Phenylbutyrate (4-phenylbutyric acid; PB) and its metabolite, phenylacetate, are effective anti-neoplastic agents in tissue culture and have shown promise in clinical trials for a variety of neoplasms. PB is a drug of remarkably low toxicity that acts in vitro as a differentiating agent, causing reversion of the transformed phenotype by an unknown mechanism. We attempted to identify the cellular target(s) for PB using Saccharomyces as a model. PB inhibits growth of yeast on rich medium at concentrations of 0.1-1.0 mM, concentrations similar to plasma concentrations observed in human trials. Yeast cells treated with 1 mM PB remain over 90% viable for 24 h. PB inhibits tryptophan uptake, and resistance to PB can be conferred by tryptophan prototrophy, by supplementing tryptophan auxotrophs with the high levels of tryptophan, by overexpression of the aromatic amino acid permeases Tat1p or Tat2p, and by disruption of TAT1. Since tryptophan auxotrophy and transport influences resistance to PB, phytosphingosine, and the immunosuppressant FK506, these drugs might affect the same pathway. We isolated and characterized a mutant resistant to 1 mM PB and identified the mutant as bul1. A chromosomal BUL1 deletion displayed all phenotypes shown by the PB-resistant mutant.

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Journal Article

Authors

Grzanowski A, Needleman R, Brusilow WS

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