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首页> 外文期刊>Life sciences >Effects of cis-unsaturated fatty acids on doxorubicin sensitivity in P388/DOX resistant and P388 parental cell lines.
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Effects of cis-unsaturated fatty acids on doxorubicin sensitivity in P388/DOX resistant and P388 parental cell lines.

机译：顺式不饱和脂肪酸对P388 / DOX耐药和P388亲本细胞系对阿霉素敏感性的影响。

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It has been reported that several cis-unsaturated fatty acids (c-UFAs) could increase doxorubicin (DOX) accumulation in cancer cells and hence elevate its cytotoxicity. However, some researchers showed that c-UFA pretreatment did not affect its cytotoxicity in special cell lines. It is possible that the different results occurred due to different cellular characteristics. We hypothesized that c-UFA treatment might modulate the activities of some antioxidant enzymes to affect the resistance of cells to DOX. In the present study, we examined how c-UFA pretreatment affected DOX cytotoxicity on mouse leukemia cell line, P388, and its resistant subline, P388/DOX, which we found to have significantly higher glutathione peroxidase (GPx) activity as well as P-glycoprotein (p-gp) overexpression. We chose two c-UFAs, gamma-linolenic acid (GLA) (18:3n-6) and docosahexaenoic acid (DHA) (22:6n-3). Cytotoxicity was measured by MTT (3-(4.5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and trypan blue exclusion assays. DOX accumulation and p-gp expression were measured by flow cytometry. The activities of catalase (CAT), superoxide dismutase (SOD), glutathione S-transferase (GST), and GPx were determined for both cell lines with and without treatment with GLA or DHA. Significant DOX accumulation occurred in both cell lines with GLA or DHA pretreatment, but without any change in p-gp expression in either cell line. Sensitivity to DOX cytotoxicity was improved by GLA or DHA pretreatment in P388/DOX in which only SOD activity was significantly increased, but not in the parental cell line P388 in which both SOD and CAT were significantly increased by the pretreatment. However, combined pretreatment of GLA or DHA with antioxidants, pyrrolidinedithiocarbamate (PDTC) or Vitamin C, could sensitize not only P388/DOX but also P388 cells to DOX. We conclude that the effects of c-UFA pretreatment on the sensitivity of cancer cells to DOX not only depend on the change in drug accumulation but also the change in the levels of antioxidant enzyme activities, and suggest that combined administration of c-UFAs, antioxidants, and DOX may be more effective in treating leukemia.
机译：据报道，几种顺式不饱和脂肪酸（c-UFAs）可以增加阿霉素（DOX）在癌细胞中的积累，从而提高其细胞毒性。但是，一些研究人员表明，c-UFA预处理不会影响其在特殊细胞系中的细胞毒性。由于细胞特性不同，可能会出现不同的结果。我们假设c-UFA处理可能会调节某些抗氧化酶的活性，从而影响细胞对DOX的抵抗力。在本研究中，我们研究了c-UFA预处理如何影响DOX对小鼠白血病细胞株P388及其耐药亚株P388 / DOX的细胞毒性，我们发现它们具有显着更高的谷胱甘肽过氧化物酶（GPx）活性以及P-糖蛋白（p-gp）过度表达。我们选择了两种c-UFAs，γ-亚麻酸（GLA）（18：3n-6）和二十二碳六烯酸（DHA）（22：6n-3）。细胞毒性通过MTT（3-（4.5-二甲基噻唑-2-基）-2,5-二苯基四氮唑溴化物）和锥虫蓝排除法测定。通过流式细胞术测量DOX的积累和p-gp表达。确定了两种细胞系经和未经GLA或DHA处理后的过氧化氢酶（CAT），超氧化物歧化酶（SOD），谷胱甘肽S-转移酶（GST）和GPx的活性。在用GLA或DHA预处理的两种细胞系中都发生了明显的DOX积累，但在任一细胞系中p-gp表达均未发生任何变化。通过GLA或DHA预处理可改善DOX细胞毒性的敏感性，在P388 / DOX中，仅SOD活性显着增加，而在亲本细胞系P388中，其SOD和CAT均显着增加，而P388 / DOX中则没有。但是，将GLA或DHA与抗氧化剂，吡咯烷二硫代氨基甲酸酯（PDTC）或维生素C联合预处理不仅可以使P388 / DOX敏感，还可以使P388细胞对DOX敏感。我们得出结论，c-UFA预处理对癌细胞对DOX敏感性的影响不仅取决于药物积累的变化，还取决于抗氧化酶活性水平的变化，并建议将c-UFA，抗氧化剂联合给药，而DOX可能更有效地治疗白血病。

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