Growth inhibitory effects of aromatic fatty acids on ovarian tumor cell lines.
Epithelial ovarian cancer is a major cause of cancer-related mortality in women, making the search for new treatment modalities essential. Sodium phenylacetate (NaPa), a phenylalanine derivative, has been shown to induce cytostasis and differentiation by inhibiting protein isoprenylation. Similar effects have been observed with phenylbutyrate, a phenylacetate congener. We examined in parallel the growth inhibitory activity against human ovarian carcinoma cell lines of phenylacetate, phenylbutyric acid (PB), and certain related compounds, and comparisons were made with lovastatin. On a molar basis, hydroxykynurenine and kynurenine showed the highest activity followed by PB and NaPa. Ovarian carcinoma cell lines were also sensitive to lovastatin in micromolar concentrations. Additive effects were observed when PB was combined with cisplatin or when NaPa or PB were combined with lovastatin. NaPa and PB, but not kynurenine, inhibited incorporation of [3H]mevalonate into ovarian carcinoma cells. An immune modulatory role might also be suggested for PB because it resulted in increased ovarian tumor cell expression of human leukocyte antigen class I and the cluster of differentiation molecule CD58, whereas transforming growth factor-beta2 expression was decreased. Phenylbutyrate, which is the ester form of PB, has shown acceptable pharmacological properties and clinical responses in patients with other malignancies, and might be considered for evaluation in ovarian cancer.
Melichar
B
B
Department of Gynecologic Oncology, The University of Texas, M. D. Anderson Cancer Center, Houston 77030, USA.
Ferrandina
G
G
Verschraegen
C F
CF
Loercher
A
A
Abbruzzese
J L
JL
Freedman
R S
RS
D000613:Aminobutyrates / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D015815:Cell Adhesion Molecules / Q000096:biosynthesis; D002455:Cell Division / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D005227:Fatty Acids / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D006680:HLA Antigens / Q000096:biosynthesis; D006801:Humans; D007737:Kynurenine / Q000494:pharmacology; D008148:Lovastatin / Q000494:pharmacology; D008798:Mevalonic Acid / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D017239:Paclitaxel / Q000494:pharmacology; D010648:Phenylacetates / Q000494:pharmacology; D015291:Transforming Growth Factors / Q000096:biosynthesis; D014407:Tumor Cells, Cultured
D000613:Aminobutyrates; D015815:Cell Adhesion Molecules; D005227:Fatty Acids; D006680:HLA Antigens; D010648:Phenylacetates; D007737:Kynurenine; D015291:Transforming Growth Factors; D008148:Lovastatin; C025136:phenylacetic acid; D017239:Paclitaxel; D002945:Cisplatin; D008798:Mevalonic Acid