Resveratrol'ün FLT3+ akut miyeloid lösemide terapötik potansiyeli ve resveratrol tarafından tetiklenen apoptozda seramid metabolizmasının rolü

The mechanisms underlying the growth inhibitory effects of resveratrol on FLT3-ITD + AML cells were investigated by targeting ceramide metabolism. Antiproliferative, apoptotic and cytostatic effects of resveratrol, SK (sphingosine kinase) inhibitor (SKI II), GCS (glucosylceramide synthase) inhibitor (PDMP) alone and on combination on MOLM-13 and MV4-11 cells were investigated by MTT, flow cytometric Annexin-V/PI staining and PI staining respectively. Caspase-3 and PARP cleavages, GCS and SK protein expressions were checked by western blot in response to resveratrol. PARP activation was also checked after co-treatments. Combination indexes were calculated by CompuSyn software. Resveratrol alone and its combinations with SKI II and PDMP suppress cell proliferation with additive or synergistic effects, induced apoptosis and resulted in cell cycle arrest. Resveratrol suppressed GCS and SK-1 expression and induced apoptosis via caspase-3 and PARP cleavage. Co-treatments induced apoptosis through PARP activation mechanistically. Overall, resveratrol's growth inhibitory effects in FLT3-ITD + AML cells are mediated by inhibiting SK-1 and GCS, which further intensify resveratrol's activity