gms | German Medical Science

Objective: Carnosine (beta-alanyl-L-histidine) is a naturally occurring dipeptide that exhibits anti-neoplastic effects in cell cultures derived from glioblastoma (GBM) as well as in animal models. Previous studies indicated that the anti-proliferative effect of carnosine is accompanied by a reduction of glycolytic ATP production, but the mechanisms responsible for this effect have not been elucidated. Therefore, we investigated whether carnosine affects genes involved in the metabolism of glucose and whether its mode of action can be mimicked by beta-alanine, L-alanine, L-histidine or L-alanyl-L-histidine.

Method: Cells from three lines derived from GBM were cultured in the absence or presence of different compounds, and cell viability and expression of genes involved in glucose metabolism were analysed by qRT-PCR. In addition, expression of carnosinase 1 and 2 was determined and compared to the expression in 19 tissues obtained from surgery of human GBM and normal brain tissue.

Results: qRT-PCR experiments identified altered mRNA expression of genes involved in glucose metabolism and an up to 37-fold enhancement of expression of pyruvate dehydrogenase kinase 4 (PDK4) compared to untreated cells only under the influence of carnosine and L-histidine but not in cells treated with beta-alanine, L-alanine or the dipeptide L-alanyl-L-histidine. The same result was obtained with regard to cell viability. In addition, we observed that the expression of serum carnosinase 1 (CN1) and tissue carnosinase (CN2) was altered in the analyzed GBM samples. Accordingly, the ratio of CN2 to CN1 changed from 7 to 9000 fold compared to normal brain tissue.

Conclusions: Loss of viability under the influence of carnosine is accompanied by a strong induction of PDK4 mRNA and can be mimicked by L-histidine. Since qRT-PCR confirmed the expression of CN2 in the tumor cells, we conclude that cleavage by CN2 is a prerequisite for the anti-neoplastic effect of carnosine. Interestingly, the analysis of mRNA from tissues derived from surgery of GBM patients demonstrated an enhanced expression of CN2 which is accompanied by a reduced expression of CN1 in tumors compared to normal brain tissue. Therefore, we conclude that carnosine can inhibit growth of cells that have an active tissue carnosinase. This is especially interesting for the treatment of tumors in the central nervous system since the effect of carnosine and L-histidine is anti-proliferative but not necrotic and only proliferating tumor cells may be affected.