Oncotarget

Research Papers:

Characterization of the novel indolylmaleimides’ PDA-66 and PDA-377 effect on canine lymphoma cells

Wen Liu, Julia Beck, Laura C. Schmidt, Catrin Roolf, Anahit Pews-Davtyan, Barbara C. Rütgen, Sabine Hammer, Saskia Willenbrock, Anett Sekora, Arndt Rolfs, Matthias Beller, Bertram Brenig, Ingo Nolte, Christian Junghanss, Ekkehard Schütz _ and Hugo Murua Escobar

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Oncotarget. 2016; 7:35379-35389. https://doi.org/10.18632/oncotarget.9297

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Abstract

Wen Liu1,2,*, Julia Beck3,*, Laura C. Schmidt1,2, Catrin Roolf1, Anahit Pews-Davtyan4, Barbara C. Rütgen5, Sabine Hammer6, Saskia Willenbrock2, Anett Sekora1, Arndt Rolfs7,8, Matthias Beller4, Bertram Brenig9, Ingo Nolte2, Christian Junghanss1, Ekkehard Schütz3,9,*, Hugo Murua Escobar1,2,*

1Department of Medicine, Clinic III - Hematology/Oncology/Palliative Care, Rostock University Medical Center, Rostock, Germany

2Small Animal Clinic, University of Veterinary Medicine Hannover, Hannover, Germany

3Chronix Biomedical, Göttingen, Germany

4Leibniz-Institute for Catalysis at the University of Rostock, Rostock, Germany

5Clinical Pathology, Department of Pathobiology, University of Veterinary Medicine Vienna, Vienna, Austria

6Institute of Immunology, Department of Pathobiology, University of Veterinary Medicine Vienna, Vienna, Austria

7Albrecht-Kossel-Institute for Neuroregeneration (Akos), Center for Mental Health, University of Rostock, Rostock, Germany

8Centogene AG, Rostock, Germany

9Institute of Veterinary Medicine, Georg-August-University Göttingen, Göttingen, Germany

*The authors contributed equally

Correspondence to:

Hugo Murua Escobar, email: hugo.murua.escobar@med.uni-rostock.de

Keywords: PDA, arylindolylmaleimides, canine lymphoma, transcriptome sequencing

Received: September 14, 2015     Accepted: April 02, 2016     Published: May 12, 2016

ABSTRACT

Protein kinase inhibitors are widely used in chemotherapeutic cancer regimens. Maleimide derivatives such as SB-216763 act as GSK-3 inhibitor targeting cell proliferation, cell death and cell cycle progression.

Herein, the two arylindolylmaleimide derivatives PDA-66 and PDA-377 were evaluated as potential chemotherapeutic agents on canine B-cell lymphoma cell lines. Canine lymphoma represents a naturally occurring model closely resembling the human high-grade non-Hodgkin’s lymphoma (NHL). PDA-66 showed more pronounced effects on both cell lines. Application of 2.5μM PDA-66 resulted in a significant induction of apoptosis (approx. 11 %), decrease of the metabolic activity (approx. 95 %), anti-proliferative effect (approx. 85 %) and cell death within 48h. Agent induced mode of action was characterized by whole transcriptome sequencing, 12 h and 24 h post-agent exposure. Key PDA-66-modulated pathways identified were cell cycle, DNA replication and p53 signaling. Expression analyses indicated that the drug acting mechanism is mediated through DNA replication and cycle arrest involving the spindle assembly checkpoint.

In conclusion, both PDA derivatives displayed strong anti-proliferation activity in canine B-cell lymphoma cells. The cell and molecular PDA-induced effect characterization and the molecular characterization of the agent acting mechanism provides the basis for further evaluation of a potential drug for canine lymphoma serving as model for human NHL.


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