gms | German Medical Science

Objective: Signaling via receptor tyrosine kinases and the PI3K/AKT and the ERK/mTOR pathway has been considered as a possible target for the therapy of glioblastoma. As recent experiments pointed toward the possibility that the naturally occurring dipeptide carnosine may exert its anti-neoplastic effect by acting on these pathways we investigated whether this is in fact the case and whether a combined action with known inhibitors of both pathways may enhance its potential.

Method: Cells from the glioblastoma cell line U87 were cultivated in the absence and presence of carnosine (50 mM), the mTOR inhibitor rapamycin (25 nM) and the PI3K inhibitor LY-294,002 (5 µM). After treatment the expression of PDK4 as a known target of both pathways was determined by qRT-PCR as readout. In addition, changes in viability were determined by cell based assays and changes in phosphorylation of mTOR and AKT were determined by Western Blot.

Results: Rapamycin and LY-294,002 were able to enhance expression of PDK4 (5.7 ± 0.6 fold, and 5.8 ± 1.1 fold, respectively) whereas this effect was more pronounced under the influence of 50 mM carnosine (14.6 ± 2.4) indicating that both pathways were targeted by the compounds. However, both inhibitors which also clearly affected phosphorylation of mTOR or AKT as determined by Western Blot experiments had no influence on cell viability. Carnosine, on the other hand, did not influence the phosphorylation of mTOR and had just a minor effect on phosphorylation on AKT but strongly reduced viability without any synergistic effect in combination with rapamycin or LY-294,002.

Conclusions: It is concluded that carnosine’s antineoplastic effect is not mediated by an influence on PI3K/AKT or ERK/mTOR signaling. As viability of U87 cells was not affected by inhibitors of both pathways, carnosine could be an option for therapy of glioblastomas which are resistant to drugs targeting these pathways downstream of receptor tyrosine signaling.