Characterization of cytotoxicity induced by sphingolipids in multidrug-resistant leukemia cells

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 ≥2log₁₀ 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.

Keywords:  Chemoresistance, Cytotoxicity/Apoptosis, Sphingosine, Ceramide

Abbreviations:  C₆-ceramide or C₆-Cer, N-hexanoyl-d-sphingosine, Dox, doxorubicin, ED₅₀, effective dose inducing 50% effect, MDR, multidrug-resistance, P-gp, P-glycoprotein, Sa, sphinganine (dihydrosphingosine), Sls, sphingolipids, SM, sphingomyelin, SMase, sphingomyelinase, So, d-sphingosine