中国药科大学学报2026，Vol.57Issue(1)：68-77,10.DOI:10.11665/j.issn.1000-5048.2025041801
五氟利多靶向HSPA6抑制黑色素瘤生长的作用研究
Inhibitory effect of penfluridol on melanoma growth by targeting HSPA6
摘要
Abstract
This study employed the drug affinity responsive target stability(DARTS)technique to investigate the molecular mechanism of the antipsychotic drug penfluridol against melanoma,revealing the biological pathway to exert its effect on the HSPA6/p53/p21 signaling axis.Experiments such as the methylthiazolyldiphenyl-tetrazolium bromide(MTT)assay and cell colony formation ability assay confirmed that penfluridol could significantly downregulate the expression of cyclin D1 and cyclin-dependent kinase 4(CDK4)in melanoma A375 and B16 cells,induce cell cycle arrest in the G1 phase,and thus inhibit the proliferation of melanoma cells.Meanwhile,the results of Western blot,Hoechst 33342 staining and Annexin V-FITC/PI double staining experiments showed that penfluridol could significantly downregulate the expression of Bcl-2 and upregulate the expression of Bax and cleaved caspase-3,inducing cell apoptosis.Further,the DARTS technique was used to identify heat shock 70 kD protein 6(HSPA6)as the key target bound by penfluridol.Penfluridol activates the p53/p21 pathway by upregulating HSPA6.Knocking down HSPA6 reverses not only the activation of the p53/p21 pathway mediated by penfluridol but also the associated cell cycle arrest and apoptosis.Animal experiments on tumor-bearing mice also confirmed that knocking down HSPA6 could reverse the in vivo anti-t umor activity of penfluridol.This study clarified that penfluridol can inhibit the progression of melanoma by targeting HSPA6 to activate the p53/p21 signaling axis,providing a new perspective for the repositioning of antipsychotic drugs in cancer treatment.关键词
黑色素瘤/五氟利多/周期阻滞/凋亡/HSPA6Key words
melanoma/penfluridol/cell cycle arrest/apoptosis/HSPA6分类
医药卫生引用本文复制引用
葛姮,姜盼,张馨,潘钊海,李德芳..五氟利多靶向HSPA6抑制黑色素瘤生长的作用研究[J].中国药科大学学报,2026,57(1):68-77,10.基金项目
国家中医药管理局科技司-山东省卫生健康委员会共建中医药科技项目(GZY-KJS-SD-2023-094) This study was supported by the Joint Project of the State Administration of Traditional Chinese Medicine and the Health Commission of Shandong Province(GZY-KJS-SD-2023-094) （GZY-KJS-SD-2023-094）
