Naturally-Derived Tumor Promoters and Inhibitors of Carcinogenesis

Abstract

Tumor promoters are agents that develop tumors from initiated cells, and tumor promotion is an important stage in multi-stage carcinogenesis in humans. We studied mechanisms of tumor promotion in two-stage carcinogenesis experiments in rodents with tumor promoters derived from various marine organisms. The compounds of the lyngbyatoxin and aplysiatoxin classes, like 12–O-tetradecanoylphorbl-13-acetate (TPA) derived from Euphorbia plants, induced tumor promotion on mouse skin mediated through activation of protein kinase C, and were identified as the TPA-type tumor promoters. The non-TPA type tumor promoters included the palytoxin and okadaic acid classes. The okadaic acid class compounds induced tumor promotion in various organs mediated through inhibition of protein phosphatases 1 and 2A. The study of the okadaic acid class of tumor promoters led us to find tumor necrosis factor-α as a tumor promoter endogenously present in human tissues. Inhibitors of tumor promotion were also found in marine organisms, such as sarcophytol A and discodermin A. In addition, agelasine-B was found to be a new activator of protein phosphatases 1 and 2A. This paper reviews our study on tumor promotion with marine toxins and presents an essential mechanism of tumor promotion in human cancer development.