Screening Of Anti-tumor Activity Compounds And The Mechanism Study Of Wyz-xm-5

Until now,cancer is still a major threat to human health.Diverse biological activities of natural products are attributed to the structural complexity and diversity,which endows natural products being irreplaceable lead compounds and the important source of new drugs.Hsp90 is a highly abundant and ubiquitous molecular chaperone whose client proteins are key proteins in the intracellular signal transduction pathways,so Hsp90 plays an essential role in many cellular processes including cell cycle control,cell survival,hormone and other signalling pathways.Hsp90 has therefore become an important target for cancer therapy.In this study,we focus on the find and develop of the anti-tumor activity compounds in 1736 natural products by MTT.We used 9 kinds of tumor cells.Based on these results,we proceeded to study the signal pathway via fluorescent staining,flow cytometry and so on.The results are as follows:1.There are 127 compounds can inhibit tumor cell proliferation at a final concentration 10μM,accounting for 7.3%of the screened compounds.And 26 compounds had been found have over 80%inhibition ratio of tumor cells,accounting for 1.5%of the screened compounds.2.We found wyz-xm-5,which was derived from the rare actinomycete Actinomadura sp.xm-4-3 isolated from root surrounding soil of firmiana simplex,has strong anti-tumor activity at a final concentration 50 nM.wyz-xm-5 demonstrates a concentration-dependent inhibitory effect on the proliferation of various tumor cells such as A549,BGC-823,HepG2,HCT-116,U20S and MCF-7,with IC50 values ranging from 50 nM to 300 nM.wyz-xm-5 has different effects on different types of cancer cell,among which BGC-823 and HepG2 are most sensitive to the inhibition of wyz-xm-5.3.Its exposure to BGC-823 cells resulted in a cell cycle arrest at S phase.wyz-xm-5 induced S phase arrest was accompanied by the upregulation of Chk1,Chk2 and cyclin-dependent kinase inhibitor p21 and the downregulation of CDK2,mytl,and p-Chkl.4.wyz-xm-5 caused a great degradation of Hsp90 client proteins(Akt,IKKα)and the upregulation of IKKp,IKKy in the BGC-823.Our study plays a significant role in developing wyz-xm-5 into new anti-cancer drugs.