Objective:Tumor cell radio-resistance and radiation-induced fibrosis of normal tissues hinder the efficacy of radiotherapy.Nintedanib,a promising therapeutic agent for radiation-induced pulmonary fibrosis and solid tu...Objective:Tumor cell radio-resistance and radiation-induced fibrosis of normal tissues hinder the efficacy of radiotherapy.Nintedanib,a promising therapeutic agent for radiation-induced pulmonary fibrosis and solid tumors,has yet to be investigated in combination with radiotherapy.This study aimed to evaluate the antitumor efficacy of nintedanib in conjunction with radiotherapy.Methods:Tumor-bearing models were utilized to assess the antitumor effects and safety of treatment with nintedanib and radiotherapy in vivo.Reactive oxygen species(ROS),lipid peroxidation assays,and transmission electron microscopy were used to determine the impact of the combined treatment strategy on tumor cell death.Overexpression plasmids and shRNA knockdown techniques were applied to explore and validate the underlying mechanisms.Results:The combination of nintedanib and radiotherapy demonstrated a potent antitumor effect in vivo.Nintedanib suppressed the SLC7A11-mediated GSH synthesis pathway by downregulating ATF4,the expression of which was elevated in response to radiation as an adaptive mechanism.Consequently,nintedanib combined with radiotherapy enhanced ferroptosis in tumor cells.Conclusion:These findings support the use of nintedanib in combination with radiotherapy as an effective,low-toxicity treatment strategy,highlighting the antitumor potential of ATF4-targeted agents.展开更多
基金supported by State Key Program of National Natural Science Foundation of China(Grant No.82130092)the General Program of National Natural Science Foundation of China(Grant No.82373522)the National Natural Science Foundation of China(Grant No.82404196).
文摘Objective:Tumor cell radio-resistance and radiation-induced fibrosis of normal tissues hinder the efficacy of radiotherapy.Nintedanib,a promising therapeutic agent for radiation-induced pulmonary fibrosis and solid tumors,has yet to be investigated in combination with radiotherapy.This study aimed to evaluate the antitumor efficacy of nintedanib in conjunction with radiotherapy.Methods:Tumor-bearing models were utilized to assess the antitumor effects and safety of treatment with nintedanib and radiotherapy in vivo.Reactive oxygen species(ROS),lipid peroxidation assays,and transmission electron microscopy were used to determine the impact of the combined treatment strategy on tumor cell death.Overexpression plasmids and shRNA knockdown techniques were applied to explore and validate the underlying mechanisms.Results:The combination of nintedanib and radiotherapy demonstrated a potent antitumor effect in vivo.Nintedanib suppressed the SLC7A11-mediated GSH synthesis pathway by downregulating ATF4,the expression of which was elevated in response to radiation as an adaptive mechanism.Consequently,nintedanib combined with radiotherapy enhanced ferroptosis in tumor cells.Conclusion:These findings support the use of nintedanib in combination with radiotherapy as an effective,low-toxicity treatment strategy,highlighting the antitumor potential of ATF4-targeted agents.
文摘目的:探讨2型糖尿病(T2DM)小鼠骨形成变化及不同运动对T2DM小鼠骨中环磷酸腺苷(c AMP)/环磷腺苷效应元件结合蛋白(CREB)/激活转录因子4(ATF4)途径和骨形成的影响。方法:40只4周龄C57BL/6雄性小鼠,适应性喂养1周后随机分为正常对照组(ZC,10只)和T2DM造模组(30只)。T2DM造模组小鼠造模成功后随机分为T2DM对照组(TC组,9只)、T2DM游泳组(TS组,9只)和T2DM下坡跑组(TD组,9只)。利用游泳和下坡跑对TS组和TD组小鼠进行8周训练。结束后,取小鼠血清并利用ELISA法检测c AMP浓度;取右侧股骨并利用RT-PCR法检测CREB、ATF4、骨钙素(OC)、骨钙蛋白(OCN)和骨涎蛋白(BSP)的m RNA表达;取右侧胫骨并利用West-blotting法检测CREB蛋白表达;取小鼠骨髓间充质干细胞(BMSCs)并诱导其向骨细胞(OB)分化,利用碱性磷酸酶(ALP)染液对OB染色;取左侧股骨并用Micro-CT对股骨远端BMD进行扫描。结果:与ZC组相比,TC组c AMP浓度下降,CREB、ATF4、OC、OCN和BSP m RNA及CREB蛋白表达均显著下降(P<0.05或P<0.01),OB成骨能力和BMD显著下降(P<0.01)。与TC组相比,TS组OC和OCN m RNA表达上调(P<0.05或P<0.01),OB骨形成能力增强;TD组c AMP浓度下降,CREB、ATF4、OC和OCN m RNA及CREB蛋白表达均显著上调(P<0.05或P<0.01),OB骨形成能力和BMD显著增加(P<0.01)。与TS组相比,TD组c AMP浓度升高,CREB、ATF4和OC的m RNA表达显著上调(P<0.05或P<0.01),OB骨形成能力增强。结论:2型糖尿病小鼠骨形成代谢被抑制;下坡跑通过激活2型糖尿病小鼠骨中c AMP/CREB/ATF4途径,促进成骨细胞分化及骨形成能力,提高骨密度,且其作用效果优于游泳。
