Inhibition of growth and invasive activity of human pancreatic cancer cells by a farnesyltransferase inhibitor, manumycin.
The effects of manumycin, a competitive farnesyltransferase (FTase) inhibitor, on pancreatic cancer cell lines with or without K-ras mutation were studied. Manumycin inhibited the growth of human pancreatic cancer cells (SUIT-2, MIA PaCa-2, AsPC-1, BxPC-3) in a dose-dependent manner. The 50% inhibitory concentration (IC50) in cell lines with a mutant K-ras gene (SUIT-2, MIA PaCa-2, AsPC-1) was lower than that in BxPC-3 with a wild-type ras. Both mitogen-activated protein kinase activity after growth stimuli and the ability for chemotactic invasion were markedly more inhibited by manumycin in SUIT-2 than in BxPC-3. These results suggest that mutated Ras is more sensitive to manumycin than the wild type. Furthermore, tumor growth and liver metastasis in nude mice inoculated with manumycin-treated SUIT-2 cells were inhibited dose dependently. Inhibition of Ras activity might be a new anticancer strategy in pancreatic cancer in which Ras plays a role.
Kainuma
O
O
Second Department of Surgery, Chiba University School of Medicine, Japan.
Asano
T
T
Hasegawa
M
M
Kenmochi
T
T
Nakagohri
T
T
Tokoro
Y
Y
Isono
K
K
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D004273:DNA, Neoplasm / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051231:Farnesyltranstransferase; D011905:Genes, ras / Q000235:genetics; D006801:Humans; D008113:Liver Neoplasms / Q000556:secondary; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D017354:Point Mutation; D011090:Polyenes / Q000494:pharmacology*; D053284:Polyunsaturated Alkamides; D011494:Protein Kinases / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D004791:Enzyme Inhibitors; D011090:Polyenes; D053284:Polyunsaturated Alkamides; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; D011494:Protein Kinases; C054474:manumycin