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.
Highlights
Canine lymphoma represent approx. 24 % of all occurring canine neoplasms and 83 % of all canine hematopoietic neoplasms [1,2,3]
The effects of PDA-66 and PDA-377 on canine lymphoma cell lines were investigated for the first time
The dimethyl sulfoxide (DMSO) concentration (≤ 0.1 %) in the control groups was chosen to be equivalent to the highest DMSO concentration of the PDA group in order to compensate for putative solvent effects
Summary
Canine lymphoma represent approx. 24 % of all occurring canine neoplasms and 83 % of all canine hematopoietic neoplasms [1,2,3]. The canine tumor shows a higher incidence with 13-33 cases per year in 100,000 dogs [4]. Concerning tumor development, progression and disease pattern www.impactjournals.com/oncotarget lymphoma in dogs presents highly similar to human high-grade non-Hodgkin’s lymphoma (NHL) and is considered to serve as a comparative animal model of human NHL [2, 5]. Most dogs suffering from malignant lymphoma die within four to six weeks [6]. Combination chemotherapy protocols are superior in multicentric lymphoma and conventional CHOP-based chemotherapy induces remission in approx. The majority of dogs undergoing chemotherapy suffer disease recurrence within 12 months. The recurrent lymphoma cells are described to be highly resistant to the initial chemotherapeutic protocol [7, 8]
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