Lapatinib potentiates cytotoxicity of YM155 in neuroblastoma via inhibition of the ABCB1 efflux transporter
Abstract Adverse side effects of cancer agents are of great concern in the context of childhood tumors where they can reduce the quality of life in young patients and cause life-long adverse effects. Synergistic drug combinations can lessen potential toxic side effects through lower dosing and simul...
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2017-06-01
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Online Access: | https://doi.org/10.1038/s41598-017-03129-6 |
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doaj-69692b39268b4938b59ac45022e3640d2020-12-08T00:21:53ZengNature Publishing GroupScientific Reports2045-23222017-06-01711810.1038/s41598-017-03129-6Lapatinib potentiates cytotoxicity of YM155 in neuroblastoma via inhibition of the ABCB1 efflux transporterBranka Radic-Sarikas0Melinda Halasz1Kilian V. M. Huber2Georg E. Winter3Kalliopi P. Tsafou4Theodore Papamarkou5Søren Brunak6Walter Kolch7Giulio Superti-Furga8CeMM Research Center for Molecular Medicine of the Austrian Academy of SciencesSystems Biology Ireland, University College Dublin, BelfieldCeMM Research Center for Molecular Medicine of the Austrian Academy of SciencesCeMM Research Center for Molecular Medicine of the Austrian Academy of SciencesCenter for Biological Sequence Analysis, Department of Systems Biology, Technical University of DenmarkSchool of Mathematics and Statistics, University of GlasgowCenter for Biological Sequence Analysis, Department of Systems Biology, Technical University of DenmarkSystems Biology Ireland, University College Dublin, BelfieldCeMM Research Center for Molecular Medicine of the Austrian Academy of SciencesAbstract Adverse side effects of cancer agents are of great concern in the context of childhood tumors where they can reduce the quality of life in young patients and cause life-long adverse effects. Synergistic drug combinations can lessen potential toxic side effects through lower dosing and simultaneously help to overcome drug resistance. Neuroblastoma is the most common cancer in infancy and extremely heterogeneous in clinical presentation and features. Applying a systematic pairwise drug combination screen we observed a highly potent synergy in neuroblastoma cells between the EGFR kinase inhibitor lapatinib and the anticancer compound YM155 that is preserved across several neuroblastoma variants. Mechanistically, the synergy was based on a lapatinib induced inhibition of the multidrug-resistance efflux transporter ABCB1, which is frequently expressed in resistant neuroblastoma cells, which allowed prolonged and elevated cytotoxicity of YM155. In addition, the drug combination (i.e. lapatinib plus YM155) decreased neuroblastoma tumor size in an in vivo model.https://doi.org/10.1038/s41598-017-03129-6 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Branka Radic-Sarikas Melinda Halasz Kilian V. M. Huber Georg E. Winter Kalliopi P. Tsafou Theodore Papamarkou Søren Brunak Walter Kolch Giulio Superti-Furga |
spellingShingle |
Branka Radic-Sarikas Melinda Halasz Kilian V. M. Huber Georg E. Winter Kalliopi P. Tsafou Theodore Papamarkou Søren Brunak Walter Kolch Giulio Superti-Furga Lapatinib potentiates cytotoxicity of YM155 in neuroblastoma via inhibition of the ABCB1 efflux transporter Scientific Reports |
author_facet |
Branka Radic-Sarikas Melinda Halasz Kilian V. M. Huber Georg E. Winter Kalliopi P. Tsafou Theodore Papamarkou Søren Brunak Walter Kolch Giulio Superti-Furga |
author_sort |
Branka Radic-Sarikas |
title |
Lapatinib potentiates cytotoxicity of YM155 in neuroblastoma via inhibition of the ABCB1 efflux transporter |
title_short |
Lapatinib potentiates cytotoxicity of YM155 in neuroblastoma via inhibition of the ABCB1 efflux transporter |
title_full |
Lapatinib potentiates cytotoxicity of YM155 in neuroblastoma via inhibition of the ABCB1 efflux transporter |
title_fullStr |
Lapatinib potentiates cytotoxicity of YM155 in neuroblastoma via inhibition of the ABCB1 efflux transporter |
title_full_unstemmed |
Lapatinib potentiates cytotoxicity of YM155 in neuroblastoma via inhibition of the ABCB1 efflux transporter |
title_sort |
lapatinib potentiates cytotoxicity of ym155 in neuroblastoma via inhibition of the abcb1 efflux transporter |
publisher |
Nature Publishing Group |
series |
Scientific Reports |
issn |
2045-2322 |
publishDate |
2017-06-01 |
description |
Abstract Adverse side effects of cancer agents are of great concern in the context of childhood tumors where they can reduce the quality of life in young patients and cause life-long adverse effects. Synergistic drug combinations can lessen potential toxic side effects through lower dosing and simultaneously help to overcome drug resistance. Neuroblastoma is the most common cancer in infancy and extremely heterogeneous in clinical presentation and features. Applying a systematic pairwise drug combination screen we observed a highly potent synergy in neuroblastoma cells between the EGFR kinase inhibitor lapatinib and the anticancer compound YM155 that is preserved across several neuroblastoma variants. Mechanistically, the synergy was based on a lapatinib induced inhibition of the multidrug-resistance efflux transporter ABCB1, which is frequently expressed in resistant neuroblastoma cells, which allowed prolonged and elevated cytotoxicity of YM155. In addition, the drug combination (i.e. lapatinib plus YM155) decreased neuroblastoma tumor size in an in vivo model. |
url |
https://doi.org/10.1038/s41598-017-03129-6 |
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