Beta Elemene induces cytotoxic effects in FLT3 ITD-mutated acute myeloid leukemia by modulating apoptosis.


Alafnan A., Dogan R., Bender O., Celik İ., Mollica A., Malik J. A., ...More

European review for medical and pharmacological sciences, vol.27, no.8, pp.3270-3287, 2023 (SCI-Expanded) identifier identifier identifier

Abstract

OBJECTIVE: beta-Elemene, a sesquiterpene with a broad anti-cancer spectrum, is particularly effective against drug-resistant and complex tumors. It can also be efficient against FLT3-expressed acute myeloid leukemia. This research aims to determine whether beta-Elemene has cytotoxic effects on FLT3 ITD-mutated AML cells. MATERIALS AND METHODS: Cytotoxicity, cell morphology, mRNA analysis with apoptotic markers, and analysis of 43 distinct protein markers related to cell death, survival, and resistance were all performed to elucidate its mechanism. Additionally, in order to understand how beta-Elemene and FLT3 interact, molecular docking, molecular dynamics simulations, and computational ADME investigations were performed. RESULTS: beta-Elemene exhibited cytotoxic activity against FLT3-mutated MV4-11 and FLT3 wild-type THP-1 cells, with an IC 50 of around 25 mu g/ml. The molecular studies revealed that beta-Elemene inhibited cell proliferation by inducing p53, and the involvement of p21, p27, HTRA, and HSPs were also demonstrated. The interactive inhibition in proliferation was confirmed via molecular docking and dynamics analyses. beta-Elemene occupied the FLT3 enzymatic pocket with good stability at the FLT3 active site. [GRAPHICS] CONCLUSIONS: We concluded from our observations that beta-Elemene causes cell death in ITD mutant AML cells, together with the effects of stress factors and inhibiting cell division.