Enhancing Chemosensitivity in Drug-Resistant Breast Cancer Cells Using β-Cyclodextrin-Loaded Quercetin and Doxorubicin Inclusion Complex via Modulating SRC/PI3K/Akt Pathway.

IF 3.1 4区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY
Charan Singh Pawar, Karankumar Balamurugan, Sugumar Baskar, N Rajendra Prasad, Haseeb A Khan
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引用次数: 0

Abstract

The challenge of multidrug resistance (MDR) in cancer, which hindered successful chemotherapy, was primarily due to the increased activity of drug efflux transporters in cancer cells. This study explored the potential of a nanosized inclusion complex to overcome drug resistance. The inclusion complex that we prepared contains a beta-cyclodextrin-based formulation encapsulating quercetin (QUE) and doxorubicin (DOX) (β-CD@QD IC), designed to enhance drug delivery and overcome MDR in cancer cells. Through integrative network pharmacology, 92 common targets were identified between QUE and cancer MDR, with SRC kinase emerging as a key target for inhibiting ABCG2 expression in MCF-7/DOX cancer cells. The β-CD@QD IC was formulated via freeze-drying method and characterized using spectroscopic and microscopic techniques. In vitro drug release studies showed that QUE and DOX from β-CD@QD IC exhibited sustained, controlled release, following Higuchi model kinetics. The anticancer efficacy of the complex was tested on MCF-7/DOX cells, where QUE modulated the ABCG2 efflux pump, enhancing the intracellular accumulation of DOX. In vitro assays demonstrated that the inclusion complex significantly increased cell cytotoxicity, induced nuclear condensation, disrupted mitochondrial membrane potential (ΔΨm), elevated reactive oxygen species (ROS) production, and triggered apoptosis-related morphological changes. Hoechst efflux studies demonstrated that QUE effectively inhibited the ABCG2 efflux pump, leading to increased accumulation of Hoechst dye in MCF-7/DOX cancer cells. QUE suppressed SRC kinase signaling, leading to decreased PI3K/Akt expression and reduced ABCG2 overexpression in MCF-7/DOX cells. This study indicated that the β-CD@QD IC loaded with QUE effectively overcame DOX resistance in MCF-7/DOX cells.

β-环糊精负载槲皮素和阿霉素包合物通过调节SRC/PI3K/Akt通路增强耐药乳腺癌细胞的化疗敏感性
癌症中多药耐药(MDR)的挑战阻碍了化疗的成功,主要是由于癌细胞中药物外排转运体活性的增加。这项研究探索了纳米级包合物克服耐药性的潜力。我们制备的包合物含有β-环糊精为基础的包合物,包合槲皮素(QUE)和阿霉素(DOX) (β-CD@QD IC),旨在增强药物在癌细胞中的传递和克服耐多药耐药。通过综合网络药理学,我们确定了QUE和癌症MDR之间的92个共同靶点,其中SRC激酶是抑制MCF-7/DOX癌细胞中ABCG2表达的关键靶点。通过冷冻干燥法制备β-CD@QD IC,并用光谱和显微技术对其进行表征。体外药物释放研究表明β-CD@QD IC中的QUE和DOX表现出持续、可控的释放,符合Higuchi模型动力学。在MCF-7/DOX细胞上测试了该复合物的抗癌功效,其中QUE调节ABCG2外排泵,增强DOX在细胞内的积累。体外实验表明,包合物显著增加细胞毒性,诱导核凝聚,破坏线粒体膜电位(ΔΨm),提高活性氧(ROS)的产生,并引发细胞凋亡相关的形态学改变。Hoechst外排研究表明,QUE有效抑制ABCG2外排泵,导致MCF-7/DOX癌细胞中Hoechst染料的积累增加。QUE抑制SRC激酶信号传导,导致MCF-7/DOX细胞中PI3K/Akt表达降低,ABCG2过表达减少。本研究表明,β-CD@QD IC负载QUE能有效克服MCF-7/DOX细胞对DOX的抗性。
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来源期刊
Applied Biochemistry and Biotechnology
Applied Biochemistry and Biotechnology 工程技术-生化与分子生物学
CiteScore
5.70
自引率
6.70%
发文量
460
审稿时长
5.3 months
期刊介绍: This journal is devoted to publishing the highest quality innovative papers in the fields of biochemistry and biotechnology. The typical focus of the journal is to report applications of novel scientific and technological breakthroughs, as well as technological subjects that are still in the proof-of-concept stage. Applied Biochemistry and Biotechnology provides a forum for case studies and practical concepts of biotechnology, utilization, including controls, statistical data analysis, problem descriptions unique to a particular application, and bioprocess economic analyses. The journal publishes reviews deemed of interest to readers, as well as book reviews, meeting and symposia notices, and news items relating to biotechnology in both the industrial and academic communities. In addition, Applied Biochemistry and Biotechnology often publishes lists of patents and publications of special interest to readers.
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