In vivo antitumor effect of a novel inhibitor of protein geranylgeranyltransferase-I.
Protein geranylgeranyltransferase-I (GGTase-I) catalyzes protein geranylgeranylation, which is critical for the function of proteins such as Rho, Rac, and Ral. We previously identified several small-molecule inhibitors of GGTase-I from an allenoate-derived compound library and showed that these compounds exhibit specific inhibition of GGTase-I resulting in the inhibition of proliferation associated with the induction of G(1) cell cycle arrest of a variety of cancer cell lines. Because inhibition of GGTase-I is expected to suppress tumor growth, we investigated in vivo effects of one of these GGTase-I inhibitors (GGTI), P61A6, by using a human pancreatic cancer xenograft model in mice. The new compound GGTI P61A6 showed an excellent antitumor effect. I.p. administration of P61A6 significantly suppressed tumor growth of the PANC-1 xenograft. Even once per week administration of GGTI was enough to suppress tumor growth. Immunohistochemical examination indicated the inhibition of cell proliferation in the tumors by P61A6 treatment, but neither apoptosis nor antiangiogenesis was observed. Increased cytosolic localization of proteins such as Rap1 and RhoA in tumors was observed. In addition, the enzyme activity of GGTase-I in tumors was inhibited. Pharmacokinetic analysis showed that the plasma half-life of GGTI is ∼6 h, suggesting its prolonged effect. These data suggest that the novel GGTI compound P61A6 is an excellent chemotherapeutic drug candidate for human pancreatic cancer. They also provide evidence that protein GGTase-I may be a valid target for cancer therapy.
Lu
Jie
J
Department of Microbiology, University of California-Los Angeles, Los Angeles, California 90095, USA.
Chan
Lai
L
Fiji
Hannah D G
HD
Dahl
Russell
R
Kwon
Ohyun
O
Tamanoi
Fuyuhiko
F
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D010649:Phenylalanine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D017368:Protein Prenylation / Q000187:drug effects; D013449:Sulfonamides / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; C585533:P61A6 compound; D013449:Sulfonamides; D010649:Phenylalanine; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I