Cargando…
Off-target based drug repurposing opportunities for tivantinib in acute myeloid leukemia
GSK3α has been identified as a new target in the treatment of acute myeloid leukemia (AML). However, most GSK3 inhibitors lack specificity for GSK3α over GSK3β and other kinases. We have previously shown in lung cancer cells that GSK3α and to a lesser extent GSK3β are inhibited by the advanced clini...
Autores principales: | , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2019
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6345777/ https://www.ncbi.nlm.nih.gov/pubmed/30679640 http://dx.doi.org/10.1038/s41598-018-37174-6 |
_version_ | 1783389622626156544 |
---|---|
author | Kuenzi, Brent M. Remsing Rix, Lily L. Kinose, Fumi Kroeger, Jodi L. Lancet, Jeffrey E. Padron, Eric Rix, Uwe |
author_facet | Kuenzi, Brent M. Remsing Rix, Lily L. Kinose, Fumi Kroeger, Jodi L. Lancet, Jeffrey E. Padron, Eric Rix, Uwe |
author_sort | Kuenzi, Brent M. |
collection | PubMed |
description | GSK3α has been identified as a new target in the treatment of acute myeloid leukemia (AML). However, most GSK3 inhibitors lack specificity for GSK3α over GSK3β and other kinases. We have previously shown in lung cancer cells that GSK3α and to a lesser extent GSK3β are inhibited by the advanced clinical candidate tivantinib (ARQ197), which was designed as a MET inhibitor. Thus, we hypothesized that tivantinib would be an effective therapy for the treatment of AML. Here, we show that tivantinib has potent anticancer activity across several AML cell lines and primary patient cells. Tivantinib strongly induced apoptosis, differentiation and G2/M cell cycle arrest and caused less undesirable stabilization of β-catenin compared to the pan-GSK3 inhibitor LiCl. Subsequent drug combination studies identified the BCL-2 inhibitor ABT-199 to synergize with tivantinib while cytarabine combination with tivantinib was antagonistic. Interestingly, the addition of ABT-199 to tivantinib completely abrogated tivantinib induced β-catenin stabilization. Tivantinib alone, or in combination with ABT-199, downregulated anti-apoptotic MCL-1 and BCL-XL levels, which likely contribute to the observed synergy. Importantly, tivantinib as single agent or in combination with ABT-199 significantly inhibited the colony forming capacity of primary patient AML bone marrow mononuclear cells. In summary, tivantinib is a novel GSK3α/β inhibitor that potently kills AML cells and tivantinib single agent or combination therapy with ABT-199 may represent attractive new therapeutic opportunities for AML. |
format | Online Article Text |
id | pubmed-6345777 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-63457772019-01-28 Off-target based drug repurposing opportunities for tivantinib in acute myeloid leukemia Kuenzi, Brent M. Remsing Rix, Lily L. Kinose, Fumi Kroeger, Jodi L. Lancet, Jeffrey E. Padron, Eric Rix, Uwe Sci Rep Article GSK3α has been identified as a new target in the treatment of acute myeloid leukemia (AML). However, most GSK3 inhibitors lack specificity for GSK3α over GSK3β and other kinases. We have previously shown in lung cancer cells that GSK3α and to a lesser extent GSK3β are inhibited by the advanced clinical candidate tivantinib (ARQ197), which was designed as a MET inhibitor. Thus, we hypothesized that tivantinib would be an effective therapy for the treatment of AML. Here, we show that tivantinib has potent anticancer activity across several AML cell lines and primary patient cells. Tivantinib strongly induced apoptosis, differentiation and G2/M cell cycle arrest and caused less undesirable stabilization of β-catenin compared to the pan-GSK3 inhibitor LiCl. Subsequent drug combination studies identified the BCL-2 inhibitor ABT-199 to synergize with tivantinib while cytarabine combination with tivantinib was antagonistic. Interestingly, the addition of ABT-199 to tivantinib completely abrogated tivantinib induced β-catenin stabilization. Tivantinib alone, or in combination with ABT-199, downregulated anti-apoptotic MCL-1 and BCL-XL levels, which likely contribute to the observed synergy. Importantly, tivantinib as single agent or in combination with ABT-199 significantly inhibited the colony forming capacity of primary patient AML bone marrow mononuclear cells. In summary, tivantinib is a novel GSK3α/β inhibitor that potently kills AML cells and tivantinib single agent or combination therapy with ABT-199 may represent attractive new therapeutic opportunities for AML. Nature Publishing Group UK 2019-01-24 /pmc/articles/PMC6345777/ /pubmed/30679640 http://dx.doi.org/10.1038/s41598-018-37174-6 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Kuenzi, Brent M. Remsing Rix, Lily L. Kinose, Fumi Kroeger, Jodi L. Lancet, Jeffrey E. Padron, Eric Rix, Uwe Off-target based drug repurposing opportunities for tivantinib in acute myeloid leukemia |
title | Off-target based drug repurposing opportunities for tivantinib in acute myeloid leukemia |
title_full | Off-target based drug repurposing opportunities for tivantinib in acute myeloid leukemia |
title_fullStr | Off-target based drug repurposing opportunities for tivantinib in acute myeloid leukemia |
title_full_unstemmed | Off-target based drug repurposing opportunities for tivantinib in acute myeloid leukemia |
title_short | Off-target based drug repurposing opportunities for tivantinib in acute myeloid leukemia |
title_sort | off-target based drug repurposing opportunities for tivantinib in acute myeloid leukemia |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6345777/ https://www.ncbi.nlm.nih.gov/pubmed/30679640 http://dx.doi.org/10.1038/s41598-018-37174-6 |
work_keys_str_mv | AT kuenzibrentm offtargetbaseddrugrepurposingopportunitiesfortivantinibinacutemyeloidleukemia AT remsingrixlilyl offtargetbaseddrugrepurposingopportunitiesfortivantinibinacutemyeloidleukemia AT kinosefumi offtargetbaseddrugrepurposingopportunitiesfortivantinibinacutemyeloidleukemia AT kroegerjodil offtargetbaseddrugrepurposingopportunitiesfortivantinibinacutemyeloidleukemia AT lancetjeffreye offtargetbaseddrugrepurposingopportunitiesfortivantinibinacutemyeloidleukemia AT padroneric offtargetbaseddrugrepurposingopportunitiesfortivantinibinacutemyeloidleukemia AT rixuwe offtargetbaseddrugrepurposingopportunitiesfortivantinibinacutemyeloidleukemia |