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Oxygenated xanthones as P-glycoprotein modulators at the intestinal barrier: in vitro and docking studies

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Abstract

P-glycoprotein (P-gp) induction and/or activation have been proposed as therapeutic strategies in intoxication scenarios, by reducing the intestinal absorption of xenobiotics, including drugs. Oxygenated xanthones (OXs) have been described as P-gp modulators and, therefore, the main goals of this study were to: (a) investigate the potential modulatory effect of six OXs on P-gp expression and activity in SW480 cells; (b) validate these cells for the screening/identification of P-gp inducers/activators; (c) explore the potential OXs-mediated protective effects against the cytotoxicity of mitoxantrone (MTX), a toxic P-gp substrate. Four OXs (OX2, OX4, OX5, and OX6) increased P-gp expression 24 h after exposure. However, a lack of correlation between P-gp expression and activity was observed for OX1 and OX4. In addition, after a short incubation with the P-gp fluorescent substrate, rhodamine 123, all the studied OXs, except OX3, efficient and immediately increased P-gp activity, suggesting their potential as P-gp activators. Despite these results, OXs failed to afford protection against MTX-induced cytotoxicity. Docking simulations performed in a human P-gp model revealed that the lack of protection may be explained by the different binding locations of OXs and MTX within the P-gp drug-binding pocket. In conclusion, the in vitro results confirmed OXs potential for P-gp induction and/or activation and suggested SW480 cells as a suitable in vitro model for these studies. However, P-gp activation did not protected SW480 cells against MTX cytotoxicity. In silico studies suggested the different binding locations as a limiting step in the P-gp-mediated efflux of its substrates under P-gp activation.

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Acknowledgements

The work was supported by UID/MULTI/04378/2019, UIDB/04423/2020 and UIDP/04423/2020 with funding from FCT/MCTES through national funds and under the projects NORTE-01-0145-FEDER-000024, supported by Norte Portugal Regional Operational Programme (NORTE2020), under the PORTUGAL 2020 Partnership Agreement (DESignBIOtecHealth-New Technologies for three Health Challenges of Modern Societies: Diabetes, Drug Abuse and Kidney Diseases) and PTDC/SAU-PUB/28736/2017 (reference POCI-01-0145-FEDER-028736), co-financed by COMPETE 2020, Portugal 2020 and the European Union through the ERDF and by FCT through national funds.

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Authors and Affiliations

  1. UCIBIO/REQUIMTE, Laboratório de Toxicologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Rua Jorge Viterbo Ferreira, 228, 4050-313, Porto, Portugal

    Vera Silva, Eva Gil-Martins, Carolina Rocha-Pereira, Maria de Lourdes Bastos, Fernando Remião & Renata Silva

  2. CIIMAR, Laboratório de Química Orgânica e Farmacêutica, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Rua Jorge Viterbo Ferreira, 228, 4050-313, Porto, Portugal

    Agostinho Lemos, Andreia Palmeira & Emília Sousa

  3. Faculty of Pharmaceutical Sciences, Khon Kaen University, Khon Kaen, 40002, Thailand

    Ploenthip Puthongking

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  1. Vera Silva
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  2. Eva Gil-Martins
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  3. Carolina Rocha-Pereira
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Correspondence to Vera Silva or Renata Silva.

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Silva, V., Gil-Martins, E., Rocha-Pereira, C. et al. Oxygenated xanthones as P-glycoprotein modulators at the intestinal barrier: in vitro and docking studies. Med Chem Res 29, 1041–1057 (2020). https://doi.org/10.1007/s00044-020-02544-1

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