Abstract
We previously designed and synthesized dehydroxyepoxyquinomicin (DHMEQ) as an inhibitor of NF-κB based on the structure of microbial secondary metabolite epoxyquinomicin C. DHMEQ showed anti-inflammatory and anticancer activity in various in vivo disease models without toxicity. On the other hand, the process of cancer metastasis consists of cell detachment from the primary tumor, invasion, transportation by blood or lymphatic vessels, invasion, attachment, and formation of secondary tumor. Cell detachment from the primary tumor and subsequent invasion are considered to be early phases of metastasis, while tumor cell attachment to the tissue and secondary tumor formation the late phases. The assay system for the latter phase was set up with intra-portal-vein injection of pancreatic cancer cells. Intraperitoneal administration of DHMEQ was found to inhibit liver metastasis possibly by decreasing the expression of MMP-9 and IL-8. Also, when the pancreatic cancer cells treated with DHMEQ were inoculated into the peritoneal cavity of mice, the metastatic foci formation was inhibited. These results indicate that DHMEQ is likely to inhibit the late phase of metastasis. Meanwhile, we have recently employed three-dimensional (3D) culture of breast cancer cells for the model of early phase metastasis, since the 3D invasion just includes cell detachment and invasion into the matrix. DHMEQ inhibited the 3D invasion of breast cancer cells at 3D-nontoxic concentrations. In this way, DHMEQ was shown to inhibit the late and early phases of metastasis. Thus, DHMEQ is likely to be useful for the suppression of cancer metastasis.
Highlights
Microbial and plant-derived bioactive metabolites are valuable sources of organic compounds having various structures and biological activities
We found that DHMEQ ameliorated we found that DHMEQ
graft-versus-host disease (GVHD) than the vehicle-injected mice. These findings suggest that administration of DHMEQ would become a new strategy for preventing fatalities from GVHD
Summary
Microbial and plant-derived bioactive metabolites are valuable sources of organic compounds having various structures and biological activities. We have isolated various signal transduction inhibitors of low molecular weight from microbial and plant secondary metabolites These inhibitors include protein-tyrosine kinase inhibitor lavendustin from Streptomyces [1], protein-tyrosine phosphatase inhibitor dephostatin from Streptomyces [2], anti-K-Ras compound aglaiastatin from a plant [3], phosphatidylinositol-specific phospholipase C inhibitor akaterpin from a marine sponge [4], lipopolysaccharide inactivating compound heptadepsin from a bacterium [5], and inhibitor of cancer cell migration migracin from Streptomyces [6]. We have have found found that that aa plant-derived plant-derived alkaloid alkaloid conophylline conophylline induces induces pancreatic pancreatic β-cell β-cell adifferentiation plant-derivedand alkaloid conophylline induces pancreatic β-cell differentiation and protects islets from differentiation protects islets from fibrosis in animals [7] These bioactive metabolites and protects islets from fibrosis in animals [7]. (DHMEQ) by molecular design based on the structure of naturally occurring epoxyquinomicin.
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