Effects of polyunsaturated fatty acids on vincristine-resistance in human neuroblastoma cells.
PUFAs such as GLA (n-6) or DHA (n-3) were shown to exert antitumor activity on a human neuroblastoma cell line (NCG) and its VCR-resistant subline (NCG/VCR1, 8.6-fold resistant to VCR) in vitro. The NCG/VCR1 line had markedly decreased intracellular accumulation of [3H]-VCR and an accelerated drug efflux, compared to the NCG. The cytotoxic activity of PUFAs was correlated with the generation of MDA-like products in these cells. When VCR was added simultaneously with GLA or DHA to culture medium, the cytotoxic effect of VCR was about 2-fold enhanced, accompanied by about 1.5-2.0-fold increase of intracellular [3H]-VCR in both cell lines. Fatty acid analysis of membrane phospholipids of the NCG and the NCG/VCR1 cells treated with GLA or DHA showed an increased total PUFAs and SFAs, associated with markedly decreased total MUFAs and an inverted PUFAs/MUFAs ratio. Such phospholipid modification may have altered the membrane physical properties and enhanced the VCR cytotoxicity by increasing intracellular VCR accumulation; however, these PUFAs did not affect the drug efflux sufficiently enough to overcome completely the VCR resistance in the NCG/VCR1 cells. These results indicate that PUFAs partially alleviate the VCR-resistance in human neuroblastoma cells, not directly acting on VCR-resistance mechanism(s).
Ikushima
S
S
Department of Pediatrics, Children's Research Hospital, Kyoto Prefectural University of Medicine, Japan.
Fujiwara
F
F
Todo
S
S
Imashuku
S
S
D002455:Cell Division / Q000187:drug effects; D004351:Drug Resistance; D005227:Fatty Acids / Q000032:analysis; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology*; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects; D008563:Membrane Lipids / Q000032:analysis; D009447:Neuroblastoma / Q000473:pathology; D014407:Tumor Cells, Cultured; D014750:Vincristine / Q000493:pharmacokinetics / Q000494:pharmacology*
D005227:Fatty Acids; D005231:Fatty Acids, Unsaturated; D008563:Membrane Lipids; D014750:Vincristine