Inhibitory effect of penfluridol on melanoma growth by targeting HSPA6
10.11665/j.issn.1000-5048.2025041801
- VernacularTitle:五氟利多靶向HSPA6抑制黑色素瘤生长的作用研究
- Author:
Heng GE
1
;
Pan JIANG
;
Xin ZHANG
;
Zhaohai PAN
;
Defang LI
Author Information
1. 滨州医学院中医学院, 山东省高等学校中药活性成分生物合成与靶点发现特色实验室, 烟台264003
- Publication Type:Journal Article 期刊文章
- Keywords:
melanoma;
penfluridol;
cell cycle arrest;
apoptosis;
HSPA6
- From:
Journal of China Pharmaceutical University
2026;57(1):68-77
- CountryChina
- Language:Chinese
-
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-tumor 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.
