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Enhancing Chemosensitivity in Drug-Resistant Breast Cancer Cells Using β-Cyclodextrin-Loaded Quercetin and

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A novel nanosized inclusion complex of quercetin and doxorubicin effectively overcomes multidrug resistance (MDR) in cancer by inhibiting the ABCG2 efflux pump and suppressing SRC kinase signaling, enhancing chemotherapy efficacy.

Keywords:
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Area of Science:

  • Nanomedicine
  • Pharmacology
  • Cancer Biology

Background:

  • Multidrug resistance (MDR) in cancer, driven by drug efflux transporters, limits chemotherapy effectiveness.
  • Nanosized drug delivery systems offer potential strategies to overcome MDR.
  • Quercetin (QUE) and doxorubicin (DOX) are key compounds with anticancer properties.

Purpose of the Study:

  • To develop and evaluate a beta-cyclodextrin-based nanosized inclusion complex (β-CD@QD IC) encapsulating QUE and DOX.
  • To investigate the potential of β-CD@QD IC to overcome doxorubicin resistance in MCF-7/DOX cancer cells.
  • To elucidate the underlying mechanisms of action, including the role of SRC kinase and ABCG2 efflux pump inhibition.

Main Methods:

  • Integrative network pharmacology to identify common targets between QUE and cancer MDR.
  • Formulation of β-CD@QD IC using freeze-drying and characterization via spectroscopic and microscopic techniques.
  • In vitro studies including drug release kinetics, cytotoxicity assays, apoptosis induction, ROS production, and Hoechst efflux studies on MCF-7/DOX cells.

Main Results:

  • Network pharmacology identified SRC kinase as a key target for inhibiting ABCG2 expression.
  • β-CD@QD IC demonstrated sustained and controlled release of QUE and DOX.
  • QUE within the complex effectively inhibited the ABCG2 efflux pump, increasing intracellular DOX accumulation.
  • The inclusion complex significantly enhanced cytotoxicity, induced apoptosis, and suppressed SRC kinase signaling, leading to reduced ABCG2 overexpression.

Conclusions:

  • The developed β-CD@QD IC effectively overcomes doxorubicin resistance in MCF-7/DOX cells.
  • QUE plays a crucial role in modulating the ABCG2 efflux pump and SRC kinase pathway.
  • This nanosized inclusion complex holds promise as a therapeutic strategy to enhance chemotherapy efficacy in MDR cancers.