manumycin and Pancreatic-Neoplasms

Ras is one of the key components in the signal transduction for cell growth. For acquisition of biological activity, Ras protein is required to bind to the inside of the plasma membrane after post-translational farnesylation. Manumycin, a competitive farnesyl transferase inhibitor, inhibits the growth of human pancreatic cancer cells (SUIT-2, MIAPaCa-2, AsPC-1, BxPC-3) in a dose dependent manner. The inhibitory concentration (IC50) of cell lines with a mutant K-ras gene (SUIT-2, MIAPaCa-2, AsPC-1) was lower than that of BxPC-3 with a wild-type. A high concentration of manumycin induced apoptosis, which is related to the inhibition of cell growth. Inhibition of Ras activity might be a new anti-cancer therapy in pancreatic cancer in which Ras plays a role.

Topics: Alkyl and Aryl Transferases; Animals; Anti-Bacterial Agents; Cell Division; Farnesyltranstransferase; Humans; Mice; Mice, Nude; Pancreatic Neoplasms; Point Mutation; Polyenes; Polyunsaturated Alkamides; ras Proteins; Transferases; Tumor Cells, Cultured

The mechanisms of action of farnesyltransferase inhibitors (FTIs) involve Rheb and the phosphatidylinositide 3-kinase/Akt/mammalian target of rapamycin (mTOR) pathway. mTOR in particular plays a key role in the regulation of autophagy. Collectively, the literature suggests that FTIs very likely induce autophagy, but thus far there have been no reports that FTIs affect this process relevant to cancer cell biology. We hypothesized that FTIs can induce autophagy. In this study, we found that the FTIs manumycin A, FTI-276, and lonafarnib induced autophagy in two human cancer cell lines. We also found that neither inhibition of apoptosis with a pan-caspase inhibitor nor inhibition of autophagy increased the number of clones of lonafarnib-treated U2OS osteosarcoma cells that formed in soft agar. Although whether autophagy is a cell death or cell survival mechanism after FTI treatment remains unresolved, our data show that cancer cells apparently can shift between apoptosis and autophagy once they are committed to die after FTI treatment.

Topics: Apoptosis; Autophagy; Cell Line, Tumor; Dose-Response Relationship, Drug; Enzyme Inhibitors; Farnesyltranstransferase; Humans; Microscopy, Electron, Transmission; Microscopy, Fluorescence; Pancreatic Neoplasms; Piperidines; Polyenes; Polyunsaturated Alkamides; Protein Kinases; Pyridines; RNA, Small Interfering; Signal Transduction; TOR Serine-Threonine Kinases

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.

Topics: Alkyl and Aryl Transferases; Animals; Antineoplastic Agents; DNA, Neoplasm; Enzyme Inhibitors; Farnesyltranstransferase; Genes, ras; Humans; Liver Neoplasms; Mice; Mice, Nude; Neoplasm Invasiveness; Pancreatic Neoplasms; Point Mutation; Polyenes; Polyunsaturated Alkamides; Protein Kinases; Tumor Cells, Cultured

Activating mutations of Ki-ras have been detected in most human pancreatic adenocarcinomas. Since Ras protein requires farnesylation to function, we investigated the effects of manumycin, a potent farnesyl:protein transferase inhibitor, on the growth in nude mice of a human pancreatic cancer cell line, MIA PaCa-2, with a point mutation in the Ki-ras gene. Tumor-bearing mice received intraperitoneal injection of 1 or 5mg/kg manumycin daily for 5 days, or 2 mg/kg manumycin daily for 2 weeks. Growth of inoculated tumors was significantly inhibited by the treatment. The treatment significantly (P<0.05) lowered the numbers of bromodeoxyuridine-incorporating tumor cells. Manumycin did not have apparent hepatotoxicity in vivo. Farnesyl:protein transferase inhibitors could offer a new approach for cancer chemotherapy.

Topics: Alkyl and Aryl Transferases; Animals; Antineoplastic Agents; DNA, Neoplasm; Dose-Response Relationship, Drug; Enzyme Inhibitors; Farnesyltranstransferase; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Pancreatic Neoplasms; Polyenes; Polyunsaturated Alkamides; Transferases; Transplantation, Heterologous