Exosomal delivery of AZD5582 to overcome TRAIL resistance as an optimal therapy against triple-negative breast cancer

IF 2.3 4区生物学 Q4 CELL BIOLOGY

Acta histochemica Pub Date : 2025-05-24 DOI:10.1016/j.acthis.2025.152270

Wanting Zhang , Quanjiang Li , Rui Tian , Zhujie Deng , Ronghui Sun , Xiubin Kuang , Jun Peng , Bin Xie , Chen Huang , Zhengqiang Yuan

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引用次数: 0

Abstract

Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer that lacks effective targeted therapies mainly due to drug resistance. Therefore, there is an urgent need to develop highly effective therapeutic strategies for TNBC. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis in transformed and cancerous cells, indicating its potential for anti-cancer therapy. Unfortunately, the clinical trials of recombinant TRAIL (rTRAIL) had actually failed due to the very common TRAIL resistance in cancers. Exosomal delivery of TRAIL (EV-T) has been shown to greatly improve the cytotoxicity of TRAIL. Moreover, the TRAIL resistance was closely correlated with the upregulation of inhibitors of apoptosis proteins (IAPs) in cancer cells. As a potent antagonist of IAPs, AZD5582 (AZD) was previously shown to drastically sensitize TRAIL response. Herein, we hypothesize that AZD may be loaded into EV-T for co-delivery of AZD and TRAIL to make a synergistic combination anticancer therapy against TNBC. First, TRAIL-expressing mesenchymal stem cells (MSCs) were used to prepare EV-Ts. Then, AZD was loaded into EV-T by ultrasound to prepare the composite nanodrug AZD@EV-T. EV encapsulation significantly improved AZD stability and cellular delivery efficiency, leading to the synergistically augmented cytotoxicity and apoptosis induction in both breast and kidney cancer cell lines, whilst sparing the normal MSCs. The potential mechanisms underlying the synergism appeared to be associated with the concomitant upregulation of death receptor 5 (DR5) and expressional suppression of various anti-apoptotic factors. Importantly, the AZD@EV-T therapy triggered strikingly enhanced growth inhibition and apoptosis in the subcutaneously established BT549 xenograft tumors, consequently leading to the complete tumor regression. It also demonstrated significant potential for treating kidney cancer in A498 kidney tumor organoids. Together, AZD@EV-T effectively overcomes TRAIL resistance and may represent a highly effective and innovative anticancer therapy for both TNBC and kidney cancers.

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外泌体递送AZD5582克服TRAIL耐药是治疗三阴性乳腺癌的最佳方法

三阴性乳腺癌（TNBC）是一种高度侵袭性的乳腺癌亚型，主要由于耐药而缺乏有效的靶向治疗。因此，迫切需要开发高效的TNBC治疗策略。肿瘤坏死因子（Tumor necrosis factor， TNF）相关凋亡诱导配体（apoptosis-inducing ligand， TRAIL）在转化细胞和癌细胞中选择性诱导凋亡，表明其具有抗癌治疗的潜力。不幸的是，重组TRAIL （rTRAIL）的临床试验实际上失败了，因为TRAIL在癌症中非常常见。外泌体递送TRAIL （EV-T）已被证明可大大改善TRAIL的细胞毒性。此外，TRAIL耐药与癌细胞中凋亡蛋白抑制剂（IAPs）的上调密切相关。作为一种有效的IAPs拮抗剂，AZD5582 （AZD）先前被证明能显著致敏TRAIL反应。在此，我们假设AZD可能被装载到EV-T中，共同递送AZD和TRAIL，从而形成针对TNBC的协同联合抗癌治疗。首先，利用表达trail的间充质干细胞（MSCs）制备EV-Ts。然后，通过超声将AZD加载到EV-T中，制备复合纳米药物AZD@EV-T。EV包封显著提高了AZD的稳定性和细胞递送效率，从而协同增强了乳腺癌和肾癌细胞系的细胞毒性和凋亡诱导，同时保留了正常的MSCs。协同作用的潜在机制似乎与死亡受体5 （DR5）的上调和各种抗凋亡因子的表达抑制有关。重要的是，AZD@EV-T治疗在皮下建立的BT549异种移植肿瘤中引发了显著增强的生长抑制和细胞凋亡，从而导致肿瘤完全消退。在A498肾肿瘤类器官中也显示出治疗肾癌的显著潜力。总之，AZD@EV-T有效地克服了TRAIL耐药性，可能代表了TNBC和肾癌的一种高效和创新的抗癌疗法。

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

Acta histochemica 生物-细胞生物学

CiteScore

4.60

自引率

4.00%

发文量

107

审稿时长

23 days

期刊介绍： Acta histochemica, a journal of structural biochemistry of cells and tissues, publishes original research articles, short communications, reviews, letters to the editor, meeting reports and abstracts of meetings. The aim of the journal is to provide a forum for the cytochemical and histochemical research community in the life sciences, including cell biology, biotechnology, neurobiology, immunobiology, pathology, pharmacology, botany, zoology and environmental and toxicological research. The journal focuses on new developments in cytochemistry and histochemistry and their applications. Manuscripts reporting on studies of living cells and tissues are particularly welcome. Understanding the complexity of cells and tissues, i.e. their biocomplexity and biodiversity, is a major goal of the journal and reports on this topic are especially encouraged. Original research articles, short communications and reviews that report on new developments in cytochemistry and histochemistry are welcomed, especially when molecular biology is combined with the use of advanced microscopical techniques including image analysis and cytometry. Letters to the editor should comment or interpret previously published articles in the journal to trigger scientific discussions. Meeting reports are considered to be very important publications in the journal because they are excellent opportunities to present state-of-the-art overviews of fields in research where the developments are fast and hard to follow. Authors of meeting reports should consult the editors before writing a report. The editorial policy of the editors and the editorial board is rapid publication. Once a manuscript is received by one of the editors, an editorial decision about acceptance, revision or rejection will be taken within a month. It is the aim of the publishers to have a manuscript published within three months after the manuscript has been accepted