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二甲双胍可提高阿霉素在小鼠乳腺癌中的疗效,并增加CD8 + T细胞频率。

Metformin boosts doxorubicin efficacy and increases CD8 + T cell frequency in mouse breast cancer.

作者信息

Hassani Elaheh, Mozzendizaji Sahand, Shafiei-Irannejad Vahid, Mohammadzadeh Adel

机构信息

Student Research Committee, Urmia University of Medical Sciences, Urmia, Iran.

Department of Immunology, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran.

出版信息

Clin Transl Oncol. 2025 May;27(5):2060-2066. doi: 10.1007/s12094-024-03764-2. Epub 2024 Oct 29.

DOI:10.1007/s12094-024-03764-2
PMID:39472348
Abstract

PURPOSE

Breast cancer is a leading cause of cancer-related deaths among women worldwide. The presence and function of CD8 + T cells in the tumor microenvironment have been associated with better patient outcomes. Drug toxicity has posed a significant challenge to the clinical implementation of chemotherapy-based strategies in cancer treatment.

METHODS

In this study, we employed flow cytometry to investigate the potential synergistic immunomodulatory effects on CD8 + T cells in a mouse model of breast cancer by combining metformin, an anti-diabetic medication, with doxorubicin.

RESULTS

Through flow cytometry analysis, we observed that the combination of the two drugs led to an increased percentage of CD8 + T cells compared to either drug alone. The modulation of HIF-1α and  STAT3 gene expression in the combination group further confirmed the efficacy of this approach.

CONCLUSIONS

Our findings suggest that combining metformin with doxorubicin can enhance the anticancer activity of doxorubicin and decrease its cytotoxicity in a 4T1 breast cancer mouse model.

摘要

目的

乳腺癌是全球女性癌症相关死亡的主要原因。肿瘤微环境中CD8 + T细胞的存在和功能与患者更好的预后相关。药物毒性对基于化疗的癌症治疗策略的临床实施构成了重大挑战。

方法

在本研究中,我们通过将抗糖尿病药物二甲双胍与阿霉素联合使用,采用流式细胞术研究其在乳腺癌小鼠模型中对CD8 + T细胞的潜在协同免疫调节作用。

结果

通过流式细胞术分析,我们观察到与单独使用任何一种药物相比,两种药物联合使用导致CD8 + T细胞百分比增加。联合组中HIF-1α和STAT3基因表达的调节进一步证实了该方法的有效性。

结论

我们的研究结果表明,在4T1乳腺癌小鼠模型中,二甲双胍与阿霉素联合使用可增强阿霉素的抗癌活性并降低其细胞毒性。

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Clin Transl Oncol. 2025 May;27(5):2060-2066. doi: 10.1007/s12094-024-03764-2. Epub 2024 Oct 29.
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本文引用的文献

1
STAT3 drives the expression of HIF1alpha in cancer cells through a novel super-enhancer.STAT3 通过新型超级增强子驱动癌细胞中 HIF1alpha 的表达。
Biochem Biophys Res Commun. 2024 Nov 26;735:150483. doi: 10.1016/j.bbrc.2024.150483. Epub 2024 Jul 31.
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The Impact of Metformin on Tumor-Infiltrated Immune Cells: Preclinical and Clinical Studies.二甲双胍对肿瘤浸润免疫细胞的影响:临床前和临床研究。
Int J Mol Sci. 2023 Aug 28;24(17):13353. doi: 10.3390/ijms241713353.
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Metabolites and Immune Response in Tumor Microenvironments.肿瘤微环境中的代谢物与免疫反应
Cancers (Basel). 2023 Jul 31;15(15):3898. doi: 10.3390/cancers15153898.
4
STAT3 and HIF1α cooperatively mediate the transcriptional and physiological responses to hypoxia.信号转导及转录激活因子3(STAT3)和缺氧诱导因子1α(HIF1α)共同介导对缺氧的转录和生理反应。
Cell Death Discov. 2023 Jul 5;9(1):226. doi: 10.1038/s41420-023-01507-w.
5
Synergistic cytotoxic effects of an extremely low-frequency electromagnetic field with doxorubicin on MCF-7 cell line.极低频电磁场与阿霉素联合对 MCF-7 细胞系的协同细胞毒性作用。
Sci Rep. 2023 May 31;13(1):8844. doi: 10.1038/s41598-023-35767-4.
6
Metformin: update on mechanisms of action and repurposing potential.二甲双胍:作用机制及再利用潜力的最新研究进展。
Nat Rev Endocrinol. 2023 Aug;19(8):460-476. doi: 10.1038/s41574-023-00833-4. Epub 2023 May 2.
7
Metformin and Dapagliflozin Attenuate Doxorubicin-Induced Acute Cardiotoxicity in Wistar Rats: An Electrocardiographic, Biochemical, and Histopathological Approach.二甲双胍和达格列净减轻多柔比星诱导的 Wistar 大鼠急性心脏毒性:心电图、生化和组织病理学方法。
Cardiovasc Toxicol. 2023 Feb;23(2):107-119. doi: 10.1007/s12012-023-09784-8. Epub 2023 Feb 15.
8
Understanding breast cancer as a global health concern.理解乳腺癌作为一个全球健康问题。
Br J Radiol. 2022 Feb 1;95(1130):20211033. doi: 10.1259/bjr.20211033. Epub 2021 Dec 14.
9
Cytotoxic T cells are able to efficiently eliminate cancer cells by additive cytotoxicity.细胞毒性 T 细胞能够通过附加细胞毒性有效地消除癌细胞。
Nat Commun. 2021 Sep 1;12(1):5217. doi: 10.1038/s41467-021-25282-3.
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Biochem Pharmacol. 2021 Oct;192:114743. doi: 10.1016/j.bcp.2021.114743. Epub 2021 Aug 26.