Effective cytotoxicity against human leukemias and chemotherapy-resistant leukemia cell lines by N-N-dimethylsphingosine.
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.
Jendiroba
David B
DB
Departments of Special Medical Education Programs, Molecular and Cellular Oncology and Genitourinary Medical Oncology, Division of Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Klostergaard
Jim
J
Keyhani
Afsaneh
A
Pagliaro
Lance
L
Freireich
Emil J
EJ
D000970:Antineoplastic Agents / Q000633:toxicity*; D001752:Blast Crisis / Q000473:pathology; D001854:Bone Marrow Cells / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000633:toxicity*; D018922:HL-60 Cells; D006801:Humans; D020014:K562 Cells; D007938:Leukemia / Q000473:pathology*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000097:blood / Q000473:pathology; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000633:toxicity*; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; C061800:N,N-dimethylsphingosine; D013110:Sphingosine