Coumarins Modulate the Anti-Glioma Properties of Temozolomide

In the recent years, coumarin bioactive compounds have been identified to posess anticancer properties. Therefore, the aim of the present study was to investigate for the first time the efficacy of osthole, umbelliferone, esculin, and 4-hydroxycoumarin, alone and in combination with Temozolomide, in the elimination of deadly brain tumors, anaplastic astrocytoma (AA) and glioblastoma multiforme (GBM) cells via programmed death. Our results indicated that osthole, umbelliferone, esculin, and 4-hydroxycoumarin initiated mainly apoptosis in the T98G and MOGGCCM cells. Osthole was the most effective. It also initiated autophagy in a small percentage of the cell population. The co-incubation with Temozolomide did not increase the pro-apoptotic potential of natural compounds but decreased the level of autophagy in the T98G cells. Apoptosis was associated with reduced mitochondrial membrane potential, activation of caspase 3, inhibition of Bcl-2 expression and the presence of a Bcl-2/Beclin 1. Blocking of Bcl-2 expression resulted in promotion of apoptosis, but not autophagy, in the MOGGCCM and T98G lines. It also sensitized astrocytoma cells, but not GBM, to the combined osthole and TMZ treatment, which was correlated with a reduced level of Beclin 1 and increased expression of caspase 3. Osthole and TMZ, alone and in combination, inhibited the migratory phenotype of the GBM and AA cells. In summary, our results indicated that osthole effectively eliminated glioma cells via apoptosis, what was correlated with Bcl-2/Beclin 1 complex formation. Considering the anti-migratory effect, osthole and Temozolomide display antiglioma potential but it needs further extensive studies.

Keywords: Bcl-2/Beclin 1 complex; Cell death; Coumarins; Gliomas; Temozolomide.