Abstract 4475: Inhibition of aminoacid biosynthetic pathways lead to increase sensitivity to anthracyclines in Saccharomyces cerevisiae

Abstract

Anthracycline antibiotics are commonly used antineoplastic agents that provide significant therapeutic efficacy in the treatment of both solid tumors and hematological cancers. Although there is a dose-dependent response in the use of these agents, there is also a dose related toxicity associated to them. The most serious toxicity of the use of anthracyclines is chronic cardiotoxicity. To increase our knowledge of the pathways that protect cells from the cytotoxic effects of anthracyclines, we carried out a genetic screening in the eukaryotic model organism S. cerevisiae, to identify gene defects that generate cells hypersensitive to doxorubicin. Our findings indicate that inactivation of some aminoacid biosynthetic pathways hypersensitize cells to doxorubicin. Defects in the biosynthesis of threonine lead to an increase sensitivity to doxorubicin up to 1000-fold higher than wild type cells, while inactivation of serine and tryptophan pathways lead to an increase of up to 100-fold higher than wild type cells. We present evidence that accumulation of intermediate metabolites in the pathway are responsible for the hypersensitivity to doxorubicin and discuss the potential use of these compounds as chemotherapeutic enhancing agents. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4475. doi:10.1158/1538-7445.AM2011-4475