Isoprenylation of intracellular proteins as a new target for the therapy of human neoplasms: preclinical and clinical implications.
Cell proliferation, differentiation, and survival are regulated by a number of extracellular hormones, growth factors, and cytokines in complex organisms. The transduction of the signals by these factors from the outside to the nucleus often requires the presence of small intracellular proteins (i.e. ras and other small G proteins) that are linked to the plasma membrane through a isoprenyl residue that functions as hydrophobic anchor. Isoprenylation is a complex process regulated by different enzymatic steps that could represent potential molecular targets for anti-cancer strategies. In the present paper the different transduction pathways regulated by some isoprenylated proteins such as ras and other small G proteins are described. Moreover, the molecular mechanisms of the isoprenylation process and the mode of action of the different isoprenylation inhibitors are discussed with attention to statins, farnesyltransferase inhibitors (FTI) and aminobisphosphonates. The role of different candidate targets in the determination of anti-tumour effects by FTIs is also described in order to define potential molecular markers predictor of clinical response. On the basis of several preclinical data, new strategies based on multi-step enzyme inhibition or on target prioritization are proposed in order to enhance the anti-tumour activity of agents inhibiting isoprenylation. Finally, a summary of the principal data on clinical trials based on the use of FTIs and statins is given. In conclusion, the inhibition of isoprenylation is an attractive, but still not completely investigated therapeutic alternative that requires optimization for the translation in the current treatment of neoplasms.
Caraglia
M
M
Department of Experimental Oncology, Experimental Pharmacology Unit, National Institute of Tumours Fondaz. G. Pascale of Naples, Via M. Semmola, 80131 Naples, Italy. michele.caraglia@fondazionepascale.it
Budillon
A
A
Tagliaferri
P
P
Marra
M
M
Abbruzzese
A
A
Caponigro
F
F
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001569:Benzodiazepines / Q000627:therapeutic use; D051231:Farnesyltranstransferase; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D007093:Imidazoles / Q000627:therapeutic use; D008798:Mevalonic Acid / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010880:Piperidines / Q000627:therapeutic use; D017368:Protein Prenylation / Q000187:drug effects*; D011499:Protein Processing, Post-Translational; D011725:Pyridines / Q000627:therapeutic use; D015363:Quinolones / Q000627:therapeutic use; D018631:ras Proteins / Q000737:chemistry / Q000502:physiology; D003986:Dibenzocycloheptenes
D019883:Alkyl and Aryl Transferases; D000970:Antineoplastic Agents; D001569:Benzodiazepines; D051231:Farnesyltranstransferase; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007093:Imidazoles; D008798:Mevalonic Acid; D019869:Phosphatidylinositol 3-Kinases; D010880:Piperidines; D011725:Pyridines; D015363:Quinolones; D018631:ras Proteins; C425231:L 778,123; C083291:geranylgeranyltransferase type-I; C115354:lonafarnib; D003986:Dibenzocycloheptenes; C415151:7-cyano-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4-(2-thienylsulfonyl)-1H-1,4-benzodiazepine; C402769:tipifarnib