Characterization of the novel indolylmaleimides’ PDA-66 and PDA-377 effect on canine lymphoma cells
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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
Hugo Murua Escobar, email: [email protected]
Keywords: PDA, arylindolylmaleimides, canine lymphoma, transcriptome sequencing
Received: September 14, 2015 Accepted: April 02, 2016 Published: May 12, 2016
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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