor) with ferrous oxide nanoparticles (FeO NPs) mainly conferred by inducing lipid peroxidation-dependent non-apoptotic pathways (iron accumulation-triggered ferroptosis), was reported. Accordingly, the anti-stemness activity of nanocomplexes (DE-FeO NPs) was investigated against human and mouse glioma stem cells (GSCs) and radioresistant GSCs (GSCs-RR). DE-FeO NPs exhibited the strongest growth inhibition effect on the treated human GSCs (MGG18 and JX39P), mouse GSCs (GS and PDGF-GSC) and their radioresistant cells (IC ≤ 70 and 161 μg/mL, respectively). DE-FeO NPs also revealed a higher inhibitory impact than standard chemotherapy (temozolomide, TMZ) on self-renewal, cancer repopulation, chemoresistance, and radioresistance potentials. Besides, DE-FeO NPs surpassed TMZ regarding the effect on relative expression of all studied stemness genes, as well as relative p-AKT/AKT ratio in the treated MGG18, GS and their radioresistant (MGG18-RR and GS-RR). This potent anti-stemness influence is primarily attributed to ALDH1A1 inhibition and ferroptosis induction, as confirmed by significant elevation of cellular reactive oxygen species and lipid peroxidation with significant depletion of glutathione and glutathione peroxidase 4. DE-FeO NPs recorded the optimal Log value for crossing the blood brain barrier. This novel study declared the potency of DE-FeO NPs for collapsing GSCs and GSCs-RR with improving their sensitivity to chemotherapy and radiotherapy, indicating that DE-FeO NPs may be a promising remedy for GBM. Glioma animal models will be needed for in-depth studies on its safe effectiveness.

摘要

由于胶质母细胞瘤干细胞具有侵袭性生长、化学抗性和放射抗性，而这些特性主要由醛脱氢酶（ALDH）1A1赋予，因此开发有效的根除胶质母细胞瘤干细胞的疗法仍然是一项重大挑战。后者是主要的干性调节因子，通过增强Wnt/β-连环蛋白、磷脂酰肌醇3-激酶/AKT和缺氧信号通路来实现。此外，ALDH1A1通过使药物失活、刺激药物外排转运蛋白的表达以及使活性自由基解毒来介导治疗抗性，从而阻止细胞凋亡。最近的报告披露了二乙基二硫代氨基甲酸盐（DE，ALDH1A1抑制剂）与氧化亚铁纳米颗粒（FeO NPs）形成的独特纳米复合物具有强大且广谱的抗癌活性，主要是通过诱导脂质过氧化依赖性非凋亡途径（铁积累引发的铁死亡）。因此，研究了纳米复合物（DE-FeO NPs）对人和小鼠胶质瘤干细胞（GSCs）以及放射抗性GSCs（GSCs-RR）的抗干性活性。DE-FeO NPs对经处理的人GSCs（MGG18和JX39P）、小鼠GSCs（GS和PDGF-GSC）及其放射抗性细胞表现出最强的生长抑制作用（IC分别≤70和161μg/mL）。DE-FeO NPs还显示出比标准化疗药物替莫唑胺（TMZ）对自我更新、癌症再增殖、化学抗性和放射抗性潜力具有更高的抑制作用。此外，在对经处理的MGG18、GS及其放射抗性细胞（MGG18-RR和GS-RR）中所有研究的干性基因的相对表达以及相对p-AKT/AKT比率的影响方面，DE-FeO NPs超过了TMZ。这种强大的抗干性影响主要归因于ALDH1A1的抑制和铁死亡的诱导，细胞活性氧和脂质过氧化的显著升高以及谷胱甘肽和谷胱甘肽过氧化物酶4的显著消耗证实了这一点。DE-FeO NPs记录到穿越血脑屏障的最佳Log值。这项新研究表明DE-FeO NPs具有瓦解GSCs和GSCs-RR并提高它们对化疗和放疗敏感性的潜力，表明DE-FeO NPs可能是胶质母细胞瘤的一种有前景的治疗方法。需要胶质瘤动物模型来深入研究其安全性和有效性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9587/11076782/ec8fda714cc9/fphar-15-1363511-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9587/11076782/5bf08ec419bb/fphar-15-1363511-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9587/11076782/2d4668c61206/fphar-15-1363511-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9587/11076782/3ef3f817a8c5/fphar-15-1363511-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9587/11076782/3fa5b9637645/fphar-15-1363511-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9587/11076782/a6be8f96825a/fphar-15-1363511-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9587/11076782/9abde140f3bb/fphar-15-1363511-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9587/11076782/0107fac24542/fphar-15-1363511-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9587/11076782/d56af273d3e4/fphar-15-1363511-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9587/11076782/ec8fda714cc9/fphar-15-1363511-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9587/11076782/5bf08ec419bb/fphar-15-1363511-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9587/11076782/2d4668c61206/fphar-15-1363511-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9587/11076782/3ef3f817a8c5/fphar-15-1363511-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9587/11076782/3fa5b9637645/fphar-15-1363511-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9587/11076782/a6be8f96825a/fphar-15-1363511-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9587/11076782/9abde140f3bb/fphar-15-1363511-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9587/11076782/0107fac24542/fphar-15-1363511-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9587/11076782/d56af273d3e4/fphar-15-1363511-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9587/11076782/ec8fda714cc9/fphar-15-1363511-g009.jpg

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[3]
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Front Oncol. 2025-1-30

[4]
Ferroptosis- and stemness inhibition-mediated therapeutic potency of ferrous oxide nanoparticles-diethyldithiocarbamate using a co-spheroid 3D model of pancreatic cancer.

J Gastroenterol. 2025-5

[5]
NFE2L2 and ferroptosis resistance in cancer therapy.

Cancer Drug Resist. 2024-10-25

[6]
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本文引用的文献

[1]
Synergistic eradicating impact of 5-fluouracil with FeO nanoparticles-diethyldithiocarbamate in colon cancer spheroids.

Nanomedicine (Lond). 2024

[2]
CREB5 promotes the proliferation and self-renewal ability of glioma stem cells.

Cell Death Discov. 2024-2-28

[3]
Deciphering the link: ferroptosis and its role in glioma.

Front Immunol. 2024

[4]
NIR-promoted ferrous ion regeneration enhances ferroptosis for glioblastoma treatment.

J Control Release. 2024-4

[5]
Research progress on ferroptosis in gliomas (Review).

Oncol Lett. 2023-11-27

[6]
A comparative study of smart nanoformulations of diethyldithiocarbamate with CuO nanoparticles or zinc oxide nanoparticles for efficient eradication of metastatic breast cancer.

Sci Rep. 2023-3-2

[7]
Targeted ferroptotic potency of ferrous oxide nanoparticles-diethyldithiocarbamate nanocomplex on the metastatic liver cancer.

Front Pharmacol. 2023-1-4

[8]
Drug and apoptosis resistance in cancer stem cells: a puzzle with many pieces.

Cancer Drug Resist. 2022-8-2

[9]
ALDH1: A potential therapeutic target for cancer stem cells in solid tumors.

Front Oncol. 2022-10-28

[10]
Ferroptosis and Its Potential Role in Glioma: From Molecular Mechanisms to Therapeutic Opportunities.

Antioxidants (Basel). 2022-10-28

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