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

Abstract

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.

• Authors: Hirota Fujiki, Masami Suganuma
• Journal: Anti-cancer agents in medicinal chemistry (Anticancer Agents Med Chem) Vol. 11 Issue 1 Pg. 4-18 (Jan 2011) ISSN: 1875-5992 [Electronic] Netherlands
• PMID: 21269254 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)

Chemical References

• Carcinogens
• Marine Toxins
• Microcystins
• Peptides, Cyclic
• Tumor Necrosis Factor-alpha
• nodularin
• Okadaic Acid
• Protein Tyrosine Phosphatases
• cyanoginosin LR

Topics

• Animals
• Carcinogens (chemistry, metabolism, pharmacology)
• Cell Transformation, Neoplastic (chemically induced)
• Humans
• Marine Toxins
• Microcystins (chemistry, pharmacology)
• Neoplasms (enzymology, metabolism, pathology)
• Okadaic Acid (chemistry, pharmacology)
• Peptides, Cyclic (chemistry, pharmacology)
• Protein Tyrosine Phosphatases (antagonists & inhibitors, genetics, metabolism)
• Structure-Activity Relationship
• Tumor Necrosis Factor-alpha (genetics, metabolism)