Ikushima S, Fujiwara F, Todo S, Imashuku S
Department of Pediatrics, Children's Research Hospital, Kyoto Prefectural University of Medicine, Japan.
Anticancer Res. 1991 May-Jun;11(3):1215-20.
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).
体外实验表明，γ-亚麻酸（n-6）或二十二碳六烯酸（n-3）等多不饱和脂肪酸（PUFAs）对人神经母细胞瘤细胞系（NCG）及其长春新碱（VCR）耐药亚系（NCG/VCR1，对VCR耐药8.6倍）具有抗肿瘤活性。与NCG相比，NCG/VCR1细胞系中[3H]-VCR的细胞内蓄积明显减少，药物外排加速。PUFAs的细胞毒性活性与这些细胞中丙二醛样产物的生成相关。当将VCR与γ-亚麻酸或二十二碳六烯酸同时添加到培养基中时，VCR的细胞毒性作用增强约2倍，同时两种细胞系中的细胞内[3H]-VCR增加约1.5 - 2.0倍。用γ-亚麻酸或二十二碳六烯酸处理的NCG和NCG/VCR1细胞的膜磷脂脂肪酸分析显示，总多不饱和脂肪酸和饱和脂肪酸增加，同时总单不饱和脂肪酸明显减少，多不饱和脂肪酸/单不饱和脂肪酸比值倒置。这种磷脂修饰可能改变了膜的物理性质，并通过增加细胞内VCR蓄积增强了VCR的细胞毒性；然而，这些多不饱和脂肪酸对药物外排的影响不足以完全克服NCG/VCR1细胞中的VCR耐药性。这些结果表明，多不饱和脂肪酸可部分缓解人神经母细胞瘤细胞中的VCR耐药性，并非直接作用于VCR耐药机制。
