Secondary Logo

Institutional members access full text with Ovid®

The patellazoles inhibit protein synthesis at nanomolar concentrations in human colon tumor cells

Richardson, Adam D.a; Aalbersberg, Williamb; Ireland, Chris M.a

PRECLINICAL REPORTS
Buy

The patellazoles are a family of compounds consisting of a 24-member macrolide ring with a thiazole-epoxide tail. The opening of this epoxide does not greatly affect the bioactivity of these compounds, although the cellular toxicity is generally decreased. The patellazoles are extremely cytotoxic towards HCT 116 human colon tumor cells. Treatment with nanomolar amounts of these compounds results in immediate inhibition of protein synthesis and cell cycle arrest at the G1 and S phase. HCT 116 wild-type cells underwent apoptosis after extended patellazole treatment. Although treatment with the patellazoles resulted in an increased amount of p53, the p53 null cells were still strongly affected by treatment. The inhibition of translation by patellazole treatment is linked to the inhibition of the mTOR/p70 pathway. Like the mTOR inhibitor rapamycin, the patellazoles inhibit translation through the 4EBP1 and S6 kinase pathways. However, the cytotoxicity of rapamycin and the patellazoles differs greatly in HCT 116 cells. The cellular target of the patellazoles is still unknown; the patellazole-induced inhibition of this pathway occurs either downstream or parallel to AKT.

aDepartment of Medicinal Chemistry, University of Utah, Salt Lake City, UT, USA

bInstitute of Applied Sciences, University of the South Pacific, Suva, Fiji

Sponsorship: A. D. R. has been supported by fellowships from the American Foundation for Pharmaceutical Education and the American Chemical Society Division of Medicinal Chemistry. This project was funded by NIH grant CA36622.

Correspondence to C. M. Ireland, Department of Medicinal Chemistry, University of Utah, Salt Lake City, UT 84112, USA

Tel: +1 801 581-8305; fax: +1 801 585-6208;

e-mail: cireland@pharm.utah.edu

Received 9 September 2004 Revised form accepted 9 February 2005

© 2005 Lippincott Williams & Wilkins, Inc.