Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Proteins belonging to the ras superfamily are involved in cell proliferation of normal and neoplastic tissues. To be biologically active, they require post-translational isoprenylation by farnesyl-transferase and geranylgeranyl-transferase. Enzyme inhibition by drugs may thus represent a promising approach to the treatment of cancer. Therefore, the combined effect of BAL9611, a novel inhibitor of geranylgeranylation, and manumycin, a farnesyl-transferase inhibitor, was evaluated on the SW620 human colon cancer cell line which harbours a mutated K-ras gene. BAL9611 and manumycin dose-dependently inhibited SW620 cell growth with 50% inhibitory concentration (IC(50)) of 0.47 +/- 0.03 and 5.24 +/- 1.41 microM (mean +/- SE), respectively. The isobologram analysis performed at the IC(50)level revealed that the combined treatment was highly synergistic with respect to cell growth inhibition. BAL9611 and manumycin were able to inhibit the geranylgeranylation of p21rhoA and farnesylation of p21ras; both drugs inhibited p42ERK2/MAPK phosphorylation, but their combination was more effective than either drug alone. Moreover, the enhanced inhibition of cell growth in vitro by the BAL9611-manumycin combination was also observed in vivo in CD nu/nu female mice xenografted with SW620 tumours. Finally, both drugs were able to induce cell death by apoptosis in vitro and in vivo, as demonstrated by perinuclear chromatin condensation, cytoplasm budding and nuclear fragmentation, and interoligonucleosomal DNA digestion. In conclusion, the inhibition of protein farnesylation enhances the chemotherapeutic effect of BAL9611 in vitro and in vivo in a synergistic fashion, as a result of the impairment of post-translational isoprenylation of proteins and phosphorylation of p42ERK2/MAPK, whose activation is associated with post-translational geranylgeranylation and farnesylation of p21rhoA and p21ras.
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PMID:Inhibition of protein farnesylation enhances the chemotherapeutic efficacy of the novel geranylgeranyltransferase inhibitor BAL9611 in human colon cancer cells. 1138 5

Phospholipids and lipid second messengers mediate mitogenic signal transduction and oncogenesis, but there have been few successful examples of small molecules that affect biologically important phospholipid metabolism. Here we investigated the actions of a previously described antitumor agent, 4-(benzyl-(2-[(2,5-diphenyloxazole-4-carbonyl)amino]ethyl)carbamoyl)- 2-decanoylaminobutyric acid (SC-alpha alpha delta 9), which has antisignaling properties, on phospholipases. Although SC-alpha alpha delta 9 had been shown to be a potent and selective inhibitor of the Cdc25 family of dual-specificity phosphatases, many of its cellular effects are not readily reconciled with phosphatase inhibition. Molecular modeling studies suggested that SC-alpha alpha delta 9 shared several structural features with membrane phospholipids. Enzyme inhibition studies in vitro revealed that SC-alpha alpha delta 9 was a potent inhibitor of phospholipase C (PLC; IC50 = 25 microM) but did not inhibit phospholipase D activity at concentrations up to 100 microM. In H-ras (Q61L)-transformed Rat-1 fibroblasts with constitutively elevated levels of phosphorylated extracellular signal-regulated kinase (Erk), SC-alpha alpha delta 9 inhibited both proliferation and oncogenic Erk activation at concentrations that inhibited PLC in vitro. A SC-alpha alpha delta 9 congener that lacked antiproliferative activity also did not inhibit PLC in vitro. In the PLC-dependent scratch wound healing model, SC-alpha alpha delta 9 was 10-fold more potent than the phosphatidylcholine-specific PLC inhibitor D-609. We propose that the structural resemblance of SC-alpha alpha delta 9 to phospholipids allows it to inhibit cellular PLC, thereby providing a possible molecular mechanism for SC-alpha alpha delta 9's effects on oncogenic Erk activation.
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PMID:The antisignaling agent SC-alpha alpha delta 9, 4-(benzyl-(2-[(2,5-diphenyloxazole-4-carbonyl)amino]ethyl)carbamoyl)- 2-decanoylaminobutyric acid, is a structurally unique phospholipid analogue with phospholipase C inhibitory activity. 1248 9