Artikel
Carnosine increases the efficiency of treatment with temozolomide and x-irradiation of primary glioblastoma cell cultures
Carnosine steigert die Effektivität der Behandlungvon primären Glioblastom-Zellkulturen mitTemozolomid und Bestrahlung
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Veröffentlicht: | 8. Mai 2019 |
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Objective: Despite ongoing research, glioblastoma (GBM) still has a poor prognosis even under standard therapy, combining surgery, temozolomide (TMZ) and irradiation (Rx). It was demonstrated before that the dipeptide carnosine (β-alanyl-L-histidine; Car) not only reduces growth, migration and metastasis of glioblastoma cells in vitro but also increases the effect of TMZ and Rx treatment in several GBM cell lines. Here, we investigated whether Car increases the response of primary glioblastoma cells to standard adjuvant therapy with TMZ and Rx.
Methods: Primary GBM cell cultures from 5 patients (all IDH-wt, 2 with unmethylated, 3 with methylated MGMT promoter) were used to investigate interactions between Car (0, 10 mM, 20 mM, 30 mM), Rx (0, 4 Gy, 8 Gy) and TMZ (0, 100 µM, 200 µM, 300 µM) and all three compounds together (20 mM Car, 200 µM TMZ, 4 Gy). Cells were incubated in medium with or without compounds and irradiated. 7 days after irradiation, viability of cells was determined by measuring ATP in cell lysates (ACL) and dehydrogenase activity in living cells (DHA).
Results: With increasing concentrations, Car reduced cell viability in all cultures, achieving a maximum effect at 30 mM (up to 55.6±6.5% (ACL) and 51.0±7.9% (DHA) for the 5 cultures). TMZ treatment was less effective in the 2 cell cultures with unmethylated MGMT promoter compared to the 3 others (maximum reduction for cells with methylated MGMT promoter at 300 μM from 22.4±3.2% to 46.6±4.8% (ACL) and 40.2±6.2% to 46.3±5.7% (DHA) of untreated controls; all p<0.0005). Independent from MGMT promoter methylation, the combination of Car with TMZ was more effective than treatment with TMZ or Car alone. In all cells, radiation up to 8 Gy alone reduced viability up to 42.6±16.8% (ACL) and 44.1±1.0 (DHA) and an additive effect of all Car concentrations at all radiation doses employed was observed. Finally, the combination of Car with TMZ and Rx revealed maximum reduction of viability (from 4.3±0.7% to 73.3±3.2% (ACL) and 20.0±2.7 to 69.7±3.3% (DHA); all p<0.05) compared to single or dual compound treatment.
Conclusion: Here we demonstrate that in cell cultures derived from glioblastoma, carnosine increases the efficiency of standard therapy composed of irradiation and temozolomide by a factor of ~1.54±0.90. Therefore, carnosine may be considered as an adjuvant to standard therapy.