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The ruthenium compound KP1339 potentiates the anticancer activity of sorafenib in vitro and in vivo()

KP1339 is a promising ruthenium-based anticancer compound in early clinical development. This study aimed to test the effects of KP1339 on the in vitro and in vivo activity of the multi-kinase inhibitor sorafenib, the current standard first-line therapy for advanced hepatoma. Anticancer activity of...

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Autores principales: Heffeter, Petra, Atil, Bihter, Kryeziu, Kushtrim, Groza, Diana, Koellensperger, Gunda, Körner, Wilfried, Jungwirth, Ute, Mohr, Thomas, Keppler, Bernhard K., Berger, Walter
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier Science Ltd 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3807657/
https://www.ncbi.nlm.nih.gov/pubmed/23790465
http://dx.doi.org/10.1016/j.ejca.2013.05.018
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author Heffeter, Petra
Atil, Bihter
Kryeziu, Kushtrim
Groza, Diana
Koellensperger, Gunda
Körner, Wilfried
Jungwirth, Ute
Mohr, Thomas
Keppler, Bernhard K.
Berger, Walter
author_facet Heffeter, Petra
Atil, Bihter
Kryeziu, Kushtrim
Groza, Diana
Koellensperger, Gunda
Körner, Wilfried
Jungwirth, Ute
Mohr, Thomas
Keppler, Bernhard K.
Berger, Walter
author_sort Heffeter, Petra
collection PubMed
description KP1339 is a promising ruthenium-based anticancer compound in early clinical development. This study aimed to test the effects of KP1339 on the in vitro and in vivo activity of the multi-kinase inhibitor sorafenib, the current standard first-line therapy for advanced hepatoma. Anticancer activity of the parental compounds as compared to the drug combination was tested against a panel of cancer cell lines with a focus on hepatoma. Combination of KP1339 with sorafenib induced in the majority of all cases distinctly synergistic effects, comprising both sorafenib-resistant as well as sorafenib-responsive cell models. Several mechanisms were found to underlie these multifaceted synergistic activities. Firstly, co-exposure induced significantly enhanced accumulation levels of both drugs resulting in enhanced apoptosis induction. Secondly, sorafenib blocked KP1339-mediated activation of P38 signalling representing a protective response against the ruthenium drug. In addition, sorafenib treatment also abrogated KP1339-induced G2/M arrest but resulted in check point-independent DNA-synthesis block and a complete loss of the mitotic cell populations. The activity of the KP1339/sorafenib combination was evaluated in the Hep3B hepatoma xenograft. KP1339 monotherapy led to a 2.4-fold increase in life span and, thus, was superior to sorafenib, which induced a 1.9-fold prolonged survival. The combined therapy further enhanced the mean survival by 3.9-fold. Synergistic activity was also observed in the VM-1 melanoma xenograft harbouring an activating braf mutation. Together, our data indicate that the combination of KP1339 with sorafenib displays promising activity in vitro and in vivo especially against human hepatoma models.
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spelling pubmed-38076572013-10-25 The ruthenium compound KP1339 potentiates the anticancer activity of sorafenib in vitro and in vivo() Heffeter, Petra Atil, Bihter Kryeziu, Kushtrim Groza, Diana Koellensperger, Gunda Körner, Wilfried Jungwirth, Ute Mohr, Thomas Keppler, Bernhard K. Berger, Walter Eur J Cancer Article KP1339 is a promising ruthenium-based anticancer compound in early clinical development. This study aimed to test the effects of KP1339 on the in vitro and in vivo activity of the multi-kinase inhibitor sorafenib, the current standard first-line therapy for advanced hepatoma. Anticancer activity of the parental compounds as compared to the drug combination was tested against a panel of cancer cell lines with a focus on hepatoma. Combination of KP1339 with sorafenib induced in the majority of all cases distinctly synergistic effects, comprising both sorafenib-resistant as well as sorafenib-responsive cell models. Several mechanisms were found to underlie these multifaceted synergistic activities. Firstly, co-exposure induced significantly enhanced accumulation levels of both drugs resulting in enhanced apoptosis induction. Secondly, sorafenib blocked KP1339-mediated activation of P38 signalling representing a protective response against the ruthenium drug. In addition, sorafenib treatment also abrogated KP1339-induced G2/M arrest but resulted in check point-independent DNA-synthesis block and a complete loss of the mitotic cell populations. The activity of the KP1339/sorafenib combination was evaluated in the Hep3B hepatoma xenograft. KP1339 monotherapy led to a 2.4-fold increase in life span and, thus, was superior to sorafenib, which induced a 1.9-fold prolonged survival. The combined therapy further enhanced the mean survival by 3.9-fold. Synergistic activity was also observed in the VM-1 melanoma xenograft harbouring an activating braf mutation. Together, our data indicate that the combination of KP1339 with sorafenib displays promising activity in vitro and in vivo especially against human hepatoma models. Elsevier Science Ltd 2013-10 /pmc/articles/PMC3807657/ /pubmed/23790465 http://dx.doi.org/10.1016/j.ejca.2013.05.018 Text en © 2013 The Authors https://creativecommons.org/licenses/by/3.0/ Open Access under CC BY 3.0 (https://creativecommons.org/licenses/by/3.0/) license
spellingShingle Article
Heffeter, Petra
Atil, Bihter
Kryeziu, Kushtrim
Groza, Diana
Koellensperger, Gunda
Körner, Wilfried
Jungwirth, Ute
Mohr, Thomas
Keppler, Bernhard K.
Berger, Walter
The ruthenium compound KP1339 potentiates the anticancer activity of sorafenib in vitro and in vivo()
title The ruthenium compound KP1339 potentiates the anticancer activity of sorafenib in vitro and in vivo()
title_full The ruthenium compound KP1339 potentiates the anticancer activity of sorafenib in vitro and in vivo()
title_fullStr The ruthenium compound KP1339 potentiates the anticancer activity of sorafenib in vitro and in vivo()
title_full_unstemmed The ruthenium compound KP1339 potentiates the anticancer activity of sorafenib in vitro and in vivo()
title_short The ruthenium compound KP1339 potentiates the anticancer activity of sorafenib in vitro and in vivo()
title_sort ruthenium compound kp1339 potentiates the anticancer activity of sorafenib in vitro and in vivo()
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3807657/
https://www.ncbi.nlm.nih.gov/pubmed/23790465
http://dx.doi.org/10.1016/j.ejca.2013.05.018
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