| 廖广辉,张广顺,楼招欢,等.三氧化二砷联合丹参酮对肝癌的作用效果与机制研究[J].浙江中医药大学学报,2020,44(1):15-23. |
| 三氧化二砷联合丹参酮对肝癌的作用效果与机制研究 |
| Study on the Efficiency and Attenuating Mechanism of Arsenic Trioxide Combined with Tanshinone Against Liver Cancer |
| DOI：10.16466/j.issn1005-5509.2020.01.003 |
| 中文关键词: As2O3 丹参酮 肝癌 细胞凋亡 裸鼠移植瘤 增效减毒 |
| 英文关键词: arsenic trioxide tanshinone liver cancer cell apoptosis nude mouse transplantation tumor increased efficacy and reduced toxicity |
| 基金项目:浙江省教育厅高校访问学者教师专业发展项目(FX2016019)；国家自然科学基金面上项目(81573962)；浙江中医药大学药学院时珍青年人才培养计划资助项目(SZZ201812) |
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| 中文摘要: |
| [目的] 考察三氧化二砷(arsenic trioxide，As2O3)联合丹参酮对肝癌裸鼠移植瘤的作用效果并初步探讨其可能的分子机制。[方法] 建立裸鼠人肝癌移植瘤模型，待瘤体生长到体积100mm3左右，将裸鼠随机分为5组，分别为模型对照组、As2O3单用组(As2O3低剂量组，2.5mg/kg)、阳性对照组(As2O3高剂量组，5.0mg/kg)、丹参酮单用组(500mg/kg)、As2O3-丹参酮组(As2O3 2.5mg/kg+丹参酮500mg/kg)，每组8只，每天腹腔注射给药，共19d。比较各组肿瘤生长曲线和瘤体质量；采集血液进行血常规和生化常规分析；以原位末端转移酶标记(TdT-mediated dUTP nick end labeling, TUNEL)法检测瘤体组织细胞凋亡情况；免疫组化和Western blot检测凋亡相关蛋白的表达。[结果] 随着给药时间的延长，与模型对照组比较，As2O3 单用组、丹参酮单用组、As2O3-丹参酮组以及阳性对照组均表现出一定的抑瘤效果(P＜0.01)。与阳性对照组比较，As2O3-丹参酮组的抑瘤效果更显著(P＜0.05)。与模型对照组比较，As2O3单用组、阳性对照组、As2O3-丹参酮组白细胞(white blood cell，WBC)计数均上调，其中As2O3单用组差异具有统计学意义(P＜0.05)；As2O3单用组、阳性对照组红细胞(red blood cell，RBC)计数显著下调(P＜0.05，P＜0.01)；各治疗组血红蛋白(hemoglobin，HGB)水平均下调，其中阳性对照组差异有统计学意义(P＜0.01)；As2O3单用组、阳性对照组、As2O3-丹参酮组血小板(platelet，PLT)计数均上调，其中As2O3单用组和阳性对照组差异具有统计学意义(P＜0.01)；与阳性对照组比较，As2O3-丹参酮组WBC、RBC计数和HGB水平均上调，但差异无统计学意义(P＞0.05)。与模型对照组比较，As2O3单用组、阳性对照组与As2O3-丹参酮组丙氨酸氨基转移酶(alanine aminotransferase，ALT)水平上调，但差异无统计学意义(P＞0.05)；各治疗组中天门冬氨酸氨基转移酶(aspartate aminotransferase，AST)水平下调，其中丹参酮单用组差异有统计学意义(P＜0.01)；各治疗组中尿素氮(blood urea nitrogen，BUN)水平下调，其中丹参酮单用组差异有统计学意义(P＜0.05)；阳性对照组、丹参酮单用组和As2O3-丹参酮组肌酐(creatinine，CREA)水平均下调(P＜0.05，P＜0.01)。与模型对照组比较，各治疗组凋亡率均明显上调(P＜0.01)；与阳性对照组比较，As2O3-丹参酮组凋亡率上调显著(P＜0.01)。与模型对照组比较，各治疗组中促凋亡蛋白Bax表达上调，其中阳性对照组、丹参酮单用组和As2O3-丹参酮组差异有统计学意义(P＜0.01)；丹参酮单用组和As2O3-丹参酮组靶向聚ADP核糖聚合酶(poly ADP-ribose polymerase，PARP)表达明显上调(P＜0.01)；阳性对照组、丹参酮单用组和As2O3-丹参酮组抗凋亡蛋白X连锁凋亡抑制蛋白(X-linked inhibitor of apoptosis protein，XIAP)表达明显下调(P＜0.01)。[结论]As2O3与丹参酮联用抗肝癌具有协同增效、减毒的作用，丹参酮可以减轻As2O3造成的血常规改变和肝肾功能损伤。 |
| 英文摘要: |
| [Objective]To investigate the effect of arsenic trioxide(As2O3) combined with tanshinone on transplanted hepatocellular carcinoma in nude mice and explore its possible molecular mechanism. [Methods]Human liver cancer transplantation tumor model was established in BALB/C-nu mice. When the tumor body grew to a volume of about 100mm3, the nude mice were randomly divided into five groups: Model control group, As2O3 single-use group (As2O3 low-dose group, 2.5mg/kg), positive control group(As2O3 high-dose group,5.0mg/kg), tanshinone single-use group(500mg/kg), and As2O3-tanshinone group(As2O3 2.5mg/kg+tanshinone 500mg/kg), with 8 mice in each group. All mice were injected intraperitoneally every day for 19 days. The growth curve and weight of tumor were compared in each group; blood samples were collected for blood routine and biochemical analysis; apoptotic status of tumor tissues was detected by TdT-mediated dUTP nick end labeling(TUNEL); expression of apoptotic-related proteins was detected by immunohistochemistry and Western blot. [Results]With the prolongation of administration time, compared with model control group, As2O3 single-use group, tanshinone single-use group, As2O3-tanshinone group and positive control group all showed a certain anti-tumor effect(P＜0.01). Compared with positive control group, the effect of As2O3-tanshinone group was more obvious(P＜0.05).Compared with model control group, the white blood cell(WBC) count of As2O3 single-use group, positive control group, and As2O3-tanshinone group increased, the difference of As2O3 single-use group was statistically significant(P＜0.05); the red blood cell(RBC) count of As2O3 single-use group and positive control group decreased, the difference was statistically significant(P＜0.05, P＜0.01); the hemoglobin(HGB) level of all treatment groups decreased, and the difference of positive control group was statistically significant(P＜0.01); the platelet(PLT) count of As2O3 single-use group, positive control group, As2O3-tanshinone group increased, the difference of As2O3 single-use group and positive control group was statistically significant(P＜0.01). Compared with positive control group, the WBC, RBC count and HGB level of As2O3-tanshinone group increased, but the difference was not statistically significant(P＞0.05). Compared with model control group, the level of alanine aminotransferase(ALT) in As2O3 single-use group, positive control group, and As2O3-tanshinone group increased, but the difference was not statistically significant(P＞0.05); the level of aspartate aminotransferase(AST) in all treatment groups decreased, and the difference in tanshinone single-use group was statistically significant(P＜0.01).The level of blood urea nitrogen(BUN) decreased in all treatment groups, and the difference of tanshinone single-use group was statistically significant(P＜0.05); the levels of creatinine(CREA) in positive control group, tanshinone single-use group and As2O3-tanshinone group decreased, the difference was statistically significant(P＜0.05, P＜0.01). Compared with model control group, the apoptotic rates of all treatment groups increased(P＜0.01); compared with positive control group, the apoptotic rate of As2O3-tanshinone group increased(P＜0.01). Compared with model control group, the expression of Bax in all treatment groups upregulated, and the difference of positive control group, tanshinone single-use group and As2O3-tanshinone group was statistically significant(P＜0.01). The expression of poly ADP-ribose polymerase(PARP) upregulated in tanshinone single-use group and As2O3-tanshinone group(P＜0.01). The expression of X-linked inhibitor of apoptosis protein (XIAP) downregulated in positive control group,tanshinone single-use group and As2O3-tanshinone group(P＜0.01). [Conclusion]The combination of As2O3 and Tanshinone has synergistic effect, attenuation and anti-hepatocarcinoma effect. Tanshinone can reduce the blood routine changes and liver and kidney function damage caused by As2O3. |
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