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Characterization of cytotoxicity induced by sphingolipids in multidrug-resistant leukemia cells
J Klostergaard1, E Auzenne, E Leroux
1Department of Tumor Biology, The University of Texas MD Anderson Cancer Center, Houston 77030, USA.
Abstract:
Certain sphingolipids (SLs) exert fundamental roles in differentiative, growth-inhibitory and apoptotic pathways induced by a number of agents in leukemia cells. Multidrug-resistance (MDR) is a major cause of therapeutic failure in leukemia. SLs are among the diverse substrates for the MDR p-170 glycoprotein drug-efflux pump. We tested the hypothesis that expression of MDR would thereby block the cytotoxicity induced by the SLs sphingosine, sphinganine and N-hexanoyl-sphingosine. An MDR-expressing subline of murine P388 leukemia cells demonstrated an ED50 value > or = 2 log10 higher than the parental line in response to doxorubicin. In contrast, the ED50 values for each of the SLs were only approximately 1.5 to two-fold higher in the MDR line than in the parental; induction of DNA damage by SLs was comparable or actually greater in MDR compared to parental cells. Therefore, expression of MDR does not significantly affect the cytotoxic function of these SLs, nor do these SLs likely contribute to MDR.
Insights
Multidrug resistance (MDR) does not significantly impact the cell-killing effects of sphingolipids (SLs) like sphingosine in leukemia. These SLs are unlikely to contribute to the development of MDR in cancer therapy.
Area of Science:
- Biochemistry
- Cancer Biology
- Pharmacology
Background:
- Sphingolipids (SLs) play critical roles in cell differentiation, growth inhibition, and apoptosis in leukemia cells.
- Multidrug resistance (MDR) is a significant obstacle in leukemia treatment, often mediated by drug-efflux pumps like p-170 glycoprotein.
- SLs can be substrates for the MDR p-170 glycoprotein pump, raising questions about their efficacy in MDR leukemia.
Purpose of the Study:
- To investigate whether MDR expression in leukemia cells affects the cytotoxicity of specific sphingolipids: sphingosine, sphinganine, and N-hexanoyl-sphingosine.
- To determine if MDR mechanisms can block the anti-leukemic effects of these sphingolipids.
- To assess the potential contribution of these SLs to the development of MDR.
Main Methods:
- Comparison of cytotoxicity (ED50 values) of doxorubicin and selected SLs in parental and MDR-expressing murine P388 leukemia cell lines.
- Assessment of DNA damage induction by SLs in both cell lines.
- Evaluation of the impact of MDR expression on SL-induced cell death and DNA damage.
Main Results:
- MDR-expressing cells showed significantly higher resistance to doxorubicin compared to parental cells (ED50 > or = 2 log10 higher).
- Cytotoxicity of sphingosine, sphinganine, and N-hexanoyl-sphingosine was only marginally affected by MDR expression (ED50 approximately 1.5 to 2-fold higher).
- Induction of DNA damage by SLs was comparable or even greater in MDR cells than in parental cells.
Conclusions:
- The expression of MDR does not significantly impair the cytotoxic activity of sphingosine, sphinganine, and N-hexanoyl-sphingosine against leukemia cells.
- These specific SLs are unlikely to be significant contributors to the development or maintenance of multidrug resistance in leukemia.
- Targeting these SLs may remain a viable strategy in leukemia treatment, even in the presence of MDR.
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