Phenylacetate inhibits isoprenoid biosynthesis and suppresses growth of human pancreatic carcinoma Journal Article

Authors: Harrison, L. E.; Wojciechowicz, D. C.; Brennan, M. F.; Paty, P. B.
Article Title: Phenylacetate inhibits isoprenoid biosynthesis and suppresses growth of human pancreatic carcinoma
Abstract: Background. Phenylacetate is growth inhibitor for a variety of tumors at concentrations that have been safely achieved in human beings. This antitumor effect is related to inhibition of the isoprenoid synthetic pathway by blocking the enzyme, mevalonate pyrophosphate (MVAPP) decarboxylase. The purpose of this study was to evaluate the effects of phenylacetate on human pancreatic carcinoma. Methods. For in vitro studies, six human pancreatic carcinoma cell lines (BxPc, AsPc, MIAPaCa-2, Panc-1, CFPAC, and HS 766T) were studied. For in vivo studies, nude mice were inoculated with pancreatic cells (BxPc and MIA PaCa-2) and randomized to receive phenylacetate or saline control. Results. Phenylacetate produces reversible in vitro growth arrest at doses of 2.5 to 10 mmol. The antiproliferative effect is cytostatic, producing accumulation of cells in G1, and is not associated with cell toxicity. Systemic treatment of nude mice bearing heterotopic human pancreatic carcinoma results in growth inhibition of tumors without host toxicity. Phenylacetate blocks the processing of mevalonate to isopentenyl- pyrophosphate by inhibiting MVAPP and exhibits suppression of biosynthetic pathways requiring isoprenoids, including cholesterol and dolichol biosynthesis, protein glycosylation, and isoprenylation of proteins. Conclusions. These results indicate that phenylacetate has cytostatic activity in pancreatic carcinoma and support the conclusion that suppression of multiple biosynthetic pathways requiring isoprenoids is contributing to the drug's antiproliferative action. The safety profile and efficacy of phenylacetate make it an attractive agent for the treatment of pancreatic cancer.
Keywords: human cell; cancer growth; nonhuman; pancreatic neoplasms; flow cytometry; mouse; animals; mice; cell division; antimetabolites, antineoplastic; animal experiment; antineoplastic activity; tumor cells, cultured; mice, inbred balb c; pancreas carcinoma; drug mechanism; mice, nude; glycosylation; lipid metabolism; cytostasis; growth inhibition; phenylacetates; phenylacetic acid; isoprenoid; mevalonic acid; human; female; priority journal; article; carboxy-lyases
Journal Title: Surgery
Volume: 124
Issue: 3
ISSN: 0039-6060
Publisher: Elsevier Inc.  
Date Published: 1998-09-01
Start Page: 541
End Page: 550
Language: English
DOI: 10.1016/s0039-6060(98)70101-1
PUBMED: 9736908
PROVIDER: scopus
Notes: Article -- Export Date: 12 December 2016 -- Source: Scopus
Citation Impact
MSK Authors
  1. Murray F Brennan
    1013 Brennan
  2. Philip B Paty
    419 Paty