Effective cytotoxicity against human leukemias and chemotherapy-resistant leukemia cell lines by N-N-dimethylsphingosine

Abstract 

We evaluated the cytotoxicity of dimethylsphingosine (DMS) against four human leukemia cell lines: two acute (HL60 and a multi-drug resistance MDR-positive derivative HL60-dox) and two blast crisis chronic myelogenous leukemias (JFP1, from a treatment refractory patient and K562), and against blasts isolated from 11 leukemia patients. Cell line viability decreased proportionally to DMS concentration and treatment time (P<0.001). HL60-dox and JFP1 were the most sensitive, indicating DMS efficacy against human leukemia MDR. Importantly, leukemia samples showed a similar sensitivity to DMS as that of the cell lines, firstly demonstrating PKC-independent sphingolipid activity against fresh human tumor specimens. DMS-based chemotherapy may improve leukemia treatment.

Keywords:  Leukemia patients, Sphingolipids, Dimethylsphingosine, Cytotoxicity

Abbreviations:  AML, acute myelogenous leukemia, ANOVA, analysis of variance, CML, chronic myelogenous leukemia, DMS, dimethylsphingosine, FBS, fetal bovine serum, MDR, multi-drug resistance, MTS, (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt), PBS, phosphate-buffered saline, PMS, phenazine methosulfate, TB, trypan blue