Cytostatic activity of phenylacetate and derivatives against tumor cells: Correlation with lipophilicity and inhibition of protein prenylation

The aromatic fatty acid phenylacetate, a common metabolite of phenylalanine, shows promise as a relatively non-toxic drug for cancer treatment. This slowly metabolized fatty acid alters tumor cell lipid metabolism causing, among other effects, inhibition of protein prenylation critical to malignant...

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Bibliographic Details
Published in:Biochemical pharmacology 1995-10, Vol.50 (8), p.1273-1279
Main Authors: Hudgins, W.Robert, Shack, Sonsoles, Myers, Charles E., Samid, Dvorit
Format: Article
Language:English
Subjects:
Antimetabolites, Antineoplastic - pharmacology
Antineoplastic agents
aromatic fatty acids
Biological and medical sciences
Cell Division - drug effects
Cell Line - drug effects
Cell Survival - drug effects
Chemotherapy
cytostasis
Drug Design
glioblastoma
Humans
Lipid Metabolism
lipophilicity
Medical sciences
melanoma
Pharmacology. Drug treatments
Phenotype
phenotypic reversion
Phenylacetates - chemistry
Phenylacetates - pharmacology
plants
prostate cancer
Protein Prenylation - drug effects
Structure-Activity Relationship
Tumor Cells, Cultured - drug effects
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Summary:The aromatic fatty acid phenylacetate, a common metabolite of phenylalanine, shows promise as a relatively non-toxic drug for cancer treatment. This slowly metabolized fatty acid alters tumor cell lipid metabolism causing, among other effects, inhibition of protein prenylation critical to malignant growth. In pursuit of more potent analogues, we have examined the activity of related compounds against tumor cell lines established from patients with advanced prostatic carcinoma, glioblastomas, and malignant melanoma. Like phenylacetate, derivatives containing α-carbon or ring substitutions induced cytostasis and phenotypic reversion at non-toxic concentrations. Potency was correlated with the degree of calculated lipophilicity of the aromatic fatty acid, and the extent of inhibition of protein prenylation. Remarkably, a parallel cytostatic activity was reported in embryonic plant cells, which respond to phenylacetate and its analogues in the same concentration range and the same rank order of lipophilicity. These data suggest that phenylacetate and its analogues may act through common mechanisms to inhibit the growth of vastly divergent, undifferentiated cell types, and provide a basis for the development of new agents for the treatment of human malignancies.
ISSN:0006-2952
1873-2968
DOI:10.1016/0006-2952(95)02013-3