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Discovery of pyridoquinoxaline-based new P-gp inhibitors as coadjutant against Multi Drug Resistance in cancer.

Author information

Affiliations

  • 1. Department of Medicine, Surgery and Pharmacy, University of Sassari, 07100, Sassari, Italy.
      Authors
    • Ibba R 1
    • Piras S 1
    • Carta A 1
    (3 authors)
  • 2. Department of Chemical, Physical, Mathematical and Natural Sciences, University of Sassari, 07100, Sassari, Italy.
      Authors
    • Sestito S 2
    (1 author)
  • 3. Department of Health Sciences, University "Magna Græcia" of Catanzaro, Campus "S. Venuta", 88100, Catanzaro, Italy.
      Authors
    • Ambrosio FA 3
    • Marchese E 3
    (2 authors)
  • 4. Department of Health Sciences, University "Magna Græcia" of Catanzaro, Campus "S. Venuta", 88100, Catanzaro, Italy; Net4Science Academic Spin-Off, University "Magna Græcia" of Catanzaro, Campus "S. Venuta", 88100, Catanzaro, Italy.
      Authors
    • Costa G 4
    • Alcaro S 4
    (2 authors)
  • 5. Kitos Biotech Srls, Tramariglio, Alghero, SS, Italy.
      Authors
    • Fiorentino FP 5
    • Marchesi I 5
    (2 authors)
    • Show all (7)

ORCIDs linked to this article

European Journal of Medicinal Chemistry, 07 Jul 2024, 276:116647
https://doi.org/10.1016/j.ejmech.2024.116647 PMID: 38981337 

Abstract 

Multi-drug resistance (MDR) is a serious challenge in contemporary clinical practice and is mostly responsible for the failure of cancer medication therapies. Several experimental evidence links MDR to the overexpression of the drug efflux transporter P-gp, therefore, the discovery of novel P-glycoprotein inhibitors is required to treat or prevent MDR and to improve the absorption of chemotherapy drugs via the gastrointestinal system. In this work, we explored a series of novel pyridoquinoxaline-based derivatives designed from parental compounds, previously proved active in enhancing anticancer drugs in MDR nasopharyngeal carcinoma (KB). Among them, derivative 10d showed the most potent and selective inhibition of fluorescent dye efflux, if compared to reference compounds (MK-571, Novobiocin, Verapamil), and the highest MDR reversal activity when co-administered with the chemotherapeutic agents Vincristine and Etoposide, at non-cytotoxic concentrations. Molecular modelling predicted the two compound 10d binding mode in a ratio of 2:1 with the target protein. No cytotoxicity was observed in healthy microglia cells and off-target investigations showed the absence of CaV1.2 channel blockade. In summary, our findings indicated that 10d could potentially be a novel therapeutic coadjutant by inhibiting P-gp transport function in vitro, thereby reversing cancer multidrug resistance.

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Read article at publisher's site: https://doi.org/10.1016/j.ejmech.2024.116647

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Funding 

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Ministero dell'Istruzione dell'Universita e della Ricerca

    Ministero dell’Istruzione, dell’Università e della Ricerca