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ONC201/TIC10 和 2-脱氧葡萄糖双重代谢重编程导致脑胶质瘤能量耗竭和协同抗癌活性。

Dual metabolic reprogramming by ONC201/TIC10 and 2-Deoxyglucose induces energy depletion and synergistic anti-cancer activity in glioblastoma.

机构信息

Department of Neurological Surgery, Ulm University Medical Center, Ulm, Germany.

IIAIG, Study Center, Burlington, VT, USA.

出版信息

Br J Cancer. 2020 Apr;122(8):1146-1157. doi: 10.1038/s41416-020-0759-0. Epub 2020 Mar 2.

DOI:10.1038/s41416-020-0759-0
PMID:32115576
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7156767/
Abstract

BACKGROUND

Dysregulation of the metabolome is a hallmark of primary brain malignancies. In this work we examined whether metabolic reprogramming through a multi-targeting approach causes enhanced anti-cancer activity in glioblastoma.

METHODS

Preclinical testing of a combined treatment with ONC201/TIC10 and 2-Deoxyglucose was performed in established and primary-cultured glioblastoma cells. Extracellular flux analysis was used to determine real-time effects on OXPHOS and glycolysis. Respiratory chain complexes were analysed by western blotting. Biological effects on tumour formation were tested on the chorioallantoic membrane (CAM).

RESULTS

ONC201/TIC10 impairs mitochondrial respiration accompanied by an increase of glycolysis. When combined with 2-Deoxyglucose, ONC201/TIC10 induces a state of energy depletion as outlined by a significant decrease in ATP levels and a hypo-phosphorylative state. As a result, synergistic anti-proliferative and anti-migratory effects were observed among a broad panel of different glioblastoma cells. In addition, this combinatorial approach significantly impaired tumour formation on the CAM.

CONCLUSION

Treatment with ONC201/TIC10 and 2-Deoxyglucose results in a dual metabolic reprogramming of glioblastoma cells resulting in a synergistic anti-neoplastic activity. Given, that both agents penetrate the blood-brain barrier and have been used in clinical trials with a good safety profile warrants further clinical evaluation of this therapeutic strategy.

摘要

背景

代谢组的失调是原发性脑恶性肿瘤的一个标志。在这项工作中，我们研究了通过多靶点方法进行代谢重编程是否会导致胶质母细胞瘤的抗癌活性增强。

方法

在已建立的和原代培养的胶质母细胞瘤细胞中，对 ONC201/TIC10 和 2-脱氧葡萄糖的联合治疗进行了临床前测试。利用细胞外通量分析来实时测定对 OXPHOS 和糖酵解的影响。通过 Western blot 分析呼吸链复合物。在鸡胚尿囊膜 (CAM) 上测试对肿瘤形成的生物学影响。

结果

ONC201/TIC10 损害线粒体呼吸，同时增加糖酵解。当与 2-脱氧葡萄糖联合使用时，ONC201/TIC10 会导致能量耗竭，表现为 ATP 水平显著下降和低磷酸化状态。结果，在广泛的不同胶质母细胞瘤细胞中观察到协同的抗增殖和抗迁移作用。此外，这种组合方法显著抑制了 CAM 上的肿瘤形成。

结论

ONC201/TIC10 和 2-脱氧葡萄糖的治疗导致胶质母细胞瘤细胞的双重代谢重编程，从而产生协同的抗肿瘤活性。鉴于这两种药物都能穿透血脑屏障，并已在具有良好安全性的临床试验中使用，因此值得进一步评估这种治疗策略的临床应用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/44f5/7156767/8f1f57292543/41416_2020_759_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/44f5/7156767/ff596a41128e/41416_2020_759_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/44f5/7156767/b0474e8fcbfb/41416_2020_759_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/44f5/7156767/8ea9a15eb3fc/41416_2020_759_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/44f5/7156767/62e57dc70cc7/41416_2020_759_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/44f5/7156767/d9c24102d896/41416_2020_759_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/44f5/7156767/8f1f57292543/41416_2020_759_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/44f5/7156767/ff596a41128e/41416_2020_759_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/44f5/7156767/b0474e8fcbfb/41416_2020_759_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/44f5/7156767/8ea9a15eb3fc/41416_2020_759_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/44f5/7156767/62e57dc70cc7/41416_2020_759_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/44f5/7156767/d9c24102d896/41416_2020_759_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/44f5/7156767/8f1f57292543/41416_2020_759_Fig6_HTML.jpg

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