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Growth inhibitory effects of aromatic fatty acids on ovarian tumor cell lines
B Melichar1, G Ferrandina, C F Verschraegen
1Department of Gynecologic Oncology, The University of Texas, M. D. Anderson Cancer Center, Houston 77030, USA.
Abstract:
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.
Insights
Phenylbutyric acid (PB) and sodium phenylacetate (NaPa) show promise in inhibiting ovarian cancer cell growth. These compounds, along with related molecules, demonstrated significant anti-cancer activity and potential synergistic effects with existing treatments.
Area of Science:
- Oncology
- Biochemistry
- Pharmacology
Background:
- Epithelial ovarian cancer is a leading cause of cancer mortality in women.
- Novel treatment strategies are crucial for improving patient outcomes.
- Sodium phenylacetate (NaPa) and phenylbutyrate (PB) are known to induce cytostasis and differentiation by inhibiting protein isoprenylation.
Purpose of the Study:
- To evaluate the in vitro growth inhibitory activity of phenylacetate, PB, and related compounds against human ovarian carcinoma cell lines.
- To compare the efficacy of these compounds with lovastatin.
- To investigate potential additive effects with chemotherapy and immune modulatory roles.
Main Methods:
- Assessing growth inhibitory activity of phenylacetate, PB, and related compounds on ovarian carcinoma cell lines.
- Comparing efficacy with lovastatin on a molar basis.
- Investigating additive effects with cisplatin, NaPa, PB, and lovastatin.
- Measuring [3H]mevalonate incorporation and analyzing immune marker expression (HLA class I, CD58, TGF-β2).
Main Results:
- Hydroxykynurenine and kynurenine exhibited the highest activity, followed by PB and NaPa.
- Ovarian carcinoma cell lines were sensitive to lovastatin in micromolar concentrations.
- Additive effects were observed when PB was combined with cisplatin, and NaPa or PB with lovastatin.
- NaPa and PB inhibited mevalonate incorporation, suggesting interference with the mevalonate pathway.
- PB increased HLA class I and CD58 expression while decreasing TGF-β2 expression on ovarian tumor cells.
Conclusions:
- Phenylacetate derivatives, particularly PB and NaPa, demonstrate significant in vitro anti-cancer activity against ovarian carcinoma.
- These compounds may offer synergistic effects when combined with cisplatin or lovastatin.
- PB exhibits immune modulatory effects, suggesting a potential role in enhancing anti-tumor immunity.
- Phenylbutyrate, with established pharmacological properties, warrants further investigation for ovarian cancer treatment.