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Induction of P-glycoprotein expression by dandelion in tumor and heart tissues: Impact on the anti-tumor activity and cardiotoxicity of doxorubicin
Phytomedicine ( IF 7.9 ) Pub Date : 2022-06-12 , DOI: 10.1016/j.phymed.2022.154275
Jiameng Qu 1 , Fan Ke 2 , Xiao Yang 2 , Yue Wang 2 , Huarong Xu 2 , Qing Li 2 , Kaishun Bi 2
Affiliation  

Background

Previously, we have investigated the anti-tumor activity and mechanism through which dandelion acts against triple-negative breast cancer (TNBC). However, traditional Chinese medicine is mostly accepted as an adjunct therapy during chemotherapy in clinical practice. So far, little is known about the effects of dandelion in conjunction with chemotherapeutic drugs.

Purpose

To investigate the effects of dandelion on the anti-tumor activity and cardiotoxicity of doxorubicin (DOX), and to further explore the molecular mechanisms through which these effects occur.

Study design

At the beginning of this study, dandelion was observed to alleviate DOX-induced cardiotoxicity and reduce the anti-tumor activity of DOX. Subsequently, we investigated whether the resistance to DOX mediated by P-glycoprotein was involved in the above effects.

Methods

The cardioprotective effect of dandelion was investigated on DOX-treated mice by histological analysis, myocardial enzyme assays, and an untargeted metabolomics study based on LC-Q-TOF/MS. TNBC cell lines and 4T1 tumor-bearing mice were employed to investigate the combined anti-tumor activity. Laser scanning confocal microscope and a flow cytometry analysis were employed to measure the intracellular accumulation of DOX. A specific, sensitive, and rapid LC–MS/MS method was developed to detect the efflux of DOX from cells. Expression of P-glycoprotein in mouse tumor and heart tissues was detected via Western blotting analysis.

Results

Dandelion was found to significantly alleviate DOX-induced cardiotoxicity, as was evidenced by improved cardiomyocyte morphology, decreased LDH and CK-MB release, and adjusted metabolic biomarker levels. However, in vitro and in vivo studies showed that dandelion could reduce the anti-tumor activity of DOX. This counteraction was achieved by activating of the drug efflux transporter P-glycoprotein, thereby promoting the efflux of DOX from cells and reducing the intracellular accumulation of DOX. Moreover, the activation of P-glycoprotein by dandelion in mouse heart tissue was also observed, thus suggesting that the decrease of cardiac DOX accumulation plays an important role in the cardioprotective effect of dandelion.

Conclusion

Dandelion can activate the P-glycoprotein in heart and tumor tissues, which ameliorates DOX-induced cardiotoxicity but attenuates DOX cytotoxicity toward TNBC. Our findings have important implications for the correct clinical use of dandelion.



中文翻译:

蒲公英在肿瘤和心脏组织中诱导P-糖蛋白表达:对多柔比星抗肿瘤活性和心脏毒性的影响

背景

此前,我们研究了蒲公英对抗三阴性乳腺癌 (TNBC) 的抗肿瘤活性和机制。然而,在临床实践中,中药大多被接受为化疗期间的辅助疗法。到目前为止,关于蒲公英与化疗药物联合使用的效果知之甚少。

目的

研究蒲公英对阿霉素(DOX)的抗肿瘤活性和心脏毒性的影响,并进一步探索这些影响发生的分子机制。

学习规划

在本研究开始时,观察到蒲公英可减轻 DOX 诱导的心脏毒性并降低 DOX 的抗肿瘤活性。随后,我们研究了P-糖蛋白介导的对DOX的抗性是否与上述作用有关。

方法

通过组织学分析、心肌酶测定和基于 LC-Q-TOF/MS 的非靶向代谢组学研究,研究了蒲公英对 DOX 治疗小鼠的心脏保护作用。采用 TNBC 细胞系和 4T1 荷瘤小鼠研究联合抗肿瘤活性。激光扫描共聚焦显微镜和流式细胞仪分析用于测量 DOX 的细胞内积累。开发了一种特异性、灵敏和快速的 LC-MS/MS 方法来检测 DOX 从细胞中流出。通过蛋白质印迹分析检测P-糖蛋白在小鼠肿瘤和心脏组织中的表达。

结果

发现蒲公英可显着减轻 DOX 诱导的心脏毒性,这可以通过改善心肌细胞形态、减少 LDH 和 CK-MB 释放以及调整代谢生物标志物水平来证明。然而,体外体内研究表明,蒲公英可以降低 DOX 的抗肿瘤活性。这种抵消作用是通过激活药物流出转运蛋白 P-糖蛋白来实现的,从而促进 DOX 从细胞中流出并减少 DOX 的细胞内积累。此外,还观察到蒲公英对小鼠心脏组织中P-糖蛋白的活化作用,表明减少心脏DOX积累在蒲公英的心脏保护作用中起重要作用。

结论

蒲公英可以激活心脏和肿瘤组织中的 P-糖蛋白,从而改善 DOX 诱导的心脏毒性,但减弱 DOX 对 TNBC 的细胞毒性。我们的研究结果对蒲公英的正确临床使用具有重要意义。

更新日期:2022-06-12
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