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 elicobacter pylori genome is presented as an example of a tumor promoter of human stomach cancer development.
Keywords: Apparent activation of protein kinases, microcystin-LR, nodularin, liver carcinogenesis, okadaic acid, protein phosphatases 1 and 2A, tumor necrosis factor, tumor promotion, IARC, TNF, DEN
Anti-Cancer Agents in Medicinal Chemistry
Title: Tumor Promoters - Microcystin-LR, Nodularin and TNF-α and Human Cancer Development
Volume: 11 Issue: 1
Author(s): Hirota Fujiki and Masami Suganuma
Affiliation:
Keywords: Apparent activation of protein kinases, microcystin-LR, nodularin, liver carcinogenesis, okadaic acid, protein phosphatases 1 and 2A, tumor necrosis factor, tumor promotion, IARC, TNF, DEN
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 elicobacter pylori genome is presented as an example of a tumor promoter of human stomach cancer development.
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Cite this article as:
Fujiki Hirota and Suganuma Masami, Tumor Promoters - Microcystin-LR, Nodularin and TNF-α and Human Cancer Development, Anti-Cancer Agents in Medicinal Chemistry 2011; 11 (1) . https://dx.doi.org/10.2174/187152011794941163
DOI https://dx.doi.org/10.2174/187152011794941163 |
Print ISSN 1871-5206 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5992 |
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