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: D M Vigushin, N Mirsaidi, G Brooke, C Sun, P Pace, L Inman, C J Moody, R C Coombes
• Journal: Medical oncology (Northwood, London, England) (Med Oncol) Vol. 21 Issue 1 Pg. 21-30 ( 2004) ISSN: 1357-0560 [Print] United States
• PMID: 15034210 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Immunosuppressive Agents
• Gliotoxin
• Alkyl and Aryl Transferases
• geranylgeranyltransferase type-I
• Farnesyltranstransferase

Topics

• Alkyl and Aryl Transferases (antagonists & inhibitors)
• Animals
• Cell Division (drug effects)
• Cell Line, Tumor
• Dose-Response Relationship, Drug
• Farnesyltranstransferase
• Female
• Gliotoxin (chemistry, pharmacology, therapeutic use)
• Humans
• Immunosuppressive Agents (chemistry, pharmacology, therapeutic use)
• Mammary Neoplasms, Experimental (drug therapy)
• Random Allocation
• Rats
• Treatment Outcome