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Updated: Jun 27, 2026
Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia
Published on: September 18, 2013
In vitro anti-leukaemia activity of sphingosine kinase inhibitor
Clara Ricci1, Francesco Onida, Federica Servida
1Laboratory of Biochemistry & Molecular Biology, San Paolo University Hospital and University of Milan, Milan, Italy.
Abstract:
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.
Insights
The novel SK inhibitor (SKI) effectively targets sphingosine kinase 1 (SPHK1) in leukemia cells, showing anti-cancer effects and overcoming imatinib resistance in chronic myeloid leukemia (CML) patients.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Sphingosine kinase 1 (SPHK1) deregulation is implicated in cancer development and drug resistance.
- Selective SPHK1 inhibitors are crucial for research but largely unavailable.
- The newly discovered 'SK inhibitor' (SKI) offers a potential tool for studying SPHK1.
Purpose of the Study:
- To evaluate the efficacy of SKI as a selective SPHK1 inhibitor in myeloid leukemia.
- To assess SKI's anti-proliferative and cytotoxic effects on leukemia cell lines.
- To investigate SKI's potential in overcoming imatinib resistance in chronic myeloid leukemia (CML).
Main Methods:
- Assessed basal SPHK1 levels in myeloid leukemia cell lines.
- Exposed cell lines to SKI and measured anti-proliferative and cytotoxic effects.
- Analyzed SKI's impact on cell cycle progression and apoptosis.
- Investigated SKI's synergistic effects with imatinib mesylate (IM).
- Tested SKI's effects on primary CML patient cells, including those with T315I mutation.
Main Results:
- Basal SPHK1 levels correlated with SKI inhibition efficacy.
- SKI demonstrated anti-proliferative and cytotoxic effects across leukemia cell lines.
- SKI significantly inhibited SPHK1 activity, impaired cell cycle, and induced apoptosis in K562 cells.
- SKI synergized with IM to reduce cell growth and survival.
- SKI impacted clonogenic potential and viability of primary CML cells, including IM-resistant cases.
Conclusions:
- SKI is a potent inhibitor of SPHK1 with anti-leukemic activity.
- SKI demonstrates potential as a therapeutic agent, particularly in overcoming IM resistance in CML.
- Further investigation of SKI is warranted for its clinical relevance in CML treatment.
