Combination Treatment Strategy Of Lung Cancer Based On PPARγ Nuclear Location

Cancer has become one of the major life-threatening diseases of which morbidity increased every year. The morbidity and mortality of lung cancer rank first in different cancer types. Smoking, genetic and pollution are the three major factors that cause lung cancer. However, the specific molecular mechanism remained unclear. Currently, the treatment methods of lung cancer include traditional methods and targeted therapeutic methods. Traditional methods refer to surgery or radiation therapy. Targeted therapeutic methods refer to small molecules which can home at aberrant proteins or signaling pathways in lung cancer. Unfortunately, these two treatment methods mentioned above have so far failed to treat lung cancer well. Therefore, it is imminent to explore new methods to treat lung cancer.In this paper, we used lung cancer cells and lung normal cells as experimental subjects. We frist selected the protein target for lung cancer. Then, we found small targeted molecules which could regulate the celluar location of the protein target based on the result of virtual computer screening. Finally, we proposed combination treatment strategy according to the molecular mechanism of physiological activities of the protein target. Subsequently, we designed and performed related experiments as proposed.Our conclusions are shown as follows:(1) Transcriptional factor PPARy can be used as a target for the treatment of lung cancer. In particular, its activicty, contents and celluar location is essential.(2) We selected natural product SFE as the inhibitor of Crml by Pubchem virtual screening and designed its derivative S-25.(3) SFE and S-25 can inhibit Crml efficiently, retend PPARy in the nuclear and kill lung cancer cells. The IC50 concentration of SFE is about 7 μM, and the IC50 concentration of S-25 is about 250 nM. At the same time, these two small molecules barely kill any lung normal cells which indicate they are safe in human body.(4) The combination of TZDs and SFE, or the combination of TZDs and S-25 could kill lung cancer cells more efficiently compared with these molecules used alone.Our research is the first study to use the nuclear localization of PPARγ as the key to design anti-lung cancer strategy. Also, we first find that the natural product SFE and its derivative S-25 can inhibit Crm1. The most significant merit of our study is using the activator of PPARγ together with the inhibitor of Crm1 to treat lung cancer. Our research provides a new approach for lung cancer targeted therapy.