Chaga Mushroom Triterpenoids Inhibit Dihydrofolate Reductase and Act Synergistically with Conventional Therapies in Breast Cancer.

IF 4.8 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biomolecules Pub Date : 2024-11-17 DOI:10.3390/biom14111454

Junbiao Wang, Daniela Beghelli, Augusto Amici, Stefania Sut, Stefano Dall'Acqua, Giulio Lupidi, Diego Dal Ben, Onelia Bistoni, Daniele Tomassoni, Barbara Belletti, Sanaa Musa, Jamal Mahajna, Stefania Pucciarelli, Cristina Marchini

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Abstract

Inonotus obliquus (Chaga) is a medicinal mushroom with several pharmacological properties that is used as a tea in traditional Chinese medicine. In this study, Chaga water extract was digested in vitro to mimic the natural processing and absorption of its biocomponents when it is consumed as functional beverage, and its anticancer activities were evaluated in breast cancer (BC) cell lines, representing HER2-positive and triple-negative subtypes. After chemical characterization by liquid chromatography/mass spectrometry (HR-QTOF) analysis, the effect of Chaga biocomponents on cell viability and cell cycle progression was assessed by MTT assay, FACS analysis, and Western blot. Dihydrofolate reductase (DHFR) activity was measured by an enzymatic assay. Four highly bioactive triterpenoids (inotodiol, trametenolic acid, 3-hydroxy-lanosta-8,24-dien-21-al, and betulin) were identified as the main components, able to decrease BC cell viability and block the cell cycle in G0/G1 by inducing the downregulation of cyclin D1, CDK4, cyclin E, and phosphorylated retinoblastoma protein. DHFR was identified as their crucial target. Moreover, bioactive Chaga components exerted a synergistic action with cisplatin and with trastuzumab in SK-BR-3 cells by inhibiting both HER2 and HER1 activation and displayed an immunomodulatory effect. Thus, Inonotus obliquus represents a source of triterpenoids that are effective against aggressive BC subtypes and display properties of targeted drugs.

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查加蘑菇三萜类化合物可抑制二氢叶酸还原酶，并与乳腺癌的常规疗法协同作用。

黑木耳（Chaga）是一种具有多种药理特性的药用蘑菇，在传统中药中被用作茶饮。本研究在体外消化了 Chaga 水提取物，以模拟其生物成分在作为功能饮料饮用时的自然加工和吸收过程，并在代表 HER2 阳性和三阴性亚型的乳腺癌（BC）细胞系中评估了其抗癌活性。通过液相色谱/质谱（HR-QTOF）分析确定化学特征后，采用MTT试验、FACS分析和Western印迹法评估了Chaga生物成分对细胞活力和细胞周期进展的影响。二氢叶酸还原酶（DHFR）的活性是通过酶法测定得出的。四种高生物活性的三萜类化合物（肌醇、曲美烯醇酸、3-羟基-lanosta-8,24-dien-21-al 和 betulin）被确定为主要成分，它们能够通过诱导细胞周期蛋白 D1、CDK4、细胞周期蛋白 E 和磷酸化视网膜母细胞瘤蛋白的下调，降低 BC 细胞的活力并阻滞 G0/G1 细胞周期。DHFR 被确定为其关键靶点。此外，在SK-BR-3细胞中，生物活性Chaga成分通过抑制HER2和HER1的活化，与顺铂和曲妥珠单抗发挥协同作用，并显示出免疫调节效应。因此，黑木耳是一种三萜类化合物的来源，可有效抑制侵袭性BC亚型，并显示出靶向药物的特性。

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来源期刊

Biomolecules Biochemistry, Genetics and Molecular Biology-Molecular Biology

CiteScore

9.40

自引率

3.60%

发文量

1640

审稿时长

18.28 days

期刊介绍： Biomolecules (ISSN 2218-273X) is an international, peer-reviewed open access journal focusing on biogenic substances and their biological functions, structures, interactions with other molecules, and their microenvironment as well as biological systems. Biomolecules publishes reviews, regular research papers and short communications. Our aim is to encourage scientists to publish their experimental and theoretical results in as much detail as possible. There is no restriction on the length of the papers. The full experimental details must be provided so that the results can be reproduced.