Universität zu Köln

Pajtler, Kristian W. ORCID: 0000-0002-3562-6121, Sadowski, Natalie, Ackermann, Sandra, Althoff, Kristina, Schoenbeck, Kerstin, Batzke, Katharina, Schaefers, Simon, Odersky, Andrea, Heukamp, Lukas ORCID: 0000-0002-3388-3482, Astrahantseff, Kathy, Kuenkele, Annette, Deubzer, Hedwig E., Schramm, Alexander ORCID: 0000-0001-7670-7529, Spruessel, Annika, Thor, Theresa, Lindner, Sven, Eggert, Angelika, Fischer, Matthias and Schulte, Johannes H. (2017). The GSK461364 PLK1 inhibitor exhibits strong antitumoral activity in preclinical neuroblastoma models. Oncotarget, 8 (4). S. 6730 - 6742. ORCHARD PARK: IMPACT JOURNALS LLC. ISSN 1949-2553

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Abstract

Polo-like kinase 1 (PLK1) is a serine/threonine kinase that promotes G2/M-phase transition, is expressed in elevated levels in high-risk neuroblastomas and correlates with unfavorable patient outcome. Recently, we and others have presented PLK1 as a potential drug target for neuroblastoma, and reported that the BI2536 PLK1 inhibitor showed antitumoral actvity in preclinical neuroblastoma models. Here we analyzed the effects of GSK461364, a competitive inhibitor for ATP binding to PLK1, on typical tumorigenic properties of preclinical in vitro and in vivo neuroblastoma models. GSK461364 treatment of neuroblastoma cell lines reduced cell viability and proliferative capacity, caused cell cycle arrest and massively induced apoptosis. These phenotypic consequences were induced by treatment in the low-dose nanomolar range, and were independent of MYCN copy number status. GSK461364 treatment strongly delayed established xenograft tumor growth in nude mice, and significantly increased survival time in the treatment group. These preclinical findings indicate PLK1 inhibitors may be effective for patients with high-risk or relapsed neuroblastomas with upregulated PLK1 and might be considered for entry into early phase clinical trials in pediatric patients.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Pajtler, Kristian W. UNSPECIFIED orcid.org/0000-0002-3562-6121 UNSPECIFIED Sadowski, Natalie UNSPECIFIED UNSPECIFIED UNSPECIFIED Ackermann, Sandra UNSPECIFIED UNSPECIFIED UNSPECIFIED Althoff, Kristina UNSPECIFIED UNSPECIFIED UNSPECIFIED Schoenbeck, Kerstin UNSPECIFIED UNSPECIFIED UNSPECIFIED Batzke, Katharina UNSPECIFIED UNSPECIFIED UNSPECIFIED Schaefers, Simon UNSPECIFIED UNSPECIFIED UNSPECIFIED Odersky, Andrea UNSPECIFIED UNSPECIFIED UNSPECIFIED Heukamp, Lukas UNSPECIFIED orcid.org/0000-0002-3388-3482 UNSPECIFIED Astrahantseff, Kathy UNSPECIFIED UNSPECIFIED UNSPECIFIED Kuenkele, Annette UNSPECIFIED UNSPECIFIED UNSPECIFIED Deubzer, Hedwig E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schramm, Alexander UNSPECIFIED orcid.org/0000-0001-7670-7529 UNSPECIFIED Spruessel, Annika UNSPECIFIED UNSPECIFIED UNSPECIFIED Thor, Theresa UNSPECIFIED UNSPECIFIED UNSPECIFIED Lindner, Sven UNSPECIFIED UNSPECIFIED UNSPECIFIED Eggert, Angelika UNSPECIFIED UNSPECIFIED UNSPECIFIED Fischer, Matthias UNSPECIFIED UNSPECIFIED UNSPECIFIED Schulte, Johannes H. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-242273
DOI:	10.18632/oncotarget.14268
Journal or Publication Title:	Oncotarget
Volume:	8
Number:	4
Page Range:	S. 6730 - 6742
Date:	2017
Publisher:	IMPACT JOURNALS LLC
Place of Publication:	ORCHARD PARK
ISSN:	1949-2553
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language KINASE 1 INHIBITOR; POLO-LIKE KINASE-1; SPINDLE ASSEMBLY CHECKPOINT; CANCER-CELLS; EARLY EVENT; PLK1-DEPENDENT PHOSPHORYLATION; POLO-LIKE-KINASE-1 PLK1; CHROMOSOMAL INSTABILITY; TUMOR-SUPPRESSOR; IN-VITRO Multiple languages Oncology; Cell Biology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/24227