Reduced efficacy of the plk1 inhibitor bi 2536 on the progression of hepatocellular carcinoma due to low intratumoral drug levels

  • Highly promising preclinical data obtained in cultured cells and in nude mice bearing xenografts contrast with the rather modest clinical efficacy of Polo-like kinase 1 (Plk1) inhibitors. In the present study, we investigated if Plk1 might be a suitable target in hepatocellular carcinoma (HCC) and if a genetically engineered mouse tumor model that well reflects the tumor cell and micro-environmental features of naturally occurring cancers might be suitable to study anti-Plk1 therapy. Analysis of Plk1 expression in human HCC samples confirmed that HCC express much higher Plk1 levels than the adjacent normal liver tissue. Inhibition of Plk1 by an adenovirus encoding for a short hairpin RNA against Plk1 or by the small-molecule inhibitor BI 2536 reduced the viability of HCC cell lines and inhibited HCC xenograft progression in nude mice. Treatment of transforming growth factor (TGF) α/c-myc bitransgenic mice with BI 2536 during hepatocarcinogenesis reduced the number of dysplastic foci and of Ki-67-positive cells within the foci, indicating diminished tumorigenesis. In contrast, BI 2536 had no significant effect on HCC progression in the transgenic mouse HCC model as revealed by magnetic resonance imaging. Measurement of BI 2536 by mass spectrometry revealed considerably lower BI 2536 levels in HCC compared with the adjacent normal liver tissue. In conclusion, low intratumoral levels are a novel mechanism of resistance to the Plk1 inhibitor BI 2536. Plk1 inhibitors achieving sufficient intratumoral levels are highly promising in HCC treatment.

Download full text files

Export metadata

Metadaten
Author:Jörg HaupenthalORCiDGND, Verena Bihrer, Hüdayi KorkusuzGND, Otto KollmarGND, Christian Schmithals, Susanne Kriener, Knut Engels, Thomas PleliORCiD, Alexander Benz, Marta Canamero, Thomas Longerich, Bernd KronenbergerORCiDGND, Swantje Richter, Oliver WaidmannORCiDGND, Thomas J. VoglORCiDGND, Stefan ZeuzemORCiDGND, Albrecht PiiperORCiD
URN:urn:nbn:de:hebis:30:3-551048
DOI:https://doi.org/10.1596/neo.111366
ISSN:1476-5586
ISSN:1522-8002
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/22745587
Parent Title (English):Neoplasia
Publisher:Stockton Press
Place of publication:Basingstoke
Document Type:Article
Language:English
Year of Completion:2014
Date of first Publication:2014/03/04
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2020/07/15
Volume:14
Issue:5
Page Number:15
First Page:410
Last Page:419
Note:
Under a Creative Commons license
HeBIS-PPN:467516669
Institutes:Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung-Nicht kommerziell-Keine Bearbeitung 3.0