ChemInform Abstract: Microbial Secondary Metabolites Inhibiting Oncogene Functions

Abstract

Streptomyces and other microorganisms produce antibiotics, anticancer agents and enzyme inhibitors as secondary metabolites. Microorganisms are a treasury of organic compounds which have various structures and biological activities. Therefore, isolation of the specific bioactive products in culture broths is dependent upon the testing method. Since oncogene theory has been extensively developed, we have screened oncogene function inhibitors as a new group of microbial secondary metabolites. Oncogene functions include acting as a modified growth factor receptor (erb B, erb B 2 fms), acting as a growth factor itself (sis, hst), the tyrosine kinase activity (src oncogene group), and acting as a G protein to activate phosphatidylinositol turnover (ras).Erbstatin is an inhibitor of erb B, erb B 2 and src products-associated tyrosine kinase. In cell culture it inhibited EGF receptor internalization, delayed the onset of EGF-induced DNA synthesis in quiescent cells, and induced normal phenotypes in src oncogene expressing cells. It inhibited the growth of human breast and esophageal carcinomas in nude mice. Lavendustin A was isolated from Streptomyces as a potent inhibitor of tyrosine kinase. It is a novel compound and about 50 times stronger than erbstatin in in vitro inhibition of tyrosine kinase. Many oncogenes including ras, src, sis, fms, and fes are considered to activate cellular phosphatidylinositol turnover. We have isolated psi-tectorigenin, inostamycin and piericidin B1 N-oxide as inhibitors of inositol incorporation into phospholipids. Thus, various inhibitors of oncogene functions including novel structures have been discovered in microbial secondary metabolites. They are useful for the dynamic study of oncogenes.