Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Rozic, Gabriela, Paukov, Lena, Jakubikova, Jana, Ben-Shushan, Dikla, Duek, Adrian, Leiba, Adi, Avigdor, Abraham, Nagler, Arnon, Leiba, Merav
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2016
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
_version_ 1782507591927070720
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
work_keys_str_mv AT rozicgabriela thenovelcompoundstk405759isamicrotubuletargetingagentwithpotentandselectivecytotoxicityagainstmultiplemyelomainvitroandinvivo
AT paukovlena thenovelcompoundstk405759isamicrotubuletargetingagentwithpotentandselectivecytotoxicityagainstmultiplemyelomainvitroandinvivo
AT jakubikovajana thenovelcompoundstk405759isamicrotubuletargetingagentwithpotentandselectivecytotoxicityagainstmultiplemyelomainvitroandinvivo
AT benshushandikla thenovelcompoundstk405759isamicrotubuletargetingagentwithpotentandselectivecytotoxicityagainstmultiplemyelomainvitroandinvivo
AT duekadrian thenovelcompoundstk405759isamicrotubuletargetingagentwithpotentandselectivecytotoxicityagainstmultiplemyelomainvitroandinvivo
AT leibaadi thenovelcompoundstk405759isamicrotubuletargetingagentwithpotentandselectivecytotoxicityagainstmultiplemyelomainvitroandinvivo
AT avigdorabraham thenovelcompoundstk405759isamicrotubuletargetingagentwithpotentandselectivecytotoxicityagainstmultiplemyelomainvitroandinvivo
AT naglerarnon thenovelcompoundstk405759isamicrotubuletargetingagentwithpotentandselectivecytotoxicityagainstmultiplemyelomainvitroandinvivo
AT leibamerav thenovelcompoundstk405759isamicrotubuletargetingagentwithpotentandselectivecytotoxicityagainstmultiplemyelomainvitroandinvivo
AT rozicgabriela novelcompoundstk405759isamicrotubuletargetingagentwithpotentandselectivecytotoxicityagainstmultiplemyelomainvitroandinvivo
AT paukovlena novelcompoundstk405759isamicrotubuletargetingagentwithpotentandselectivecytotoxicityagainstmultiplemyelomainvitroandinvivo
AT jakubikovajana novelcompoundstk405759isamicrotubuletargetingagentwithpotentandselectivecytotoxicityagainstmultiplemyelomainvitroandinvivo
AT benshushandikla novelcompoundstk405759isamicrotubuletargetingagentwithpotentandselectivecytotoxicityagainstmultiplemyelomainvitroandinvivo
AT duekadrian novelcompoundstk405759isamicrotubuletargetingagentwithpotentandselectivecytotoxicityagainstmultiplemyelomainvitroandinvivo
AT leibaadi novelcompoundstk405759isamicrotubuletargetingagentwithpotentandselectivecytotoxicityagainstmultiplemyelomainvitroandinvivo
AT avigdorabraham novelcompoundstk405759isamicrotubuletargetingagentwithpotentandselectivecytotoxicityagainstmultiplemyelomainvitroandinvivo
AT naglerarnon novelcompoundstk405759isamicrotubuletargetingagentwithpotentandselectivecytotoxicityagainstmultiplemyelomainvitroandinvivo
AT leibamerav novelcompoundstk405759isamicrotubuletargetingagentwithpotentandselectivecytotoxicityagainstmultiplemyelomainvitroandinvivo