P3.02c-022 Anticancer Activity of Sorafenib in Combined Treatment with Betulin in Human Non-Small Cell Lung Cancer Cell Lines: Topic: Targeted Therapy

Abstract

The highly selective multi-targeted agent sorafenib is an inhibitor of a number of intracellular signaling kinases with anti-proliferative, anti-angiogenic and pro-apoptotic effects in various types of tumors, including human non-small cell lung cancer (NSCLC). Betulin displays a broad spectrum of biological and pharmacological properties including the anticancer and chemopreventive activity. Combination of drugs with different targets is a logical approach to overcome multilevel cross-stimulation among key pathways in NSCLC progression. The NSCLC cell lines A549, H358, A427, HCC827, H1703, normal lung microvascular endothelial cells HLMEC and normal human PBMC were treated with sorafenib and betulinic acid alone and in combination. We examined the effect of different combined treatment on viability (MTS test), proliferation and apoptotic susceptibility analyzed by flow cytometry, alterations in signaling pathways by western blotting and as well colony-forming ability. The combination of sorafenib with betulinic acid had strong effect on induction of apoptosis of different non-small cell lung cancer cell lines but not effect on normal cells. Combination treatment inhibited phosphorylation of ERK, AKT and mTOR in the A549 cells line and in low concentrations significantly reduced the colony-forming ability of A549, H358 and A427 cells as compared to either compound alone. In this study we show that sorafenib significantly suppressed the proliferation of lung cancer cells and treatment with the combination of low concentrations of sorafenib with betulinic acid exhibited ability to induce a high level of cell death in some non-small cell lung cancer cell lines.