Tumor promoters--microcystin-LR, nodularin and TNF-α and human cancer development

• Published in: Anti-cancer agents in medicinal chemistry Vol. 11; no. 1; p. 4
• Main Authors: Fujiki, Hirota, Suganuma, Masami
• Format: Journal Article
• Language: English
• Published: Netherlands 01.01.2011
• Subjects: Animals; Carcinogens - chemistry; Carcinogens - metabolism; Carcinogens - pharmacology; Cell Transformation, Neoplastic - chemically induced; Humans; Microcystins - chemistry; Microcystins - pharmacology; Neoplasms - enzymology; Neoplasms - metabolism; Neoplasms - pathology; Okadaic Acid - chemistry; Okadaic Acid - pharmacology; Peptides, Cyclic - chemistry; Peptides, Cyclic - pharmacology; Protein Tyrosine Phosphatases - antagonists & inhibitors; Protein Tyrosine Phosphatases - genetics; Protein Tyrosine Phosphatases - metabolism; Structure-Activity Relationship; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 1875-5992
• DOI: 10.2174/187152011794941163

Microcystin-LR and nodularin, along with okadaic acid, are potent inhibitors of protein phosphatases 1 and 2A (PP1 and PP2A). The mechanisms of action of microcystin-LR and nodularin in the liver and that of okadaic acid, a potent tumor promoter on mouse skin, have attracted the attention of the scientists. This paper reviews several topics: new inhibitors of PP1 and PP2A with new chemical structures, structure-function relationships for both receptor binding and inhibition of protein phosphatases, the crystal structure of PP1 or PP2A-toxin complex, induction of gene expression and apoptosis. These subjects were studied by using in vitro and in vivo experimental systems. Two-stage carcinogenesis experiments with microcystin-LR and nodularin for the first time demonstrated that microcystin-LR is a new tumor promoter in rat liver initiated with diethylnitrosamine (DEN), and that nodularin is a potent tumor promoter associated with weak initiating activity in rat liver initiated with DEN. A working group of WHO (IARC) concluded that microcystin-LR is "possibly carcinogenic to humans" and that nodularin is "not classifiable as to carcinogenicity". Our studies revealed that chemical tumor promoters are inducers of TNF-α in the cells of target tissues and that TNF-α is an endogenous tumor promoter. This advance in carcinogenesis made it possible to look for the link between chemical tumor promoters and endogenous tumor promoters, such as TNF-α and IL-1. The carcinogenic features of TNF-α are described in this review, and the TNF-α inducing protein (Tipα) of Helicobacter pylori genome is presented as an example of a tumor promoter of human stomach cancer development.