ω - 3 多不饱和脂肪酸单药或联合用药逆转多发性骨髓瘤耐药性及细胞凋亡的机制研究

Role and mechanisms of ω - 3 polyunsaturated fatty acids in inducing cell apoptosis and reversing drug resistance in multiple myeloma

    摘要
  • 摘要: 目的：探讨ω - 3 多不饱和脂肪酸（ω - 3 polyunsaturated fatty acids ，ω - 3 PUFA）单药或联合糖皮质激素地塞米松（dexamethasone ，DEX ）逆转多发性骨髓瘤（multiple myeloma，MM）耐药性及诱导细胞凋亡的作用及其机制。方法：采用不同浓度的两种ω - 3PUFA，二十碳五烯酸（eicosapentaenoic acid ，EPA ）和二十二碳六烯酸（docosahexaenoic acid ，DHA）单药处理，或与DEX 联合处理DEX 耐药细胞系MM1R 在24h 或48h 后，采用MTT 法检测细胞的增殖，流式细胞术检测细胞周期的细胞凋亡，Westernblot检测相关凋亡蛋白的表达水平。分析方法采用两样本间t 检验，以P < 0.05为差异具有统计学意义。结果：不同浓度EPA 或DHA（10、20、50、100 μ M），及50μ MEPA或DHA与10μ MDEX 联合处理均能够抑制MM1R 细胞的增殖，且呈剂量和时间依赖性，联合组抑制效果较EPA（50μ M）或DHA（50μ M）单药组更明显（P = 0.014，0.032）。 不同浓度EPA 或DHA作用MM1R 细胞48h 后，随着药物浓度增加，G 0/G1 期细胞逐渐增加，S 期和G 2 期细胞逐渐减少，细胞凋亡率逐渐升高，细胞阻滞在G 0/G1 期；而两药联合组与EPA（50μ M）或DHA（50μ M）单药处理组相比，细胞阻滞和细胞凋亡率更加明显（P = 0.015，0.004）；凋亡相关Cleaved caspase-3、Bax 蛋白水平逐渐升高，Pro-caspase-3、BCL-2 蛋白水平逐渐降低，且呈剂量依赖性。不同浓度EPA 或DHA作用MM1R 细胞，随药物浓度增加，耐药倍数逐渐下降，逆转倍数逐渐上升，而两药联合组较单药组细胞耐药倍数下降及逆转倍数上升更明显。结论：ω - 3PUFA 能够抑制DEX 耐药MM细胞增殖，阻滞细胞周期，诱导细胞凋亡，与DEX 联合应用对抑制MM细胞增殖、诱导细胞凋亡具有协同作用，是一种新型且有效的逆转MM耐药的治疗药物。

     

    Abstract: Objective:To explore the role and mechanisms of ω - 3 polyunsaturated fatty acids ( ω - 3PUFAs) alone or in combination with dexamethasone (DEX) in inducing cell apoptosis and reversing drug resistance in multiple myeloma (MM). Methods:DEX-resistant MM cell line MM1R was treated with different concentrations of eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) alone or in combination with DEX for 24 or 48 h. Cell proliferation was detected by MTT assay. Cell cycle and apoptosis were measured by flow cytometry. Expression levels of apoptosis-related proteins were analyzed by Western blot. Two-tailed, unpaired Student's t-test was used to compare the two treatment groups. A value of P<0.05 was considered statistically significant.Results:MM1R proliferation was inhibited by different concentrations ( 10, 20, 50, and 100 μ M) of EPA or DHA alone or in combination with 10μ M DEX in a dose- and time-dependent manner. The inhibition effect was significantly higher in combinative groups than in single EPA or DHA treatment group (P=0. 014 , P=0. 032 ). The percentage of G0/G1 phase and cell apoptosis rate in MM1R treated with different concentrations of EPA or DHA alone increased in a dose-dependent manner. This percentage was also significantly higher in the combinative groups than in the single EPA or DHA treatment group (P=0.015, P=0.004). The expression levels of cleaved caspase-3 and Bax were upregulated, whereas those of pro-caspase- 3 and BCL- 2 were downregulated in a dose-dependent manner. Drug resistance gradually decreased in MM1R cells at different concentrations of EPA or DHA with the increase of drug concentration. The reversal fold also increased gradually, whereas the cells decreased in the two drug-combination groups compared with the single-drug group. Moreover, the drug-resistance reversal index increased significantly. Conclusion: ω - 3PUFAs can inhibit DEX-resistant MM cell proliferation, arrest cell cycle, and induce cell apoptosis. ω - 3PUFAs also exhibit a synergistic anti-resistant effect in combination with DEX. Furthermore, ω -3PUFAs can serve as novel effective drugs for MM treatment.

     

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