Rojas M, et al. (2008)
Genomewide expression profiling of cryptolepine-induced toxicity in Saccharomyces cerevisiae. Antimicrob Agents Chemother
Abstract: We have used the budding yeast Saccharomyces cerevisiae to identify genes that may confer sensitivity in vivo to the antimalarial and cytotoxic agent cryptolepine. Five S. cerevisiae strains, with different genetic backgrounds in cell permeability and DNA damage repair mechanisms, were exposed to several concentrations of cryptolepine. Cryptolepine showed a relatively mild toxicity in wild type strains, which was augmented by either increasing cell permeability (Deltaerg6 or ISE2 strains) or disrupting DNA damage repair (Deltarad52 strains). These results are compatible with the ability of cryptolepine to intercalate into DNA and, therefore, promote DNA lesions. The effects of low concentrations of cryptolepine (IC20 and IC40) were analyzed by comparison between gene expression profiles of treated and untreated Deltaerg6 yeast cells. Significant changes in expression levels were observed for 349 genes (117 up-regulated and 232 down-regulated). General stress-related genes constituted the only recognizable functional cluster whose expression was increased upon cryptolepine treatment, making up about 20% of up-regulated genes. In contrast, analysis of characteristics of down-regulated genes revealed a specific effect of cryptolepine on genes related to iron-transport or acid phosphatases, as well as a significant proportion of cell wall components. The effects of cryptolepine on transcription of iron transport-related genes were consistent with a loss-of-function of the iron sensor Aft1p, indicating a possible disruption of the iron metabolism in S. cerevisiae. Since the interference of cryptolepine with iron metabolism is considered one of its putative antimalarial targets, this finding supports the utility of S. cerevisiae in drug-developing schemes.
||Type: Journal Article ||PubMed ID: 18710911 |