title: Gliotoxin is a dual inhibitor of farnesyltransferase and geranylgeranyltransferase I with antitumor activity against breast cancer in vivo.
abstract: Gliotoxin is a natural mycotoxin with immunosuppressive and antimicrobial activity. Inhibition of farnesyltransferase (IC50 80 microM) and geranylgeranyltransferase I (IC50 17 microM) stimulated interest in the potential antitumor activity of this epidithiodioxopiperazine. Gliotoxin inhibited proliferation of six breast cancer cell lines in culture with mean +/- SD IC50 289 +/- 328 microM (range 38-985 microM); intracellular farnesylation of Lamin B and geranylgeranylation of Rap1A were inhibited in a dose-dependent manner. In randomized controlled studies using the N-methyl-N-nitrosourea rat mammary carcinoma model, gliotoxin had pronounced antitumor activity in vitro and little systemic toxicity when administered to 10 animals at 10 mg/kg by subcutaneous injection weekly for 4 wk compared with 10 controls. Single doses up to 25 mg/kg were well tolerated. The present studies confirm that gliotoxin is a dual inhibitor of farnesyltransferase and geranylgeranyltransferase I with pronounced antitumor activity and favorable toxicity profile against breast cancer in vitro and in vivo.
authors.affiliation: Department of Cancer Medicine, 6th Floor MRC Cyclotron Building, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK. d.vigushin@imperial.ac.uk
authors.forename: D M
authors.initials: DM
authors.lastname: Vigushin
authors.forename: N
authors.initials: N
authors.lastname: Mirsaidi
authors.forename: G
authors.initials: G
authors.lastname: Brooke
authors.forename: C
authors.initials: C
authors.lastname: Sun
authors.forename: P
authors.initials: P
authors.lastname: Pace
authors.forename: L
authors.initials: L
authors.lastname: Inman
authors.forename: C J
authors.initials: CJ
authors.lastname: Moody
authors.forename: R C
authors.initials: RC
authors.lastname: Coombes
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D051231:Farnesyltranstransferase; D005260:Female; D005912:Gliotoxin / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D007166:Immunosuppressive Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy*; D011897:Random Allocation; D051381:Rats; D016896:Treatment Outcome
chemical_list: D007166:Immunosuppressive Agents; D005912:Gliotoxin; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; D051231:Farnesyltranstransferase