Universität zu Köln

Peiffer, Lukas, Poll-Wolbeck, Simon Jonas, Flamme, Hanna, Gehrke, Iris, Hallek, Michael and Kreuzer, Karl-Anton (2014). Trichostatin A effectively induces apoptosis in chronic lymphocytic leukemia cells via inhibition of Wnt signaling and histone deacetylation. J. Cancer Res. Clin. Oncol., 140 (8). S. 1283 - 1294. NEW YORK: SPRINGER. ISSN 1432-1335

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Abstract

Background T he ontogenetic Wnt pathway shows almost no activity in adult tissues. In contrast, chronic lymphocytic leukemia (CLL) cells show constitutionally active Wnt signaling, which is associated with upregulated levels of pathway members such as Wnt3 and lymphoid enhancer-binding factor-1. Functionally, this results in increased resistance to apoptosis. We therefore assumed that targeting members of the pathway could reveal new therapeutic options for the treatment of CLL. Methods Screening a Wnt compound library with 75 Wnt modulators via AT P assay revealed Trichostatin A as an outstanding substance with strong viability decreasing effects on CLL cells and little effect on healthy peripheral blood mononuclear cells (PBMCs). Further survival analysis was performed via fluorescence-activated cell sorting analysis. Results A maximum effect was achieved after 48 h with a wide therapeutic window in contrast to PBMCs (CLL cells: 0.253 mu M, PBMCs: 145.22 mu M). Trichostatin A induced caspases and acted via a dual mechanism to reveal histone and non-histone targets. Histone targets were displayed in deacetylation inhibition at DNA level, and non-histone targeting was demonstrated by elevated levels of Dickkopf-related protein 1 mRNA. Primary cells of patients with critical mutations such as TP53 or those who had already undergone extensive previous treatment responded well to the treatment. Moreover, the approved histone deacetylase (HDAC) inhibitor suberoylanilidehydroxamic acid (SAHA) was not as effective as Trichostatin A (Trichostatin A: 0.253 mu M, SAHA: 7.88 mu M). Combining Trichostatin A with established CLL drugs fludarabine or bendamustine showed an additive effect in vitro. Conclusion Taken together, Trichostatin A appears to act via a dual anti-HDAC/Wnt mechanism with a high selectivity and efficacy in CLL and therefore warrants further investigation.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Peiffer, Lukas UNSPECIFIED UNSPECIFIED UNSPECIFIED Poll-Wolbeck, Simon Jonas UNSPECIFIED UNSPECIFIED UNSPECIFIED Flamme, Hanna UNSPECIFIED UNSPECIFIED UNSPECIFIED Gehrke, Iris UNSPECIFIED UNSPECIFIED UNSPECIFIED Hallek, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED Kreuzer, Karl-Anton UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-432640
DOI:	10.1007/s00432-014-1689-0
Journal or Publication Title:	J. Cancer Res. Clin. Oncol.
Volume:	140
Number:	8
Page Range:	S. 1283 - 1294
Date:	2014
Publisher:	SPRINGER
Place of Publication:	NEW YORK
ISSN:	1432-1335
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language REFRACTORY CLL; PATHWAY; LYMPHOMA; SURVIVAL; POTENT; VORINOSTAT; DICKKOPF-1; DELETION; THERAPY; ANALOGS Multiple languages Oncology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/43264