文章摘要
秦逸杨,徐晓楠,张光霁.丹参二萜醌对顺铂的增效作用及抗肺癌相关机制研究[J].浙江中医药大学学报,2024,48(4):379-387.
丹参二萜醌对顺铂的增效作用及抗肺癌相关机制研究
Investigation on Increase Efficiency of Tanshinones Diterpenoid on Cisplatin and the Related Mechanisms of Anti-lung Cancer
DOI:10.16466/j.issn1005-5509.2024.04.001
中文关键词: 肺癌  活血化瘀  丹参二萜醌  顺铂  增效  剂量
英文关键词: lung cancer  promoting blood circulation and removing blood stasis  diterpenoid tanshinones  cisplatin  increase efficiency  dose
基金项目:浙江省重点研发计划中药创新药物研究项目(2019C03072)
作者单位
秦逸杨 浙江中医药大学基础医学院 杭州 310053
浙江省中医“瘀毒”证重点实验室
中医“治未病”智慧健康浙江省工程研究中心 
徐晓楠 浙江中医药大学基础医学院 杭州 310053
浙江省中医“瘀毒”证重点实验室
中医“治未病”智慧健康浙江省工程研究中心 
张光霁 浙江中医药大学基础医学院 杭州 310053
浙江省中医“瘀毒”证重点实验室
中医“治未病”智慧健康浙江省工程研究中心 
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中文摘要:
      [目的] 对活血化瘀代表药物丹参的有效成分丹参二萜醌(diterpenoid tanshinones,DT)抗肺癌进行研究,验证DT的抗肺癌效能以及其对顺铂的增效作用,并探寻DT抗肺癌的相关机制。[方法] 构建A549肺癌BALB/c-nu裸鼠模型56只,根据腹腔注射及灌胃药物不同分为空白组、模型组、顺铂组、DT低剂量组、DT中剂量组、DT高剂量组、顺铂+DT高剂量组,测量并记录各组肿瘤直径,计算肿瘤体积和抑瘤率。采用免疫印迹法检测各组肿瘤组织血管内皮生长因子A(vascular endothelial growth factor A,VEGFA)、Ras、细胞周期蛋白依赖性激酶抑制剂1B(cyclin dependent kinase inhibitor 1B,CDKN1B)、Bcl-2关联X(Bcl-2 associated X,Bax)蛋白表达。采用实时荧光定量聚合酶链式反应(Real-time quantitative polymerase chain reaction,Real-time qPCR)分析维甲酸受体相关孤儿受体-γt(retinoic acid receptor-related orphan receptor-γt,ROR-γt)和转录因子叉头框蛋白P3(forkhead box protein P3,Foxp3)的变化。[结果] DT干预后的肺癌小鼠体质量上升,炎性细胞浸润好转,转移灶计数减少,瘤体积减小且抑瘤率升高,说明DT对肺癌移植瘤起到了较好的抑制作用。与空白组比较,模型组肿瘤组织中VEGFA、Ras蛋白表达水平显著升高(P<0.01),CDKN1B、Bax蛋白表达水平显著降低(P<0.01,P<0.05)。与模型组比较,顺铂组,DT低、中、高剂量组和顺铂+DT高剂量组肿瘤组织中VEGFA、Ras蛋白表达水平降低(P<0.01),CDKN1B、Bax蛋白表达水平升高(P<0.01,P<0.05),其中顺铂+DT高剂量组致癌基因表达降低和抑癌基因表达升高程度最为明显(P<0.01)。与顺铂组比较,顺铂+DT高剂量组VEGFA、Ras表达有所降低,CDKN1B、Bax表达有所升高,但差异无统计学意义(P>0.05)。DT剂量越高,致癌基因的表达水平越低,抑癌基因的表达水平越高,但差异无统计学意义(P>0.05)。Real-time qPCR显示,与空白组比较,模型组肿瘤组织中ROR-γt和Foxp3的表达水平显著升高(P<0.01)。与模型组比较,顺铂组,DT低、中、高剂量组和顺铂+DT高剂量组肿瘤组织中ROR-γt和Foxp3表达水平降低(P<0.01,P<0.05),其中顺铂+DT高剂量组ROR-γt和Foxp3表达下降最明显(P<0.01)。DT剂量越高,ROR-γt和Foxp3的表达水平越低,但差异无统计学意义(P>0.05)。[结论] DT具有较为可靠的抗肺癌效能,且这种效能具备剂量依赖性;DT与顺铂联用有增强顺铂抗肿瘤疗效的趋势。
英文摘要:
      [Objective] To investigate the anti-lung cancer effect of diterpenoid tanshinones(DT), an effective component of Salvia miltiorrhiza, and to verify the synergistic effect of DT on cisplatin and explore the mechanism of DT anti-lung cancer. [Methods] Fifty-six BALB/c nude mice were constructed to A549 lung cancer models and divided into blank group, model group, cisplatin group, DT low-dose group, DT medium-dose group, DT high-dose group Province and cisplatin+DT high-dose group according to different intraperitoneal injection and administration of drugs. Tumor diameter of nude mice was measured and recorded, and tumor volume and inhibitory rate were calculated. The expression of vascular endothelial growth factor A(VEGFA), Ras, cyclin dependent kinase inhibitor 1B(CDKN1B), Bcl-2 associated X(Bax) were detected by Western blot. Real-time quantitative polymerase chain reaction(Real-time qPCR) was used to analyze changes in retinoic acid receptor-related orphan receptor-γt(ROR-γt) and transcription factors forkhead box protein P3(Foxp3). [Results] After DT intervention, the body weight of nude mice with lung cancer increased, inflammatory cell infiltration relieved, metastasis count and tumor volume decreased, tumor inhibition rate increased, indicating DT played a good inhibitory effect on lung cancer transplantation tumors. Compared with blank group, the expression levels of VEGFA and Ras protein in tumor tissue of model group were significantly increased(P<0.01), while the expression levels of CDKN1B and Bax protein were significantly decreased(P<0.01, P<0.05). Compared with model group, the expression levels of VEGFA and Ras protein in cisplatin group, DT low-dose group, DT medium-dose group, DT high-dose group and cisplatin+DT high-dose group were decreased(P<0.01), CDKN1B and Bax protein expression levels were increased(P<0.01,P<0.05). The decrease of oncogene expression and increase of tumor suppressor gene were most obvious in cisplatin+DT high-dose group(P<0.01). Compared with cisplatin group, the expressions of VEGFA and Ras in cisplatin+DT high-dose group were decreased, while the expressions of CDKN1B and Bax were increased, but there was no statistical significance(P>0.05). The higher the dose of DT, the lower the expression level of oncogene and the higher the expression level of tumor suppressor gene was, but there was no statistical significance(P>0.05). Real-time qPCR showed that compared with blank group, the expression levels of ROR-γt and Foxp3 in tumor tissue of model group were significantly increased(P<0.01). Compared with model group, the expression levels of ROR-γt and Foxp3 in tumor tissue of cisplatin group, DT low-dose group, DT medium-dose group, DT high-dose group and cisplatin +DT high-dose group were decreased(P<0.01,P<0.05), and the expression levels of ROR-γt and Foxp3 were decreased most significantly in cisplatin+DT high-dose group(P<0.01). The higher the dose of DT, the lower the expression levels of ROR-γt and Foxp3 were, but there was no statistical significance(P>0.05). [Conclusion] DT has relatively reliable anti-lung cancer efficacy, which is concentration-dependent. DT combined with cisplatin has the tendency to enhance the anti-tumor efficacy of cisplatin.
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