Overcoming MDR-associated chemoresistance in HL-60 acute myeloid leukemia cells by targeting shingosine kinase-1

Abstract

We examined the involvement of sphingosine kinase-1, a critical regulator of the sphingolipid balance, in susceptibility to antineoplastic agents of either sensitive or multidrugresistant acute myeloid leukemia cells. Contrary to parental HL-60 cells, doxorubicin and etoposide failed to trigger apoptosis in chemoresistant HL-60/Doxo and HL-60/VP16 cells overexpressing MRP1 and MDR1, respectively. Chemosensitive HL-60 cells displayed sphingosine kinase-1 inhibition coupled with ceramide generation. In contrast, chemoresistant HL-60/ Doxo and HL-60/VP16 had sustained sphingosine kinase-1 activity and did not produce ceramide during treatment. Enforced expression of sphingosine kinase-1 in chemosensitive HL-60 cells resulted in marked inhibition of apoptosis that was mediated by blockade of mitochondrial cytochrome c efflux hence suggesting a control of apoptosis at the premitochondrial level. Incubation with cell-permeable ceramide of chemoresistant cells led to a sphingosine kinase-1 inhibition and apoptosis both prevented by sphingosine kinase-1 overexpression. Furthermore, F-12509a, a new sphingosine kinase inhibitor, led to ceramide accumulation, decrease in sphingosine 1-phosphate content and caused apoptosis equally in chemosensitive and chemoresistant cell lines that is inhibited by adding sphingosine 1-phosphate or overexpressing sphingosine kinase-1. F-12509a induced classical apoptosis hallmarks namely nuclear fragmentation, caspase-3 cleavage as well as downregulation of antiapoptotic XIAP, and release of cytochrome c and SMAC/Diablo. Leukemia (2006) 20, 95-102.

Sphingosine kinase-1 mediates BCR/ABL-induced upregulation of Mcl-1 in chronic myeloid leukemia cells

“…Recently, sphingosine kinase-1 (SPK1), the enzyme that phosphorylates sphingosine to form sphingosine-1-phosphate (S1P), could be activated by a number of growth factors and intracellular oncoproteins, and has been proven to be involved in signal transduction (Duan et al, 2004;Granata et al, 2004;Wattenberg et al, 2006). SPK1 activation is involved in the multistep progression and multidrug resistance of leukemia (Le Scolan et al, 2005;Bonhoure et al, 2006). Here, we show that SPK1 signal is also involved in the pathological progression of CML.…”

Chemosensitizing effects of sphingosine kinase-1 inhibition in prostate cancer cell and animal models

“…SphK1 mRNA content was found elevated in various human (9,10) and rodent tumor tissues (11). On the contrary, SphK1 down-regulation has been associated with cell death induced by anticancer treatments (6,8,12).…”

“…A key regulator of this balance is sphingosine kinase-1 (SphK1), which phosphorylates sphingosine (the catabolite of ceramide) to generate S1P, because it reduces proapoptotic ceramide levels by driving the sphingolipid metabolism toward antiapoptotic S1P. Accordingly, SphK1 overexpression promotes survival in response to stresses that increase ceramide content (6,8). SphK1 mRNA content was found elevated in various human (9,10) and rodent tumor tissues (11).…”

Reversion of Multidrug Resistance by SKI-II in SGC7901/DDP Cells and Exploration of Underlying Mechanisms

“…SphK1 mRNA content was found elevated in cancers, such as lung cancer, glioblastoma and colon carcinoma (Johnson et al, 2005;Van Brocklyn et al, 2005;Kawamori et al, 2006). On the contrary, down-regulation of SphK1 could arrest cell cycle and induce apoptosis (Pchejetski et al, 2005;Bonhoure et al, 2006;Cuvillier et al, 2007). Moreover, it has been shown that SphK1 impairs the efficacy of chemotherapy in prostate adenocarcinoma cells (Pchejetski et al, 2005).…”