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Applied biochemistry and biotechnology
Mar 26, 2025;

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

Charan Singh Pawar, Karankumar Balamurugan, Sugumar Baskar, N Rajendra Prasad, Haseeb A Khan
Author Information
  1. Charan Singh Pawar: Department of Biochemistry and Biotechnology, Annamalai University, Annamalai Nagar, 608002, Tamil Nadu, India.
  2. Karankumar Balamurugan: Department of Biochemistry and Biotechnology, Annamalai University, Annamalai Nagar, 608002, Tamil Nadu, India.
  3. Sugumar Baskar: Department of Biochemistry and Biotechnology, Annamalai University, Annamalai Nagar, 608002, Tamil Nadu, India.
  4. N Rajendra Prasad: Department of Biochemistry and Biotechnology, Annamalai University, Annamalai Nagar, 608002, Tamil Nadu, India. drprasadnr@gmail.com.
  5. Haseeb A Khan: Department of Biochemistry, College of Science, King Saud University, 11451, Riyadh, Saudi Arabia.
PMID: 40138138 DOI: 10.1007/s12010-025-05219-y

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.

Keywords

β-cyclodextrin inclusion complex ABCG2 Doxorubicin Multidrug resistance Network pharmacology Quercetin

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Grants

  1. DRD/RUSA 2.0/ R&I/Field 2/2021/Rashtriya Uchchatar Shiksha Abhiyan
  2. RSPD2025R770/Researchers Supporting Project Number
Journal Article

Word Cloud

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