Antiproliferative and proapoptotic activity of CLM3, a novel multiple tyrosine kinase inhibitor, alone and in combination with SN-38 on endothelial and cancer cells

摘要: Abstract Aims To demonstrate the antiproliferative and pro-apoptotic activity of novel pyrazolopyrimidine derivative multiple tyrosine kinase inhibitor CLM3, alone in combination with SN-38 (the active metabolite irinotecan), on endothelial tumor cells to show its mechanism action. Methods Proliferation apoptotic assays were performed microvascular (HMVEC-d) lung (A549) thyroid cancer (8305C, TT) cell lines exposed CLM3 simultaneous SN38 for 72 h. Cell-based phospho-VEGFR-2, phospho-EGFR phospho-RET inhibition ERK1/2 Akt phosphorylation quantified by ELISA kits. Cyclin D1 gene expression was real-time PCR cyclin intracellular concentrations measured ELISA. Results A strong effect found cells, synergistically enhanced SN38. Phospho-VEGFR-2, levels significantly decreased after treatments activated cells; inhibited lower drug if compared cells. Moreover, treatment greatly decreasing protein concentration. Conclusions The demonstrated a highly significant promising proapoptotic activity, SN-38, These effects are mainly due VEGFR-2, EGFR RET kinases their related signaling pathways.