Open Access
Archives of Toxicology, volume 93, issue 4, pages 953-964
Identification of anticancer OATP2B1 substrates by an in vitro triple-fluorescence-based cytotoxicity screen
Windt Tímea
1
,
Tóth Szilárd
1
,
Patik Izabel
1
,
Sessler Judit
1
,
Kucsma Nóra
1
,
Szepesi Áron
1
,
Zdrazil Barbara
2
,
Özvegy-Laczka Csilla
1
,
Szakacs Gergely
1, 3
1
Institute of Enzymology, Research Centre for National Sciences, HAS, Budapest, Hungary
|
2
Department of Pharmaceutical Chemistry, Division of Drug Design and Medicinal Chemistry, University of Vienna, Vienna, Austria
|
Publication type: Journal Article
Publication date: 2019-03-12
Journal:
Archives of Toxicology
Quartile SCImago
Q1
Quartile WOS
Q1
Impact factor: 6.1
ISSN: 03405761, 14320738, 01719750
PubMed ID:
30863990
General Medicine
Health, Toxicology and Mutagenesis
Toxicology
Abstract
Membrane transporters play an important role in the absorption, distribution, metabolism and excretion of drugs. The cellular accumulation of many drugs is the result of the net function of efflux and influx transporters. Efflux transporters such as P-glycoprotein/ABCB1 have been shown to confer multidrug resistance in cancer. Although expression of uptake transporters has been confirmed in cancer cells, their role in chemotherapy response has not been systematically investigated. In the present study we have adapted a fluorescence-based cytotoxic assay to characterize the influence of key drug-transporters on the toxicity of approved anticancer drugs. Co-cultures of fluorescently labeled parental and transporter-expressing cells (expressing ABCB1, ABCG2 or OATP2B1) were screened against 101 FDA-approved anticancer drugs, using a novel, automated, triple fluorescence-based cytotoxicity assay. By measuring the survival of parental and transporter-expressing cells in co-cultures, we identify those FDA-approved anticancer drugs, whose toxicity is influenced by ABCB1, ABCG2 or OATP2B1. In addition to confirming known substrates of ABCB1 and ABCG2, the fluorescence-based cytotoxicity assays identified anticancer agents whose toxicity was increased in OATP2B1 expressing cells. Interaction of these compounds with OATP2B1 was verified in dedicated transport assays using cell-impermeant fluorescent substrates. Understanding drug-transporter interactions is needed to increase the efficacy of chemotherapeutic agents. Our results highlight the potential of the fluorescence-based HT screening system for identifying transporter substrates, opening the way for the design of therapeutic approaches based on the inhibition or even the exploitation of transporters in cancer cells.
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Citations by publishers
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1 publication, 5%
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1 publication, 5%
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- We do not take into account publications that without a DOI.
- Statistics recalculated only for publications connected to researchers, organizations and labs registered on the platform.
- Statistics recalculated weekly.
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Windt T. et al. Identification of anticancer OATP2B1 substrates by an in vitro triple-fluorescence-based cytotoxicity screen // Archives of Toxicology. 2019. Vol. 93. No. 4. pp. 953-964.
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Windt T., Tóth S., Patik I., Sessler J., Kucsma N., Szepesi Á., Zdrazil B., Özvegy-Laczka C., Szakacs G. Identification of anticancer OATP2B1 substrates by an in vitro triple-fluorescence-based cytotoxicity screen // Archives of Toxicology. 2019. Vol. 93. No. 4. pp. 953-964.
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TY - JOUR
DO - 10.1007/s00204-019-02417-6
UR - https://doi.org/10.1007%2Fs00204-019-02417-6
TI - Identification of anticancer OATP2B1 substrates by an in vitro triple-fluorescence-based cytotoxicity screen
T2 - Archives of Toxicology
AU - Windt, Tímea
AU - Tóth, Szilárd
AU - Patik, Izabel
AU - Sessler, Judit
AU - Kucsma, Nóra
AU - Szepesi, Áron
AU - Zdrazil, Barbara
AU - Özvegy-Laczka, Csilla
AU - Szakacs, Gergely
PY - 2019
DA - 2019/03/12 00:00:00
PB - Springer Nature
SP - 953-964
IS - 4
VL - 93
PMID - 30863990
SN - 0340-5761
SN - 1432-0738
SN - 0171-9750
ER -
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@article{2019_Windt,
author = {Tímea Windt and Szilárd Tóth and Izabel Patik and Judit Sessler and Nóra Kucsma and Áron Szepesi and Barbara Zdrazil and Csilla Özvegy-Laczka and Gergely Szakacs},
title = {Identification of anticancer OATP2B1 substrates by an in vitro triple-fluorescence-based cytotoxicity screen},
journal = {Archives of Toxicology},
year = {2019},
volume = {93},
publisher = {Springer Nature},
month = {mar},
url = {https://doi.org/10.1007%2Fs00204-019-02417-6},
number = {4},
pages = {953--964},
doi = {10.1007/s00204-019-02417-6}
}
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MLA
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Windt, Tímea, et al. “Identification of anticancer OATP2B1 substrates by an in vitro triple-fluorescence-based cytotoxicity screen.” Archives of Toxicology, vol. 93, no. 4, Mar. 2019, pp. 953-964. https://doi.org/10.1007%2Fs00204-019-02417-6.