Objectives:Chemotherapy-induced lung inflammation limits the efficacy of anticancer therapies such as gefitinib in non-small cell lung cancer(NSCLC).Glutamic acid-leucine-arginine positive(ELR+)CXC chemokines and thei...Objectives:Chemotherapy-induced lung inflammation limits the efficacy of anticancer therapies such as gefitinib in non-small cell lung cancer(NSCLC).Glutamic acid-leucine-arginine positive(ELR+)CXC chemokines and their receptors,CXC chemokine receptor 1 and 2(CXCR1 and CXCR2),mediate both inflammatory responses and tumor progression.This study evaluated the effects of CXCR1/2 antagonism by G31P,a CXC motif chemokine ligand 8(CXCL8)-mutated peptide,alone or in combination with gefitinib,on lung cancer growth and chemotherapyinduced pulmonary inflammation.Methods:Human NSCLC cell lines(A549 and H460)were treated with gefitinib and/or G31P.Cell proliferation,apoptosis,and signaling pathways,including protein kinase B(AKT)and extracellular signal-regulated kinase(ERK)phosphorylation,were evaluated by cell counting kit-8(CCK-8)assay,flow cytometry,and Western blotting.An orthotopic lung tumor xenograft model was established in BALB/c nude mice to evaluate tumor growth,metastasis,cytokine expression,and lung histopathology.A bleomycin-induced lung injury model was also used to assess the anti-inflammatory effects of G31P,with or without gefitinib,by quantitative reverse transcription polymerase chain reaction(qRT-PCR)and flowcytometry of inflammatorymarkers.Results:G31P andGefitinib,either alone or combined,inhibited proliferation and migration of A549 and H460 cells in vitro.Combination treatment effectively reducedAKT and ERKphosphorylation in both cell lines.In vivo,G31Pwith gefitinib significantly suppressed tumor growth,metastasis,and increased apoptosis.G31P decreased CXCL1 and CXCL2,and tumor necrosis factoralpha(TNF-α)mRNA levels,lung hydroxyproline content,and myeloperoxidase(MPO)activity in the lungs of mice.In the bleomycin-induced lung injury model,G31P similarly reduced inflammatory responses.Conclusion:CXCR1/2 antagonismby G31P attenuates chemotherapy-induced pulmonary inflammation and enhances the anti-tumor efficacy of gefitinib in NSCLC.These findings support the therapeutic potential of G31P as an adjuvant to epidermal growth factor receptor tyrosine kinase inhibitors(EGFR-TKIs)to improve clinical outcomes by limiting inflammation.展开更多
基金supported by grants from the National Natural Science Foundation of China,No.U1604174Health Commission of Henan Province-Province and Ministry Co-Construction Project,Nos.20170123,SBGJ202002004Health Commission of Henan Province-Research Innovative Talents Project(51282).
文摘Objectives:Chemotherapy-induced lung inflammation limits the efficacy of anticancer therapies such as gefitinib in non-small cell lung cancer(NSCLC).Glutamic acid-leucine-arginine positive(ELR+)CXC chemokines and their receptors,CXC chemokine receptor 1 and 2(CXCR1 and CXCR2),mediate both inflammatory responses and tumor progression.This study evaluated the effects of CXCR1/2 antagonism by G31P,a CXC motif chemokine ligand 8(CXCL8)-mutated peptide,alone or in combination with gefitinib,on lung cancer growth and chemotherapyinduced pulmonary inflammation.Methods:Human NSCLC cell lines(A549 and H460)were treated with gefitinib and/or G31P.Cell proliferation,apoptosis,and signaling pathways,including protein kinase B(AKT)and extracellular signal-regulated kinase(ERK)phosphorylation,were evaluated by cell counting kit-8(CCK-8)assay,flow cytometry,and Western blotting.An orthotopic lung tumor xenograft model was established in BALB/c nude mice to evaluate tumor growth,metastasis,cytokine expression,and lung histopathology.A bleomycin-induced lung injury model was also used to assess the anti-inflammatory effects of G31P,with or without gefitinib,by quantitative reverse transcription polymerase chain reaction(qRT-PCR)and flowcytometry of inflammatorymarkers.Results:G31P andGefitinib,either alone or combined,inhibited proliferation and migration of A549 and H460 cells in vitro.Combination treatment effectively reducedAKT and ERKphosphorylation in both cell lines.In vivo,G31Pwith gefitinib significantly suppressed tumor growth,metastasis,and increased apoptosis.G31P decreased CXCL1 and CXCL2,and tumor necrosis factoralpha(TNF-α)mRNA levels,lung hydroxyproline content,and myeloperoxidase(MPO)activity in the lungs of mice.In the bleomycin-induced lung injury model,G31P similarly reduced inflammatory responses.Conclusion:CXCR1/2 antagonismby G31P attenuates chemotherapy-induced pulmonary inflammation and enhances the anti-tumor efficacy of gefitinib in NSCLC.These findings support the therapeutic potential of G31P as an adjuvant to epidermal growth factor receptor tyrosine kinase inhibitors(EGFR-TKIs)to improve clinical outcomes by limiting inflammation.
文摘目的:探讨CXCR1/CXCR2受体拮抗剂-G31P对人前列腺癌细胞PC-3增殖的体内外抑制作用。方法:采用CCK-8法研究不同浓度G31P对PC-3细胞体外增殖的抑制作用。建立体内绿色荧光蛋白(Green fluorescent protein,GFP)标记人雄激素非依赖性前列腺癌细胞PC-3裸鼠原位移植瘤模型,观察G31P对裸鼠前列腺癌原位移植瘤的体积、重量的影响。结果:CCK-8结果显示100 ng/ml G31P与对照组相比分别作用1、3 d和5 d差异具有统计学意义(1 d P=0.007、3 d P=0.001、5 d P=0.028,均为P<0.05)。前列腺癌PC-3细胞裸鼠模型体内实验显示,与对照组(100μl N.S)相比,G31P处理组(0.5 mg/kg)从给药第18天起能显著抑制前列腺肿瘤的体积(P=0.026,P<0.05);与对照组相比G31P处理组在抑制前列腺肿瘤重量方面有明显作用(P=0.027,P<0.05)。结论:G31P体内外实验均能抑制人雄激素非依赖性前列腺癌细胞系PC-3的增殖。
基金supported by the Program for Innovative Research Team of Nanchang University, ChinaOpen Foundation of CAS Key Laboratory ofOrganic Solid of China+1 种基金the Natural Science Foundation of Education Department of Jiangxi Province, Chinathe Foundation of TrainingAcademic and Technical Header for Main Majors of Jiangxi Province, China~~
