Fingolimod induces cytotoxic stress and apoptosis-like cell death in drug-sensitive and P-glycoprotein-overexpressing acute myeloid leukemia cells.

Over the last several years, sphingolipids have been shown to regulate numerous cellular processes, including cell adhesion, migration, proliferation, senescence, death, or differentiation. Dysregulation of sphingolipid metabolism or sphingolipid mediated signaling is usually found in malignant cells, supporting uncontrolled tumor growth, suppression of immune responses, or drug resistance of cancer cells. Hence, novel drugs targeting sphingolipid metabolism or signaling are investigated as promising anticancer agents. Fingolimod is a synthetic analogue of sphingosine and employed for the treatment of relapse-remitting multiple sclerosis. Furthermore, fingolimod has been also studied as a potential antineoplastic drug owing to its ability to modulate metabolism and signaling pathways of cancer cells to promote inhibition of the cell cycle progression or induction of apoptosis. In our work, acute myeloid leukemia cell lines SKM-1 and MOLM-13 were employed together with their sublines displaying a multi-drug resistant phenotype due to P-glycoprotein overexpression. Our results indicate that fingolimod acts as a potent inducer of apoptosis-like cell death with the maximum effect observed after 8 h. This is also accompanied by a decrease in mitochondrial membrane potential, the generation of reactive oxygen species, an increase in intracellular calcium concentration, and the activity of stress-activated kinases JNK and p38. Fingolimod applied in sublethal concentrations can also induce accumulation of cells in the G0/G1 phase; however, this effect is not accompanied by the differentiation of leukemia cells. Although fingolimod treatment led to a decrease in the expression of P-glycoprotein on mRNA level, the same concentration of fingolimod had virtually no effect on its activity.