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Fujiki H.,Tokushima Bunri University | Suganuma M.,Research Institute for Clinical Oncology
Anti-Cancer Agents in Medicinal Chemistry

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. © 2011 Bentham Science Publishers Ltd. Source

Ohtake F.,University of Tokyo | Fujii-Kuriyama Y.,University of Tokyo | Kawajiri K.,Research Institute for Clinical Oncology | Kato S.,University of Tokyo
Journal of Steroid Biochemistry and Molecular Biology

The arylhydrocarbon receptor (AhR) is a ligand-dependent transcription factor mediating the adverse effects of dioxins. Although cross-talk of dioxins with estrogen and androgen signaling pathways are well described, the underlying molecular mechanisms have been largely elusive. Recent studies showed that modulation of estrogen/androgen signaling by dioxins is exerted in part through direct association of AhR with estrogen (ER) or androgen (AR) receptors. Agonist-bound AhR and ERα work as a functional unit to regulate expression of target genes. In addition to such genomic actions, AhR mediates non-genomic actions of AhR-ligands through the assembly of a CUL4B-based ubiquitin ligase complex and promotes the degradation of ERα and AR. These findings reveal the roles of the ubiquitin system in sensing and biological response to environmental chemicals, in which AhR acts as a ubiquitin ligase component to enhance the destruction of specific substrates. © 2011 Elsevier Ltd. All rights reserved. Source

Suganuma M.,Research Institute for Clinical Oncology | Saha A.,Tokushima Bunri University | Fujiki H.,Tokushima Bunri University
Cancer Science

Green tea is now recognized as the most effective cancer preventive beverage. In one study, 10 Japanese-size cups of green tea daily supplemented with tablets of green tea extract limited the recurrence of colorectal polyps in humans to 50%. Thus, cancer patients who consume green tea and take anticancer drugs will have double prevention. We studied the effects of combining (-)-epigallocatechin gallate (EGCG) and anticancer drugs, focusing on inhibition of cell growth and induction of apoptosis. Numerous anticancer drugs, such as tamoxifen, COX-2 inhibitors, and retinoids were used for the experiments, and the combination of EGCG and COX-2 inhibitors consistently induced the enhancement of apoptosis. To study the mechanism of the enhancement, we paid special attention to the enhanced expressions of DDIT3 (growth arrest and DNA damage-inducible 153, GADD153), GADD45A, and CDKN1A (p21/WAF1/CIP1) genes, based on our previous evidence that a combination of EGCG and sulindac specifically induced upregulated expression of GADD153 and p21 genes in PC-9 lung cancer cells. The synergistic enhancements of apoptosis and GADD153 gene expression in human non-small cell lung cancer cells by the combination of EGCG and celecoxib were mediated through the activation of the MAPK signaling pathway. This article reviews the synergistic enhancement of apoptosis, gene expression, and anticancer effects using various combinations of EGCG and anticancer drugs, including the combination of (-)-epicatechin (EC) and curcumin. Based on the evidence, we present a new concept: green tea catechins as synergists with anticancer drugs. © 2010 Japanese Cancer Association. Source

The concept of cancer and inflammation has a long history. Virchow's irritation theory based on human cancer engendered the essential role of inflammation in carcinogenesis. Drs. Yamagiwa and Ichikawa first published a comprehensive paper entitled "Experimental study on the pathogenesis of epithelial tumors" (I report) in 1915 in German, and went on to publish five more reports (1915-1924) under the same title. They succeeded in demonstrating that inflammation is an important carcinogenic factor, and the mechanisms are now being investigated by numerous scientists all over the world. In order to introduce Yamagiwa's work to modern cancer researchers, the essentials of their six reports have been translated into English as a short review. Scientists' comments on Yamagiwa's contribution are attached by way of introduction. Drs. Yamagiwa and Ichikawa first published a comprehensive paper entitled "Experimental study on the pathogenesis of epithelial tumors" in 1915 in German. The essentials of their six reports under the same title have been translated into English as a short review. Scientists' comments on Yamagiwa's contribution are attached by way of introduction. © 2013 The Authors. Source

Fujii-Kuriyama Y.,University of Tokyo | Fujii-Kuriyama Y.,Tokyo Medical and Dental University | Kawajiri K.,Research Institute for Clinical Oncology
Proceedings of the Japan Academy Series B: Physical and Biological Sciences

The aryl hydrocarbon receptor (AhR) was originally identified as a ligandactivated transcription factor that is involved in the induction of xenobiotic-metabolizing Cytochrome P4501A1 (CYP1A1). For several decades, AhR has been studied in relation to toxicology and pharmacology. With recent discoveries on novel AhR functions, AhR research has expanded into multiple aspects of physiology, such as reproduction, innate immunity and tumor suppression. In this review, we summarize and discuss recent progress in mechanistic and functional studies on AhR with particular emphasis on physiological processes. © 2010 The Japan Academy. Source

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