LIPID-METABOLISM AS A TARGET FOR BRAIN CANCER-THERAPY - SYNERGISTIC ACTIVITY OF LOVASTATIN AND SODIUM PHENYLACETATE AGAINST HUMAN GLIOMA-CELLS

Malignant gliomas, the most common form of primary brain tumors, are h ighly dependent on the mevalonate (MVA) pathway for the synthesis of l ipid moieties critical to cell replication. Human glioblastoma cells w ere found to be uniquely vulnerable to growth arrest by lovastatin, a competitive inhibitor of the enzyme regulating MVA synthesis, 3-hydrox y-3-methylglutaryl coenzyme A reductase. The sodium salt of phenylacet ic acid (NaPA), an inhibitor of MVA-pyrophosphate decarboxylase, the e nzyme that controls MVA use, acted synergistically with lovastatin to suppress malignant growth, When used at pharmacologically attainable c oncentrations, the two compounds induced profound cytostasis and loss of malignant properties such as invasiveness and expression of the tra nsforming growth factor-beta 2 gene, coding for a potent immunosuppres sive cytokine. Supplementation with exogenous ubiquinone, an end produ ct of the MVA pathway, failed to rescue the cells, suggesting that dec reased synthesis of intermediary products are responsible for the anti tumor effects observed. In addition to blocking the MVA pathway, lovas tatin alone and in combination with NaPA increased the expression of t he peroxisome proliferator-activated receptor, a transcription factor implicated in the control of lipid metabolism, cell growth, and differ entiation. Our results indicate that targeting lipid metabolism with l ovastatin, used alone or in combination with the aromatic fatty acid N aPA, may offer a novel approach to the treatment of malignant gliomas.