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The novel compound STK405759 is a microtubule-targeting agent with potent and selective cytotoxicity against multiple myeloma in vitro and in vivo
Despite advances in treatment, multiple myeloma (MM) remains incurable. Here we propose the use of STK405759, a novel microtubule targeting agent (MTA) and member of the furan metotica family for MM therapy. STK405759 inhibited tubulin polymerization in a cell-free system and in myeloma cells. This...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Impact Journals LLC
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5308747/ https://www.ncbi.nlm.nih.gov/pubmed/27613836 http://dx.doi.org/10.18632/oncotarget.11539 |
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author | Rozic, Gabriela Paukov, Lena Jakubikova, Jana Ben-Shushan, Dikla Duek, Adrian Leiba, Adi Avigdor, Abraham Nagler, Arnon Leiba, Merav |
author_facet | Rozic, Gabriela Paukov, Lena Jakubikova, Jana Ben-Shushan, Dikla Duek, Adrian Leiba, Adi Avigdor, Abraham Nagler, Arnon Leiba, Merav |
author_sort | Rozic, Gabriela |
collection | PubMed |
description | Despite advances in treatment, multiple myeloma (MM) remains incurable. Here we propose the use of STK405759, a novel microtubule targeting agent (MTA) and member of the furan metotica family for MM therapy. STK405759 inhibited tubulin polymerization in a cell-free system and in myeloma cells. This molecule had potent cytotoxic activity against several MM cell lines and patient-derived MM cells. Moreover, STK405759 demonstrated cytotoxicity against drug-resistant myeloma cells that overexpressed the P-glycoprotein drug-efflux pump. STK405759 was not cytotoxic to peripheral blood mononuclear cells, including activated B and T lymphocytes. This compound caused mitotic arrest and apoptosis of myeloma cells characterized by cleavage of poly (ADP-ribose) polymerase-1 and caspase-8, as well as decreased protein expression of mcl-1. The combination of STK405759 with bortezomib, lenalidomide or dexamethasone had synergistic cytotoxic activity. In in vivo studies, STK405759-treated mice had significantly decreased MM tumor burden and prolonged survival compared to vehicle treated- mice. These results provide a rationale for further evaluation of STK405759 as monotherapy or part of combination therapy for treating patients with MM. |
format | Online Article Text |
id | pubmed-5308747 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-53087472017-03-09 The novel compound STK405759 is a microtubule-targeting agent with potent and selective cytotoxicity against multiple myeloma in vitro and in vivo Rozic, Gabriela Paukov, Lena Jakubikova, Jana Ben-Shushan, Dikla Duek, Adrian Leiba, Adi Avigdor, Abraham Nagler, Arnon Leiba, Merav Oncotarget Research Paper Despite advances in treatment, multiple myeloma (MM) remains incurable. Here we propose the use of STK405759, a novel microtubule targeting agent (MTA) and member of the furan metotica family for MM therapy. STK405759 inhibited tubulin polymerization in a cell-free system and in myeloma cells. This molecule had potent cytotoxic activity against several MM cell lines and patient-derived MM cells. Moreover, STK405759 demonstrated cytotoxicity against drug-resistant myeloma cells that overexpressed the P-glycoprotein drug-efflux pump. STK405759 was not cytotoxic to peripheral blood mononuclear cells, including activated B and T lymphocytes. This compound caused mitotic arrest and apoptosis of myeloma cells characterized by cleavage of poly (ADP-ribose) polymerase-1 and caspase-8, as well as decreased protein expression of mcl-1. The combination of STK405759 with bortezomib, lenalidomide or dexamethasone had synergistic cytotoxic activity. In in vivo studies, STK405759-treated mice had significantly decreased MM tumor burden and prolonged survival compared to vehicle treated- mice. These results provide a rationale for further evaluation of STK405759 as monotherapy or part of combination therapy for treating patients with MM. Impact Journals LLC 2016-08-23 /pmc/articles/PMC5308747/ /pubmed/27613836 http://dx.doi.org/10.18632/oncotarget.11539 Text en Copyright: © 2016 Rozic et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Rozic, Gabriela Paukov, Lena Jakubikova, Jana Ben-Shushan, Dikla Duek, Adrian Leiba, Adi Avigdor, Abraham Nagler, Arnon Leiba, Merav The novel compound STK405759 is a microtubule-targeting agent with potent and selective cytotoxicity against multiple myeloma in vitro and in vivo |
title | The novel compound STK405759 is a microtubule-targeting agent with potent and selective cytotoxicity against multiple myeloma in vitro and in vivo |
title_full | The novel compound STK405759 is a microtubule-targeting agent with potent and selective cytotoxicity against multiple myeloma in vitro and in vivo |
title_fullStr | The novel compound STK405759 is a microtubule-targeting agent with potent and selective cytotoxicity against multiple myeloma in vitro and in vivo |
title_full_unstemmed | The novel compound STK405759 is a microtubule-targeting agent with potent and selective cytotoxicity against multiple myeloma in vitro and in vivo |
title_short | The novel compound STK405759 is a microtubule-targeting agent with potent and selective cytotoxicity against multiple myeloma in vitro and in vivo |
title_sort | novel compound stk405759 is a microtubule-targeting agent with potent and selective cytotoxicity against multiple myeloma in vitro and in vivo |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5308747/ https://www.ncbi.nlm.nih.gov/pubmed/27613836 http://dx.doi.org/10.18632/oncotarget.11539 |
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