Myricetin sensitizes malignant glioma cells to TRAIL-mediated apoptosis by down-regulation of the short isoform of FLIP and bcl-2

The flavonoid Myricetin has been reported to exhibit therapeutic activity in cancer. In this study glioblastoma cells and human astrocytes were treated with Myricetin, tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) or the combination of both. Treatment with subtoxic doses of Myricetin in combination with TRAIL induces rapid apoptosis in glioma cells. Notably, human astrocytes were not affected by the combined treatment consisting of Myricetin and TRAIL. Combined treatment with Myricetin and TRAIL augmented the activation of initiator caspases-8/-9 and effector caspases-3/-7. Furthermore, Myricetin down regulated the expression of the long and short isoform of c-FLIP and bcl-2 and over-expression of the short isoform of c-FLIP (S) and bcl-2 attenuated apoptosis induced by the combination of Myricetin and TRAIL. Furthermore, Myricetin did not modulate the mRNA levels of c-FLIP, suggesting that Myricetin modulates the expression of c-FLIP in a posttranscriptional manner. In summary, the short isoform of c-FLIP and bcl-2 are key regulators in TRAIL–Myricetin mediated cell death in malignant glioma.