Gasdermin E多肽抑制剂对卵巢癌化疗诱导肠道损伤的改善作用

Effect of gasdermin E on the intestinal damage induced by chemotherapy in ovarian cancer

目的观察gasdermin E(GSDME)多肽抑制剂对顺铂诱导的卵巢癌小鼠肠道损伤的影响。方法采用针对半胱氨酸天冬氨酸特异性蛋白酶3(caspase-3)在GSDME剪切位点的多肽抑制剂Z-DMLD-FMK,将其作用于接受顺铂化疗的卵巢癌小鼠。选择40只6~7周龄雌性C57BL/6小鼠构建模型,随机分为健康组和卵巢癌组(n=20),两组小鼠再随机分为对照组、顺铂组、GSDME抑制剂组和顺铂+GSDME抑制剂组,各亚组5只。健康组小鼠分组后即予以对应药物干预,卵巢癌组小鼠腹腔注射ID8细胞后15 d予以对应药物干预。记录小鼠的体质量变化,利用荧光活体成像技术评估肿瘤成瘤情况,通过苏木精-伊红(H-E)染色观察肠道组织炎症、损伤程度,Western印迹检测肠道组织中GSDME的表达水平。结果GSDME抑制剂对顺铂的抗卵巢癌作用无明显影响。在所有小鼠中,与对照组相比,顺铂组体质量明显下降,肠道组织明显损伤,肠道组织中GSDME表达增加(P<0.001);与顺铂组相比,顺铂+GSDME抑制剂组体质量增加,肠道组织损伤明显减轻,肠道组织中GSDME表达降低(P<0.05)。结论GSDME多肽抑制剂能抑制顺铂诱导的GSDME活化,从而减轻顺铂诱导的小鼠肠道损伤,且对顺铂的抗卵巢癌作用无影响。

Objective To investigate the effect of gasdermin E(GSDME)inhibitor on the intestinal damage of mice with ovarian cancer induced by cisplatin.Methods Z-DMLD-FMK targeted to caspase-3 was administrated to suppress the cleavage and expression of GSDME in mice with ovarian cancer.40 female C57 BL/6 mice aged 6-7 weeks were randomly divided into the normal group and ovarian cancer group(n=20),which were further divided into control group,cisplatin group,GSDME inhibitor group,and cisplatin+GSDME inhibitor group,with 5 mice in each subgroup.Mice in the normal group were treated with cisplatin and GSDME inhibitor separately and jointly after grouping,while mice in the ovarian cancer group were given corresponding intervention 15 days after intraperitoneal injection of ID8 cells.The weight,tumor size,and intestinal damage of mice as well as activation level of GSDME were studied.In vivo fluorescent imaging technology was used to assess tumor size,hematoxylin-eosin(H-E)staining was used to observe the inflammation and intestinal damage of mice,and Western blotting was used to detect the activation level of GSDME in the intestinal tissue.Results The cisplatin significantly reduced the tumor volume of the mice,while GSDME inhibitor had no effect on the tumor burden of the mice.In normal and ovarian cancer mice,the cisplatin group showed a steady decrease in weight,obvious intestinal damage,and increased GSDME activation level in the intestinal tissue compared with the control group(P<0.001).GSDME inhibitor alleviated the weight loss,damage of the digestive tract,and decreased activation level of GSDME which is caused by cisplatin(P<0.05).Conclusion GSDME inhibitor can inhibit the activation level of GSDME in intestinal tissue,thereby reducing intestinal damage and weight loss caused by cisplatin without affecting the chemotherapeutic effect of cisplatin.