Lipid Metabolism as a Target for Brain Cancer Therapy: Synergistic Activity of Lovastatin and Sodium Phenylacetate Against Human Glioma Cells

Abstract

Malignant gliomas, the most common form of primary brain tumors, are highly dependent on the mevalonate (MVA) pathway for the synthesis of lipid moieties critical to cell replication. Human glioblastoma cells were found to be uniquely vulnerable to growth arrest by lovastatin, a competitive inhibitor of the enzyme regulating MVA synthesis, 3-hydroxy-3-methylglutaryl coenzyme A reductase. The sodium salt of phenylacetic acid (NaPA), an inhibitor of MVA-pyrophosphate decarboxylase, the enzyme that controls MVA use, acted synergistically with lovastatin to suppress malignant growth. When used at pharmacologically attainable concentrations, the two compounds induced profound cytostasis and loss of malignant properties such as invasiveness and expression of the transforming growth factor-/32 gene, coding for a potent immunosuppressive cytokine. Supplementation with exogenous ubiquinone, an end product of the MVA pathway, failed to rescue the cells, suggesting that decreased synthesis of intermediary products are responsible for the antitumor effects observed. In addition to blocking the MVA pathway, lovastatin alone and in combination with NaPA increased the expression of the peroxisome proliferator-activated receptor, a transcription factor implicated in the control of lipid metabolism, cell growth, and differentiation. Our results indicate that targeting lipid metabolism with lovastatin, used alone or in combination with the aromatic fatty acid NaPA, may offer a novel approach to the treatment of malignant gliomas.

Pharmacological inhibition of lipid droplet formation enhances the effectiveness of curcumin in glioblastoma

“…In solid malignancies, the hypoxic conditions found at the core of the tumors induce adaptive pathways aimed at maintaining lipid synthesis, homeostatic pH and cell survival [6]. The resulting metabolic changes correlate with poor prognosis, poor treatment response and recurrence in diseases such as breast, liver and brain cancer [7][8][9][10]. Emerging therapeutic approaches have thus targeted lipid synthesis to counter the effects of metabolic reprogramming in cancer cells [11,12].…”

Aponecrotic, antiangiogenic and antiproliferative effects of a novel dextran derivative on breast cancer growth in vitro and in vivo

“…At higher concentrations, NaPa induces the cytostasis and reverses in vitro the malignant phenotype of dierent cancer cells (Samid et al, 1993;1997;Adam et al, 1995). Furthermore, NaPa was described to modulate the synthesis and/or the release of some growth factors (Ferrandina et al, 1997;Thibout et al, 1998), and to increase, in a synergistic manner, the eect of some molecules aecting the intracellular signalling of growth factors (Samid et al, 1993;Prasanna et al, 1996). In addition, NaPa potentiates the antitumour activity of tamoxifene by increasing the apoptosis of breast cancer MCF-7ras xenografts in nude mice (Adam et al, 1997).…”

Potentiating antitumor effects of a combination therapy with lovastatin and butyrate in the Lewis lung carcinoma model in mice

“…19 The combination of butyrate derivative phenylacetate with lovastatin was described to exert cytostatic effects against glioma cells. 28 Because butyrate has extremely short half-life, tributyrin (glycerol ester containing three moieties of butyric acid) was used in vivo as a butyrate prodrug. Our study in the murine model of syngeneic tumour demonstrates that both drugs used in combination are able to exert antitumor effects in vivo (Fig.…”