Abstract
8-Chloro-cyclic AMP (8-Cl-cAMP) is a cAMP analogue that specifically down-regulates type I protein kinase A, a signaling protein directly involved in cell proliferation and neoplastic transformation, and that causes growth inhibition in a variety of human cancer cell types. In this report, we have investigated the effects of 8-Cl-cAMP on the expression of several growth factors in human colon (GEO and LS174T) and breast (MDA-MB468) cancer cell lines. 8-Cl-cAMP treatment caused in the three cancer cell lines a significant dose- and time-dependent inhibition in the expression of various endogenous autocrine growth factors, such as transforming growth factor alpha, amphiregulin, and CRIPTO, and of two angiogenic factors, such as vascular endothelial growth factor and basic fibroblast growth factor, at both the mRNA and protein levels. Furthermore, 8-Cl-cAMP treatment markedly inhibited the ability of all three cell lines to invade a basement membrane matrix in a chemoinvasion assay. Finally, 8-Cl-cAMP-induced inhibition of GEO tumor growth in nude mice was accompanied by a significant suppression of transforming growth factor alpha, amphiregulin, CRIPTO, basic fibroblast growth factor, and vascular endothelial growth factor production by the tumor cells, and of neoangiogenesis, as detected by factor VIII staining of host blood cells. These results demonstrate that 8-Cl-cAMP is a novel anticancer drug that inhibits the production of various autocrine and paracrine tumor growth factors that are important in sustaining autonomous local growth and facilitate invasion and metastasis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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8-Bromo Cyclic Adenosine Monophosphate / analogs & derivatives*
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8-Bromo Cyclic Adenosine Monophosphate / therapeutic use
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8-Bromo Cyclic Adenosine Monophosphate / toxicity
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Amphiregulin
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Animals
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Antineoplastic Agents / therapeutic use
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Antineoplastic Agents / toxicity*
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Breast Neoplasms
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Cell Division / drug effects
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Colonic Neoplasms / blood supply
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Colonic Neoplasms / drug therapy*
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Colonic Neoplasms / metabolism
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Colonic Neoplasms / pathology
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Colorectal Neoplasms
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EGF Family of Proteins
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Endothelial Growth Factors / biosynthesis
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Endothelial Growth Factors / genetics*
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Epidermal Growth Factor*
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Female
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Fibroblast Growth Factor 2 / biosynthesis
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Fibroblast Growth Factor 2 / genetics*
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GPI-Linked Proteins
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Glycoproteins / biosynthesis
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Glycoproteins / genetics
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Growth Substances / biosynthesis
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Growth Substances / genetics
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Humans
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Intercellular Signaling Peptides and Proteins*
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Lymphokines / biosynthesis
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Lymphokines / genetics*
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Membrane Glycoproteins*
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Mice
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Mice, Nude
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Neoplasm Proteins / biosynthesis
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Neoplasm Proteins / genetics
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Neovascularization, Pathologic / prevention & control*
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Transforming Growth Factor alpha / biosynthesis
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Transforming Growth Factor alpha / genetics
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Transplantation, Heterologous
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Tumor Cells, Cultured
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
Substances
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AREG protein, human
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Amphiregulin
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Antineoplastic Agents
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Areg protein, mouse
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EGF Family of Proteins
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Endothelial Growth Factors
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GPI-Linked Proteins
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Glycoproteins
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Growth Substances
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Intercellular Signaling Peptides and Proteins
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Lymphokines
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Membrane Glycoproteins
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Neoplasm Proteins
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TDGF1 protein, human
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Tdgf1 protein, mouse
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Transforming Growth Factor alpha
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
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Fibroblast Growth Factor 2
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8-Bromo Cyclic Adenosine Monophosphate
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Epidermal Growth Factor
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8-chloro-cyclic adenosine monophosphate