Resveratrol triggers anti-proliferative and apoptotic effects in FLT3-ITD-positive acute myeloid leukemia cells via inhibiting ceramide catabolism enzymes


Ersoz N. S. , ADAN A.

MEDICAL ONCOLOGY, vol.39, no.3, 2022 (Journal Indexed in SCI) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 39 Issue: 3
  • Publication Date: 2022
  • Doi Number: 10.1007/s12032-021-01627-2
  • Title of Journal : MEDICAL ONCOLOGY
  • Keywords: Apoptosis, FLT3-ITD acute myeloid leukemia, Glucosylceramide synthase, Resveratrol, Sphingosine kinase, SPHINGOSINE KINASE-1, SPHINGOLIPID METABOLISM, MODULATION, RESISTANCE, EXPRESSION, GROWTH, K562

Abstract

Resveratrol possesses well-defined anti-carcinogenic activities. However, how resveratrol exerts its anti-leukemic actions by modulating anti-apoptotic ceramide catabolism enzymes, mainly sphingosine kinase (SK-1) and glucosylceramide synthase (GCS), in FLT3-ITD AML remains unclear. Resveratrol, SKI II (SK inhibitor) and PDMP (GCS inhibitor) were evaluated alone or in combinations for their effect on cell proliferation (MTT assay), apoptosis (annexin V-FITC/PI staining by flow cytometry) and cell cycle progression (PI staining by flow cytometry) in MOLM-13 and MV4-11 cells. The combination indexes (CIs) were calculated based on cell proliferation data using CompuSyn software. Caspase-3 and PARP activation, changes in SK-1 and GCS levels by resveratrol alone or PARP cleavage in co-treatments were determined by western blot. Resveratrol and inhibitors alone inhibited cell proliferation in a dose- and time-dependent manner. Resveratrol downregulated SK-1 and GCS expression in both cell lines. It induced apoptosis by phosphatidylserine (PS) exposure together with caspase-3 and PARP cleavage and arrested the cell cycle slightly at the S phase. Co-administrations intensified resveratrol's effect by inhibiting cell proliferation synergistically (A CI of < 1) or additively (A CI 1.0-1.1) and inducing apoptosis via PS relocalization and PARP cleavage. Resveratrol plus SKI II did not affect cell cycle progression significantly, however, resveratrol plus PDMP blocked cycle progression at G0/G1 and S phases for MOLM-13 cells and MV4-11 cells, respectively. Overall, resveratrol may inhibit FLT3-ITD AML cell proliferation by inhibiting ceramide catabolism and be evaluated as a chemopreventive after detailed analysis of the crosstalk between resveratrol and ceramide catabolism pathway.