28 Background: Non-small cell lung cancer is the leading cause of cancer deaths in the US. The success of current treatment strategies is limited by frequent aberrations in multiple signaling pathways. This includes loss-of-function mutations in the tumor suppressor p53 and activating mutations in multiple growth factor receptors, which converge to activate PI3K/Akt pathway. This calls for the development of novel, more active treatments. We investigated the anti-cancer effects of a novel compound called 1, 3 bis (3, 5-dichlorophenyl) urea (COH-SR4) in lung cancer. Methods: The anticancer effects of COH-SR4 were tested in p53-null H358 lung cancer cells. The antiproliferative effects were investigated in vitro by MTT assay. The bio-availability and antitumor effects were determined in vivo following the administration of 4 mg/kg of COH-SR4 to mice and H358-nu/nu nude mice xenografts. Results: The treatment with COH-SR4 resulted in effective inhibition of the proliferative potential of H358 lung cancer cells [IC50: 23+2 µM], effectively inducing apoptosis. The 4 mg/kg COH-SR4 administration resulted in a free serum concentration of 1+ 0.3 µM. Regression of established H358-xenografts was achieved without any overt toxicity. The histopathology of resected tumor sections revealed an increase in pAMPK (T172) and a decrease in the nuclear proliferative marker Ki 67 and angiogenesis marker CD31. Western blot analyses of resected tumor lysates revealed a decrease in pAkt (S473) and anti-apoptotic protein Bcl2 along with an increase in pAMPK (T172), pro-apoptotic Bax and cleaved PARP levels. In addition, COH-SR4 lead to a decrease in the levels of the cell cycle regulators CDK4 and cyclin B1 as well as the mesenchymal marker vimentin, whilst increasing the epithelial marker E-cadherin. Conclusions: COH-SR4 represents a novel agent for the treatment of non small cell lung cancer. We demonstrated pronounced anti-proliferative and pro-apoptotic activity in vitro and in vivo as well as the capability to promote physiologic, epithelial differentiation. This implies not only therapeutic, but also preventive potential. Further studies are needed to establish the best possible clinical applications of COH-SR4 in lung cancer.
Aidi injection, a traditional Chinese medicine extract, reverses Gefitinib resistance in non-small cell lung cancer cells
