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A Phenylfurocoumarin Derivative Reverses ABCG2-Mediated Multidrug Resistance In Vitro and In Vivo

Shoji Kokubo1, Shinobu Ohnuma1, Megumi Murakami1,2

  • 1Department of Surgery, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan.

International Journal of Molecular Sciences
|November 27, 2021
PubMed

Insights

Researchers identified a novel compound, phenylfurocoumarin derivative (PFC), that inhibits the ABCG2 transporter. This discovery offers a promising therapeutic strategy to enhance cancer chemotherapy effectiveness by overcoming multidrug resistance.

Area of Science:

  • Biochemistry
  • Pharmacology
  • Oncology

Background:

  • The ATP-binding cassette subfamily G member 2 (ABCG2) transporter is a key factor in multidrug resistance (MDR) in cancer.
  • Existing ABCG2 inhibitors have not yet achieved clinical application, necessitating the search for novel therapeutic agents.

Purpose of the Study:

  • To identify novel inhibitors of the ABCG2 transporter through high-throughput screening.
  • To evaluate the potential of identified compounds in overcoming ABCG2-mediated multidrug resistance in cancer.

Main Methods:

  • High-throughput screening of 5812 compounds using pheophorbide a (PhA) efflux assays (fluorescent plate reader and flow cytometry).
  • Cytotoxic assays to assess the impact of compounds on chemosensitivity.
  • In vivo studies using an ABCG2-overexpressing HCT-116/BCRP cell xenograft mouse model.

Main Results:

  • Sixteen potential ABCG2 inhibitors were identified from the initial screening.
  • The phenylfurocoumarin derivative (PFC) significantly reduced SN-38 IC50 in HCT-116/BCRP cells.
  • PFC demonstrated efficacy in reversing irinotecan resistance in a mouse xenograft model without observable toxicity.

Conclusions:

  • PFC is a novel ABCG2 inhibitor with potential therapeutic applications.
  • PFC shows promise in overcoming ABCG2-mediated MDR and enhancing the efficacy of cancer chemotherapy.
Keywords:
ABC transporterABCG2 inhibitorchemosensitivitymultidrug resistancephenylfurocoumarin

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