title: Characterization of the novel indolylmaleimides' PDA-66 and PDA-377 effect on canine lymphoma cells.
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.
authors.affiliation: Department of Medicine, Clinic III - Hematology/Oncology/Palliative Care, Rostock University Medical Center, Rostock, Germany.|Small Animal Clinic, University of Veterinary Medicine Hannover, Hannover, Germany.
authors.forename: Wen
authors.initials: W
authors.lastname: Liu
authors.affiliation: Chronix Biomedical, Göttingen, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Beck
authors.affiliation: Department of Medicine, Clinic III - Hematology/Oncology/Palliative Care, Rostock University Medical Center, Rostock, Germany.|Small Animal Clinic, University of Veterinary Medicine Hannover, Hannover, Germany.
authors.forename: Laura C
authors.initials: LC
authors.lastname: Schmidt
authors.affiliation: Department of Medicine, Clinic III - Hematology/Oncology/Palliative Care, Rostock University Medical Center, Rostock, Germany.
authors.forename: Catrin
authors.initials: C
authors.lastname: Roolf
authors.affiliation: Leibniz-Institute for Catalysis at the University of Rostock, Rostock, Germany.
authors.forename: Anahit
authors.initials: A
authors.lastname: Pews-Davtyan
authors.affiliation: Clinical Pathology, Department of Pathobiology, University of Veterinary Medicine Vienna, Vienna, Austria.
authors.forename: Barbara C
authors.initials: BC
authors.lastname: Rütgen
authors.affiliation: Institute of Immunology, Department of Pathobiology, University of Veterinary Medicine Vienna, Vienna, Austria.
authors.forename: Sabine
authors.initials: S
authors.lastname: Hammer
authors.affiliation: Small Animal Clinic, University of Veterinary Medicine Hannover, Hannover, Germany.
authors.forename: Saskia
authors.initials: S
authors.lastname: Willenbrock
authors.affiliation: Department of Medicine, Clinic III - Hematology/Oncology/Palliative Care, Rostock University Medical Center, Rostock, Germany.
authors.forename: Anett
authors.initials: A
authors.lastname: Sekora
authors.affiliation: Albrecht-Kossel-Institute for Neuroregeneration (Akos), Center for Mental Health, University of Rostock, Rostock, Germany.|Centogene AG, Rostock, Germany.
authors.forename: Arndt
authors.initials: A
authors.lastname: Rolfs
authors.affiliation: Leibniz-Institute for Catalysis at the University of Rostock, Rostock, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Beller
authors.affiliation: Institute of Veterinary Medicine, Georg-August-University Göttingen, Göttingen, Germany.
authors.forename: Bertram
authors.initials: B
authors.lastname: Brenig
authors.affiliation: Small Animal Clinic, University of Veterinary Medicine Hannover, Hannover, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Nolte
authors.affiliation: Department of Medicine, Clinic III - Hematology/Oncology/Palliative Care, Rostock University Medical Center, Rostock, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Junghanss
authors.affiliation: Chronix Biomedical, Göttingen, Germany.|Institute of Veterinary Medicine, Georg-August-University Göttingen, Göttingen, Germany.
authors.forename: Ekkehard
authors.initials: E
authors.lastname: Schütz
authors.affiliation: Department of Medicine, Clinic III - Hematology/Oncology/Palliative Care, Rostock University Medical Center, Rostock, Germany.|Small Animal Clinic, University of Veterinary Medicine Hannover, Hannover, Germany.
authors.forename: Hugo
authors.initials: H
authors.lastname: Murua Escobar
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004285:Dogs; D007211:Indoles / Q000494:pharmacology*; D016393:Lymphoma, B-Cell; D008301:Maleimides / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D008301:Maleimides; C579844:PDA-66; D047428:Protein Kinase Inhibitors
keywords: PDA; arylindolylmaleimides; canine lymphoma; transcriptome sequencing