Structural and molecular characterization of lopinavir and ivermectin as breast cancer resistance protein (BCRP/ABCG2) inhibitors

Authors

  • Julia de Paula Dutra Graduate Program in Pharmaceutical Sciences, Laboratory of Cancer Drug Resistance, Federal University of Parana, Curitiba, PR, Brazil https://orcid.org/0000-0002-0259-3976
  • Gustavo Scheiffer Graduate Program in Pharmaceutical Sciences, Laboratory of Cancer Drug Resistance, Federal University of Parana, Curitiba, PR, Brazil https://orcid.org/0000-0001-9469-5584
  • Thales Kronenberger School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland; (a) Department of Internal Medicine VIII, University Hospital Tuebingen, Otfried-Müller-Strasse 14, Tuebingen DE 72076, Germany; (b) Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical Sciences, Eberhard-Karls-Universität, Tuebingen, Auf der Morgenstelle 8, 72076 Tuebingen, Germany; (c) Cluster of Excellence iFIT (EXC 2180) “Image-Guided and Functionally Instructed Tumor Therapies”, University of Tuebingen, 72076 Tuebingen, Germany; (d) Tuebingen Center for Academic Drug Discovery & Development (TüCAD2), 72076 Tuebingen, Germany https://orcid.org/0000-0001-6933-7590
  • Lucas Julian Cruz Gomes Graduate Program in Pharmaceutical Sciences, Laboratory of Cancer Drug Resistance, Federal University of Parana, Curitiba, PR, Brazil https://orcid.org/0009-0008-3277-9641
  • Isadora Zanzarini Graduate Program in Pharmaceutical Sciences, Laboratory of Cancer Drug Resistance, Federal University of Parana, Curitiba, PR, Brazil https://orcid.org/0000-0001-9374-2174
  • Kelly Karoline dos Santos Graduate Program in Pharmaceutical Sciences, Laboratory of Cancer Drug Resistance, Federal University of Parana, Curitiba, PR, Brazil https://orcid.org/0000-0001-9751-1939
  • Arun K. Tonduru School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland https://orcid.org/0000-0001-6986-4198
  • Antti Poso School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland; (a) Department of Internal Medicine VIII, University Hospital Tuebingen, Otfried-Müller-Strasse 14, Tuebingen DE 72076, Germany; (b) Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical Sciences, Eberhard-Karls-Universität, Tuebingen, Auf der Morgenstelle 8, 72076 Tuebingen, Germany; (c) Cluster of Excellence iFIT (EXC 2180) “Image-Guided and Functionally Instructed Tumor Therapies”, University of Tuebingen, 72076 Tuebingen, Germany; (d) Tuebingen Center for Academic Drug Discovery & Development (TüCAD2), 72076 Tuebingen, Germany https://orcid.org/0000-0003-4196-4204
  • Fabiane Gomes de Moraes Rego Graduate Program in Pharmaceutical Sciences, Federal University of Parana, Curitiba, PR, Brazil https://orcid.org/0000-0003-1726-8524
  • Geraldo Picheth Graduate Program in Pharmaceutical Sciences, Federal University of Parana, Curitiba, PR, Brazil https://orcid.org/0000-0003-1760-5906
  • Glaucio Valdameri Graduate Program in Pharmaceutical Sciences, Laboratory of Cancer Drug Resistance, Federal University of Parana, Curitiba, PR, Brazil https://orcid.org/0000-0003-1882-1512
  • Vivian Rotuno Moure Graduate Program in Pharmaceutical Sciences, Laboratory of Cancer Drug Resistance, Federal University of Parana, Curitiba, PR, Brazil. E-mail: vivian.moure@ufpr.br https://orcid.org/0000-0003-0968-8190

DOI:

https://doi.org/10.17179/excli2023-6427

Keywords:

ABCG2, drug repositioning, lopinavir, ivermectin, molecular modelling

Abstract

A current clinical challenge in cancer is multidrug resistance (MDR) mediated by ABC transporters. Breast cancer resistance protein (BCRP) or ABCG2 transporter is one of the most important ABC transporters implicated in MDR and the use of inhibitors is a promising approach to overcome the resistance in cancer. This study aimed to characterize the molecular mechanism of ABCG2 inhibitors identified by a repurposing drug strategy using antiviral, anti-inflammatory and antiparasitic agents. Lopinavir and ivermectin can be considered as pan-inhibitors of ABC transporters, since both compounds inhibited ABCG2, P-glycoprotein and MRP1. They inhibited ABCG2 activity showing IC50 values of 25.5 and 23.4 µM, respectively. These drugs were highly cytotoxic and not transported by ABCG2. Additionally, these drugs increased the 5D3 antibody binding and did not affect the mRNA and protein expression levels. Cell-based analysis of the type of inhibition suggested a non-competitive inhibition, which was further corroborated by in silico approaches of molecular docking and molecular dynamics simulations. These results showed an overlap of the lopinavir and ivermectin binding sites on ABCG2, mainly interacting with E446 residue. However, the substrate mitoxantrone occupies a different site, binding to the F436 region, closer to the L554/L555 plug. In conclusion, these results revealed the mechanistic basis of lopinavir and ivermectin interaction with ABCG2.

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Published

2023-11-14

How to Cite

Dutra, J. de P., Scheiffer, G., Kronenberger, T., Gomes, L. J. C., Zanzarini, I., dos Santos, K. K., … Rotuno Moure, V. (2023). Structural and molecular characterization of lopinavir and ivermectin as breast cancer resistance protein (BCRP/ABCG2) inhibitors . EXCLI Journal, 22, 1155–1172. https://doi.org/10.17179/excli2023-6427

Issue

Vol. 22 (2023)

Section

Original articles

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Copyright (c) 2023 Julia de Paula Dutra, Gustavo Scheiffer, Thales Kronenberger, Lucas Julian Cruz Gomes, Isadora Zanzarini, Kelly Karoline dos Santos, Arun K. Tonduru, Antti Poso, Fabiane Gomes de Moraes Rego, Geraldo Picheth, Glaucio Valdameri, Vivian Rotuno Moure

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