CBX5 loss drives Pl3Kδ inhibitor resistance in mantle cell lymphoma and propolis restores sensitivity by inducing CBX5-mediated ferroptosis

IF 6.7 1区医学 Q1 CHEMISTRY, MEDICINAL

Phytomedicine Pub Date : 2025-05-27 DOI:10.1016/j.phymed.2025.156911

Jun Lu , Ya-Qin Yang , Jia-Yi Tang , Si-Yue Lou , Chen Wang , Hong-Tao Hu , Ya-Nan Zheng , Hai An , Mao-Wei Ni , Hua-Jun Zhao

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引用次数: 0

Abstract

Background

The generation of drug-resistance limits chemotherapy application such as phosphoinositide 3-kinase δ (PI3Kδ) inhibitors in mantle cell lymphoma (MCL). Propolis has been regarded as a resistance reversal agent for many tumors, but its role in the sensitivity of MCL to PI3Kδ inhibitors remains unclear.

Purpose

The study investigated the synergistic effect, material basis and underlying mechanism of propolis in PI3Kδ inhibitor-resistant MCL cells.

Methods

A PI3Kδ inhibitor resistance-acquired model was established and proteomics was utilized to identify differentially expressed proteins. The ethanol extract of propolis (EEP) was obtained and its components were detected by using UPLC-Q-TOF-MS/MS analysis. Active ingredients with potential resistance-reversal effect were obtained by reverse pharmacology. The sensitizing effect of caffeic acid phenethyl ester (CAPE) on idelalisib was demonstrated by cell viability assay in vitro and tumor-growth study in vivo. RNA-sequencing was applied to obtain CAPE-regulated genes. The occurrence of ferroptosis was confirmed by relevant detections such as lipid ROS detection. The regulation of chromobox homolog 5 (CBX5) was achieved by molecular inhibitors, transfection of recombinant plasmid or siRNA.

Results

EEP combined with idelalisib synergistically reduced the viability of resistant MCL cells, with CAPE playing a major role. The combination of CAPE and idelalisib combated the growth of idelalisib-resistant MCL cells in vivo and in vitro by inducing ferroptosis. The CBX5 level influences the sensitivity to PI3Kδ inhibitors, and CAPE reversed resistance in MCL-R by inducing CBX5-mediated ferroptosis.

Conclusions

CBX5 loss drives Pl3Kδ inhibitor resistance in MCL and CAPE in propolis restores sensitivity by inducing CBX5-mediated ferroptosis. This is the first study to demonstrate the reversal of PI3Kδ inhibitor resistance through CAPE-induced ferroptosis via CBX5 modulation.

查看原文本刊更多论文

CBX5缺失驱动套细胞淋巴瘤中Pl3Kδ抑制剂的抗性，蜂胶通过诱导CBX5介导的铁凋亡来恢复敏感性

耐药的产生限制了化疗的应用，如磷酸肌苷3-激酶δ (PI3Kδ)抑制剂在套细胞淋巴瘤（MCL）中的应用。蜂胶被认为是许多肿瘤的耐药逆转剂，但其在MCL对PI3Kδ抑制剂的敏感性中的作用尚不清楚。目的探讨蜂胶对PI3Kδ抑制剂耐药MCL细胞的协同作用、物质基础及机制。方法建立PI3Kδ抑制剂获得性耐药模型，利用蛋白质组学方法鉴定差异表达蛋白。采用UPLC-Q-TOF-MS/MS对蜂胶乙醇提取物（EEP）的组分进行了检测。通过反向药理学方法获得具有潜在逆转耐药作用的有效成分。通过体外细胞活力测定和体内肿瘤生长研究证实了咖啡酸苯乙酯（CAPE）对理想细胞的增敏作用。应用rna测序获得cape调控基因。脂质ROS检测等相关检测证实铁下垂的发生。通过分子抑制剂、转染重组质粒或siRNA对CBX5进行调控。结果seep联合ideelalisib可协同降低MCL耐药细胞活力，其中CAPE起主要作用。CAPE联合idelalisib通过诱导铁凋亡，在体内和体外抑制idelalisib耐药MCL细胞的生长。CBX5水平影响对PI3Kδ抑制剂的敏感性，并且CAPE通过诱导CBX5介导的铁凋亡逆转MCL-R的耐药性。结论scbx5缺失导致MCL中Pl3Kδ抑制剂耐药，而蜂胶中的CAPE通过诱导cbx5介导的铁凋亡恢复敏感性。这是第一个通过CBX5调节cape诱导的铁下沉逆转PI3Kδ抑制剂耐药性的研究。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Phytomedicine 医学-药学

CiteScore

10.30

自引率

5.10%

发文量

670

审稿时长

91 days

期刊介绍： Phytomedicine is a therapy-oriented journal that publishes innovative studies on the efficacy, safety, quality, and mechanisms of action of specified plant extracts, phytopharmaceuticals, and their isolated constituents. This includes clinical, pharmacological, pharmacokinetic, and toxicological studies of herbal medicinal products, preparations, and purified compounds with defined and consistent quality, ensuring reproducible pharmacological activity. Founded in 1994, Phytomedicine aims to focus and stimulate research in this field and establish internationally accepted scientific standards for pharmacological studies, proof of clinical efficacy, and safety of phytomedicines.