Inhibition of epidermal-growth-factor-receptor-dependent signalling by tyrphostins A25 and AG1478 blocks growth and induces apoptosis in colorectal tumor cells in vitro.
Growth effects of tyrphostins A25 and AG1478 on colorectal tumor cells were studied to explore therapeutic potential. Cell number, DNA synthesis and apoptotic index were measured as growth parameters and cell-death-associated proteins Bcl-2 and Bak and protein phosphorylation were analyzed. Both tyrphostins inhibited DNA synthesis and induced apoptosis in tumor cell cultures with different patterns of activity. A25 displayed strong selectivity for the cell lines expressing high levels of epidermal growth factor (EGF), HT29/HI1 and SW480. Inhibition of DNA synthesis was efficient in all cells except T84, and the apoptotic index increased two- to fivefold. By contrast, AG1478 was highly effective in all cell lines. In addition, it caused cell loss in VACO235 adenoma cells at concentrations lower than those necessary to inhibit BrdU incorporation, reflecting preferential retention of cells actively synthesizing DNA. Induction of apoptosis was more efficient with AG1478 than with A25 (tenfold in VACO235). Insulin-like growth factor (IGF1) did not rescue cells exposed to A25 or to high concentrations of AG1478, but was effective with suboptimal amounts of AG1478. Both compounds inhibited phosphorylation of the EGF receptor as well as additional proteins. AG1478 induced expression of Bak and down-regulated Bcl-2. In summary, tyrphostins may provide alternatives for colorectal tumor treatment. Their broader range of activities and the lower susceptibility to interactions with IGF1 can be an advantage over receptor antibodies.
Institute of Tumor Biology-Cancer Research, University of Vienna, Austria.
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Partik
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Hochegger
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Schörkhuber
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Marian
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015179:Colorectal Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D004273:DNA, Neoplasm / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D066246:ErbB Receptors / Q000378:metabolism*; D005434:Flow Cytometry; D006801:Humans; D008565:Membrane Proteins / Q000032:analysis; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D011799:Quinazolines; D015398:Signal Transduction / Q000187:drug effects*; D014407:Tumor Cells, Cultured; D020032:Tyrphostins / Q000494:pharmacology*; D050998:bcl-2 Homologous Antagonist-Killer Protein
D000970:Antineoplastic Agents; C494772:BAK1 protein, human; D004273:DNA, Neoplasm; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011799:Quinazolines; D020032:Tyrphostins; D050998:bcl-2 Homologous Antagonist-Killer Protein; C079836:tyrphostin 25; C101044:RTKI cpd; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases