In vitro anti-leukaemia activity of sphingosine kinase inhibitor.
Compelling evidence indicates the role of sphingosine kinase 1 (SPHK1) deregulation in the processes of carcinogenesis and acquisition of drug resistance, providing the rationale for an effective anti-cancer therapy. However, no highly selective inhibitors of SPHK1 are available for in vitro and in vivo studies, except for the newly discovered 'SK inhibitor' (SKI). The present study showed that, in a panel of myeloid leukaemia cell lines, basal level of SPHK1 correlated with the degree of kinase inhibition by SKI. Exposure to SKI caused variable anti-proliferative, cytotoxic effects in all cell lines. In particular, SKI induced an early, significant inhibition of SPHK1 activity, impaired cell cycle progression and triggered apoptosis in K562 cells. Moreover, SKI acted synergistically with imatinib mesylate (IM) to inhibit cell growth and survival. Finally, the inhibitor affected the clonogenic potential and viability of primary cells from chronic myeloid leukaemia (CML) patients, including one harbouring the IM-insensitive Abl kinase domain mutation T315I. Due to the fact that the phenomenon of resistance to IM remains a major issue in the treatment of patients with CML, the identification of alternative targets and new drugs may be of clinical relevance.
Ricci
Clara
C
Laboratory of Biochemistry & Molecular Biology, San Paolo University Hospital and University of Milan, Milan, Italy.
Onida
Francesco
F
Servida
Federica
F
Radaelli
Franca
F
Saporiti
Giorgia
G
Todoerti
Katia
K
Deliliers
Giorgio Lambertenghi
GL
Ghidoni
Riccardo
R
D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D001752:Blast Crisis / Q000188:drug therapy* / Q000201:enzymology; D002453:Cell Cycle / Q000187:drug effects; D003114:Colony-Forming Units Assay; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D015870:Gene Expression; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000201:enzymology; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D010879:Piperazines / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011743:Pyrimidines / Q000627:therapeutic use; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013844:Thiazoles / Q000494:pharmacology / Q000627:therapeutic use*; D013997:Time Factors; D000099157:Sphingosine Kinase
D001549:Benzamides; D000068877:Imatinib Mesylate; D017853:Phosphotransferases (Alcohol Group Acceptor); D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D000099157:Sphingosine Kinase; C525025:4-(4-(4-chloro-phenyl)thiazol-2-ylamino)phenol