康臻姬松茸提取物FA-2-b-β通过靶向HIF-1α调控的糖酵解而增敏肺癌化疗OA

AIM:This study aims to investigate the in vitro and in vivo inhibitory effects of Kangzhen Agaricus blazei Murrill extract FA-2-b-β on lung cancer,focusing on its potential synergistic antitumor and detoxification effects with cisplatin via the hypoxia-inducible factor-1α(HIF-1α)/glycolysis axis.METHODS:Lung carcinoma cell lines and a mouse xenograft tumor model were used.Experimental groups included control,FA-2-b-β monotherapy(50,100 and 200 mg/kg),cisplatin monotherapy,and combination therapy groups.Cell viability,colony formation,migration and in-vasion were assessed using CCK8,colony formation,wound-healing and Transwell invasion assays,respectively.Apopto-sis was detected by Annexin V-FITC/PI staining.Glycolytic metabolism was evaluated by measuring glucose consumption,lactate production and extracellular acidification rate.The expression levels of HIF-1α and glycolytic enzymes[glucose transporter 1(GLUT1),hexokinase 2(HK2),pyruvate kinase M2(PKM2)and lactate dehydrogenase A(LDHA)]were analyzed using RT-qPCR and Western blot.Mechanistic validation was performed using HIF-1α overexpression experi-ments.RESULTS:In vitro,FA-2-b-β significantly inhibited Lewis lung carcinoma(LLC)cell viability,colony forma-tion,migration and invasion in a dose-dependent manner and induced apoptosis.Mechanistic studies revealed that FA-2-b-β significantly down-regulated the mRNA and protein expression levels of HIF-1α,GLUT1,HK2,PKM2 and LDHA,reduced glucose consumption and lactate production,thereby reversing the Warburg effect.Overexpression of HIF-1α res-cues the inhibitory effect of FA-2-b-β on glycolysis.In vivo experiments confirmed that combined FA-2-b-β and cisplatin inhibited xenograft tumor growth more significantly than cisplatin monotherapy(P<0.01)and completely reversed cisplatin-induced side effects,such as body weight loss,demonstrating a notable"synergistic efficacy enhancement and toxicity re-duction"effect.CONCLUSION:These findings indicate that the Agaricus blazei Murrill extract FA-2-b-β suppresses the proliferation and invasion of LLC by inhibiting the HIF-1α/glycolysis signaling axis.Moreover,FA-2-b-β demonstrates a synergistic antitumor effect with cisplatin and effectively mitigates its associated toxicities,highlighting its potential as a promising adjunctive agent in treatment of lung cancer.