Inhibition of K-ras-transformed rodent and human cancer cell growth via induction of apoptosis by irreversible inhibitors of Ras endoprotease.
Proteolytic removal of the carboxyl terminal tripeptide of Ras oncoproteins is important in the Ras function. Two chloromethyl ketones, BFCCMK and UM96001, designed to be the Ras C-terminal sequence-specific endoprotease inhibitors, at low micromolar concentrations (5.0 microM), potently inhibit the growth of ras-transformed rodent and human cancer cells, whereas untransformed NIH/3T3 cells are not affected under the same conditions. Furthermore, BFCCMK and UM96001 block more than 98% of the anchorage-independent clonogenic growth of ras-transformed rat and human cancer cells at low micromolar concentrations. The blocking of cancer cell growth may be due to the selective induction of apoptosis of ras-transformed cells by these inhibitors. These results provide the first experimental evidence that the endoproteolysis of Ras oncoproteins is important for the growth and apoptosis of ras-transformed cancer cells. Therefore, the Ras C-terminal sequence-specific endoprotease may be a potential new target for the treatment of human cancers induced by ras mutations.
Chen
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Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota Academic Health Center, Minneapolis 55455, USA. chenx112@gold.tc.umn.edu
D016475:3T3 Cells; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis; D002455:Cell Division / Q000187:drug effects; D002461:Cell Line, Transformed; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D011905:Genes, ras; D006801:Humans; D051379:Mice; D010169:Palmitic Acids / Q000494:pharmacology*; D051381:Rats; D018631:ras Proteins / Q000037:antagonists & inhibitors*
D000590:Amino Acid Chloromethyl Ketones; C116012:BFCCCMK; D004791:Enzyme Inhibitors; D010169:Palmitic Acids; C116011:UM 96001; D018631:ras Proteins