3'-epi-12β-hydroxyfroside 可诱导 ABCG2 自噬降解，克服肺癌细胞的耐药性

IF 6.9 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Biomedicine & Pharmacotherapy Pub Date : 2025-04-23 DOI:10.1016/j.biopha.2025.118085

Ri-Hong Wu, Wei-Jing Xie, Shu-Zhen Dai, Ming-Hui Chen, Guang-Hong Tan, Feng-Ying Huang

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引用次数: 0

摘要

目的：abcg2通过跨细胞膜运输化学物质促进多药耐药。3 ' -epi-12β-羟基糖苷（HyFS）作为自噬诱导剂具有抗癌特性。本研究探讨HyFS是否能通过促进自噬介导的ABCG2降解来克服耐药。方法以2株非耐药肺癌细胞株H460和A549及其耐药亚系H460/MX20和A549/MX10为实验模型。采用免疫印迹、免疫荧光和流式细胞术检测ABCG2和自噬相关分子的表达。流式细胞术定量分析ABCG2外排及细胞死亡情况。采用MTT法测定细胞活力。此外，建立小鼠H460/MX20和A549/MX10模型，评估各种联合疗法的疗效和ABCG2的表达。结果HyFS治疗的效果与剂量和时间有关，剂量和时间影响细胞的自噬通量。抑制自噬可恢复ABCG2的表达，导致ABCG2底物在细胞内积聚并促进其外排。HyFS处理使米托蒽醌耐药的H460/MX20和A549/MX10细胞对米托蒽醌增敏，增强米托蒽醌诱导的细胞活力降低并触发细胞凋亡。抑制自噬可以减轻这些影响。此外，HyFS治疗可降低ABCG2介导的米托蒽醌耐药，阻碍肿瘤进展。此外，米托蒽醌与HyFS联合在mx敏感和mx耐药小鼠肿瘤模型中均显示出良好的协同抗肿瘤作用，且无明显副作用。这些发现强调了HyFS通过自噬依赖性降解ABCG2来克服耐药的潜力，表明它有望成为一种治疗ABCG2介导的肺癌细胞耐药的方法。

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3'-epi-12β-hydroxyfroside induces autophagic degradation of ABCG2 to overcome drug resistance in lung cancer cells

Aims

ABCG2 contributes to multidrug resistance by transporting chemicals across cell membranes. 3′-epi-12β-hydroxyfroside (HyFS) is known for its anticancer properties as an autophagy inducer. This study investigates whether HyFS can overcome drug resistance by promoting autophagy-mediated ABCG2 degradation.

Methods

Two non-drug-resistant lung cancer cell lines, H460 and A549, along with their drug-resistant sublines, H460/MX20 and A549/MX10, were used as experimental models. Immunoblotting, immunofluorescence, and flow cytometry were used to assess the expression of ABCG2 and autophagy-related molecules. Flow cytometry was also used for quantitative analysis of ABCG2 efflux and cell death. Cell viability was assessed using the MTT assay. Additionally, murine models of H460/MX20 and A549/MX10 were established to evaluate the efficacy of various combination therapies and ABCG2 expression.

Results

The efficacy of HyFS treatment depends on dosage and duration, which influence autophagy flux in treated cells. Inhibition of autophagy restores ABCG2 expression, causing intracellular accumulation of ABCG2 substrates and promoting their efflux. HyFS treatment sensitizes mitoxantrone-resistant H460/MX20 and A549/MX10 cells to mitoxantrone, enhancing mitoxantrone-induced reduction in cell viability and triggering cell apoptosis. Inhibiting autophagy mitigates these effects. In addition, HyFS treatment reduces mitoxantrone resistance mediated by ABCG2 and hinders tumor progression. Moreover, the combination of mitoxantrone with HyFS shows promising synergistic antitumor effects in both MX-sensitive and MX-resistant murine tumor models without inducing any obvious side effects.

Significance

These findings highlight the potential of HyFS in overcoming drug resistance through autophagy-dependent degradation of ABCG2, suggesting its promise as a therapeutic approach against ABCG2-mediated drug resistance in lung cancer cells.

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来源期刊

Biomedicine & Pharmacotherapy 医学-药学

CiteScore

11.90

自引率

2.70%

发文量

1621

审稿时长

48 days

期刊介绍： Biomedicine & Pharmacotherapy stands as a multidisciplinary journal, presenting a spectrum of original research reports, reviews, and communications in the realms of clinical and basic medicine, as well as pharmacology. The journal spans various fields, including Cancer, Nutriceutics, Neurodegenerative, Cardiac, and Infectious Diseases.