Investigation of the anticancer, antiinflammatory and antiangiogenic effects of the combination of Motesanib and diclofenac diethylamine

Angiogenesis is an important molecular target for the development of new therapeutics in cancer treatment among cellular signaling pathways. Due to the expression levels of EGFR and PI3Kinase and the effects of inflammatory cytokines on cancer cells, regulators of this pathway are important in antineoplastic therapy. The VEGF-VEGFR system plays an important role in physiological and pathological angiogenesis, including tumor angiogenesis. In this study; It was aimed to investigate the antiproliferative, apoptotic and anti-inflammatory effects of motesanib (AMG 706), an angiokinase inhibitor, and diclofenac diethylamine in U87MG (Glioblastoma)/THP-1 (Monocyte) coculture model and the antiproliferative and antiangiogenic effects in HUVEC (Human umbilical vein endothelial cell) cells. Therefore, firstly, the cytotoxic effects of motesanib, diclofenac diethylamine and combination applications were determined by MTT method in U87MG, THP-1 and HUVEC cell lines and the CDI values of the combined applications were calculated. Especially, the antiproliferative effects of motesanib in U87MG cells and the antimigration effects in HUVEC cells were evaluated by real-time analysis system. The effects of motesanib and diclofenac diethylamine on cell migration in HUVEC cells were also studied morphologically. By establishing the U87MG/THP-1 coculture cell model, the apoptotic effects of motesanib and diclofenac diethylamine combinations in glioma cells were evaluated by Annexin V-PI, caspase-3 and mitochondrial membrane potential analyses, and the antiinflammatory effects were evaluated by IL-1β, TNFα, IL-6, IL-8 and IL-10 cytokine analyses by flow cytometry. In addition, ROS and COX-2 levels were analyzed by flow cytometry. In conclusion, it was determined that motesanib, diclofenac diethylamine and their combinations had significant antiproliferative effects on U87MG and HUVEC cells, and that additive effects occurred especially in combined applications. Motesanib showed antimigration effect and produced antiangiogenic effects in HUVEC cells depending on the increase in concentration. In the U87MG/THP-1 coculture model, significant apoptotic (40 μM motesanib+200 μM diclofenac diethylamine) and anti-inflammatory (20 or 40 μM motesanib with 200 μM diclofenac diethylamine) effects were determined in glioma cells.