从岗柃中提取的芒柄花黄素通过 STAT3 信号调节和 P-糖蛋白阻断来改善致癌性多药耐药。

Mosloflavone from Fissistigma petelotii ameliorates oncogenic multidrug resistance by STAT3 signaling modulation and P-glycoprotein blockade.

机构信息

Department of Pharmacy, China Medical University, No. 100, Sec. 1, Jingmao Rd., Beitun Dist., Taichung, Taiwan 406040, ROC; Department of Pharmacy, China Medical University Hospital, No. 2, Yude Rd., North Dist., Taichung, Taiwan 404332, ROC.

Department of Pharmacy, China Medical University, No. 100, Sec. 1, Jingmao Rd., Beitun Dist., Taichung, Taiwan 406040, ROC.

出版信息

Phytomedicine. 2024 Jan;123:155210. doi: 10.1016/j.phymed.2023.155210. Epub 2023 Nov 10.

DOI:10.1016/j.phymed.2023.155210

PMID:38006807

Abstract

BACKGROUND

Oncogenic multidrug resistance (MDR) is a tough question in cancer therapy. However, no effective medications targeting oncogenic MDR are currently available. Studies have demonstrated that mosloflavone exerts anti-inflammatory effects, yet, its potential to ameliorate MDR remains unclear.

PURPOSE

This study aimed to access the capability and elucidate molecular mechanisms of mosloflavone as a MDR resensitizing candidate.

METHODS

We investigated the ability of mosloflavone to reverse oncogenic MDR and investigated its underlying mechanisms through cytotoxicity assay, cell cycle assay, apoptosis assay, and zebrafish xenograft model. The modulatory interplay between mosloflavone and P-gp was investigated through analysis of calcein-AM uptake, substrate efflux, ATPase assays, and molecular docking simulation.

RESULTS

Mosloflavone inhibited P-gp efflux function in an uncompetitive manner without altering ABCB1 gene expression. In addition, it stimulated P-gp ATPase activity by binding to an active site distinct from that of verapamil. Regarding MDR reversal potential, mosloflavone resensitized MDR cancer cells to chemotherapies by arresting cell cycle and triggering apoptosis, possibly by enhancing reactive oxygen species accumulation and reducing phospho-STAT3. Moreover, in the zebrafish xenograft model, mosloflavone significantly potentiated the antitumor effect of paclitaxel.

CONCLUSION

Our findings underscore the potential of mosloflavone as a novel dual modulator of STAT3 and P-gp, indicating it is a promising candidate for overcoming MDR in cancer treatment.

摘要

背景

致癌性多药耐药（MDR）是癌症治疗中的一个难题。然而，目前尚无针对致癌性 MDR 的有效药物。研究表明，毛豆素具有抗炎作用，但它缓解 MDR 的潜力尚不清楚。

目的

本研究旨在评估毛豆素作为一种逆转多药耐药候选药物的能力，并阐明其分子机制。

方法

我们通过细胞毒性测定、细胞周期测定、凋亡测定和斑马鱼异种移植模型来研究毛豆素逆转致癌性 MDR 的能力，并探讨其潜在机制。通过分析 calcein-AM 摄取、底物外排、ATP 酶测定和分子对接模拟，研究了毛豆素与 P-糖蛋白之间的调节相互作用。

结果

毛豆素以非竞争性方式抑制 P-糖蛋白的外排功能，而不改变 ABCB1 基因表达。此外，它通过与维拉帕米不同的活性位点结合刺激 P-糖蛋白 ATP 酶活性。关于逆转多药耐药的潜力，毛豆素通过阻断细胞周期和触发细胞凋亡，使多药耐药癌细胞对化疗药物重新敏感，这可能是通过增加活性氧物质的积累和减少磷酸化 STAT3 来实现的。此外，在斑马鱼异种移植模型中，毛豆素显著增强了紫杉醇的抗肿瘤作用。