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复方蜥蜴散调控糖酵解降低胃癌顺铂耐药性的效应机制研究
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| 篇名： | 复方蜥蜴散调控糖酵解降低胃癌顺铂耐药性的效应机制研究 |
| TITLE： | Study on the mechanism of Compound lizard powder reducing cisplatin resistance in gastric cancer by regulating glycolysis |
| 摘要： | 目的 基于磷脂酰肌醇3激酶（PI3K）/蛋白激酶B（Akt）信号通路，探讨复方蜥蜴散调控糖酵解降低胃癌顺铂耐药性的效应机制。方法体外培养人胃癌MKN45、MKN45/DDP（顺铂耐药）细胞，以不同质量浓度顺铂（0.1、0.2、0.4、0.8、1.6、3.2μg/mL）干预，检测其存活率、半数抑制浓度（IC50）和耐药指数。于裸鼠右前腋窝皮下接种MKN45/DDP细胞悬液制备胃癌耐药裸鼠移植瘤模型，将造模成功的裸鼠随机分为模型组、顺铂组（0.002g/kg）、复方蜥蜴散组（2.8g/kg）、联合组（剂量同各单药组），每组8只；各药物组裸鼠给予相应药液，每周2次（顺铂，腹腔注射）或每天2次（复方蜥蜴散，灌胃），连续4周。实验期间，监测各组裸鼠体重并计算其肿瘤体积和肿瘤生长抑制率，检测其肿瘤组织中炎症因子（肿瘤坏死因子α、白细胞介素6）水平，多药耐药相关蛋白1（MRP1）、P糖蛋白（P-gp）、葡萄糖转运蛋白1（GLUT1）、乳酸脱氢酶A（LDHA）mRNA及蛋白，以及PI3K、磷酸化PI3K（p-PI3K）、Akt、磷酸化Akt（p-Akt）、己糖激酶2（HK2）、丙酮酸激酶M2（PKM2）蛋白的表达情况。结果在不同质量浓度顺铂的干预下，耐药细胞MKN45/DDP的存活率均显著高于亲本细胞MKN45（P＜0.05）；MKN45/DDP和MKN45细胞的IC50分别为（1.0520±0.2219）、（0.3721±0.2380）μg/mL，耐药指数为2.827。与模型组比较，顺铂组、复方蜥蜴散组、联合组裸鼠的肿瘤生长均受到不同程度的抑制，肿瘤生长抑制率显著升高（P＜0.05）；肿瘤组织中炎症因子水平，MRP1、P-gp、GLUT1、LDHAmRNA及蛋白的表达（顺铂组除外），PI3K、Akt蛋白的磷酸化水平（顺铂组除外），以及HK2、PKM2蛋白的表达均显著降低或下调，且联合组的效果显著优于顺铂组（P＜0.05）。结论复方蜥蜴散可通过减少肿瘤相关炎症因子的分泌，抑制糖酵解、耐药相关蛋白及基因的表达，抑制PI3K/Akt信号通路的活化来抑制胃癌耐药细胞移植瘤裸鼠的肿瘤生长，具有一定的顺铂增效及逆转耐药的作用。 |
| ABSTRACT： | OBJECTIVE To explore the mechanism of Compound lizard powder reducing cisplatin resistance in gastric cancer by regulating glycolytic activity based on phosphoinositide 3-kinase（PI3K）/protein kinase B（Akt） signaling pathway. METHODS Human gastric cancer MKN45 and MKN45/DDP （cisplatin-resistant） cells were cultured in vitro and intervened with different mass concentrations of cisplatin （0.1， 0.2， 0.4， 0.8， 1.6， 3.2 μg/mL） to detect the survival rate， half inhibitory concentration （IC50） and drug resistance index. MKN45/DDP cells were inoculated subcutaneously in the right anterior axilla of nude mice to prepare a transplanted tumor model of gastric cancer. After successful modeling， they were randomly divided into model group， cisplatin group （0.002 g/kg）， Compound lizard powder group （2.8 g/kg） and combination group （the same dose as each single drug group）， with 8 nude mice in each group. Each administration group was given relevant solution， twice a week （cisplatin， i.p.） or twice a day （Compound lizard powder， i. g.）， for 4 consecutive weeks. During the experiment， the body weight of nude mice was monitored， and tumor volume and inhibitory rate of tumor were calculated. The levels of inflammatory factors （tumor necrosis factor- α， interleukin-6） in tumor tissue， the mRNA and protein expressions of multidrug resistance-associated protein 1 （MRP1）， P-glycoprotein （P-gp）， glucose transporter-1 （GLUT1） and lactate dehydrogenase A （LDHA）， as well as the protein expressions of PI3K， phosphorylated PI3K （p-PI3K）， Akt， phosphorylated Akt （p-Akt）， hexokinase-2 （HK2） and pyruvate kinase M2 （PKM2） were all detected. RESULTS With the intervention of different concentrations of cisplatin， the survival rate of MKN45/DDP-resistant cells was significantly higher than that of MKN45 parent cells （P＜0.05）. IC50 value of MKN45/DDP and MKN45 cells were（1.052 0±0.221 9） and （0.372 1±0.238 0）μg/mL， and the drug resistant index was 2.827. Compared with the model group， cisplatin group， Compound lizard powder group and combination group all had certain inhibitory effects on the tumor growth in nude mice； the inhibitory rates of tumor increased significantly （P＜0.05）； the levels of inflammatory factors， the mRNA and protein expressions of MRP1， P-gp， GLUT1 and LDHA （except for cisplatin group）， the phosphorylation levels of PI3K and Akt protein （except for cisplatin group） as well as the protein expressions of HK2 and PKM2 were decreased significantly， while the combination group was significantly better than the cisplatin group （P＜0.05）. CONCLUSIONS Compound lizard powder may inhibit tumor growth in transplanted tumor model nude mice with gastric cancer-resistant cells by reducing the secretion of tumor-related inflammatory factors， inhibiting the expression of glycolysis， drug resistance-related proteins and genes， inhibiting the activation of the PI3K/Akt signaling pathway， thus having a certain effect of enhancing cisplatin efficacy and reversing drug resistance. |
| 期刊： | 2024年第35卷第10期 |
| 作者： | 程翻娥；李铮；刘彩月；师小茜；李卫强 |
| AUTHORS： | CHENG Fan’e，LI Zheng，LIU Caiyue，SHI Xiaoqian，LI Weiqiang |
| 关键字： | 复方蜥蜴散；胃癌；顺铂耐药；糖酵解；PI3K/Akt信号通路 |
| KEYWORDS： | Compound lizard powder； gastric cancer； cisplatin resistance； glycolysis； PI3K/Akt signaling pathway |
| 阅读数： | 30 次 |
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