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<p>Osteosarcoma is a highly malignant primary bone neoplasm that primarily affects pediatric, adolescent, and young adult populations, representing a significant oncologic concern in these age groups globally. Current therapeutic strategies for osteosarcoma primarily involve neoadjuvant and adjuvant chemotherapy, combined with wide surgical resection. While these treatments have significantly improved prognosis in localized osteosarcoma, their clinical utility is limited by substantial systemic toxicity. These limitations underscore the urgent need for novel, more tolerable therapeutic options. Our research was designed to investigate the antiproliferative potential of hellebrigenin, a naturally derived bufadienolide-type cardiac glycoside, against osteosarcoma cells. The cytotoxicity of hellebrigenin was quantified with the MTT assay in human osteosarcoma MG63 cells and non-cancerous Vero epithelial cells. MG63 cells were treated with 7.5&#xa0;µM hellebrigenin for 24&#xa0;h, followed by a series of assays to delineate its antiproliferative effects. Lipid peroxidation (TBARS) and antioxidant assays were conducted to assess hellebrigenin-induced oxidative stress. ROS generation was confirmed using DCFH-DA staining. Apoptotic induction was examined through nuclear, mitochondrial membrane potential, and dual AO/EtBr staining, with further validation by quantifying key apoptotic proteins. To evaluate anti-inflammatory effects, pro-inflammatory cytokine levels were measured. The compound’s anti-metastatic potential was assessed via analysis of the PI3K/AKT signaling axis. Hellebrigenin markedly reduced cell viability in MG63 cells, while showing minimal cytotoxicity in Vero cells. Biochemical and fluorescence-based assays confirmed hellebrigenin-induced oxidative stress and apoptosis in MG63 cells, corroborated by ELISA data on apoptotic markers. Moreover, hellebrigenin significantly downregulated pro-inflammatory cytokines and suppressed PI3K/AKT signaling, indicating strong anti-inflammatory and anti-metastatic properties. Collectively, these findings suggest that hellebrigenin exhibits marked antiproliferative potential in osteosarcoma cells through triggering apoptosis alongside reducing inflammation and metastasis-associated signaling pathways. Further animal model studies are necessary to confirm its therapeutic efficacy as a natural antiproliferative agent for osteosarcoma treatment.</p> Graphical Abstract <p></p>

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Hellebrigenin Induces Apoptosis and Inhibits PI3K/AKT-Mediated Inflammation and Metastasis in Human Osteosarcoma Cells

  • 期刊论文

  • 发表日期：

    2025年10月30日

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  • Yihong Shi,
  • Tianqi Jiang,
  • Zhiming Zhao,
  • Shubin Wang

摘要

Osteosarcoma is a highly malignant primary bone neoplasm that primarily affects pediatric, adolescent, and young adult populations, representing a significant oncologic concern in these age groups globally. Current therapeutic strategies for osteosarcoma primarily involve neoadjuvant and adjuvant chemotherapy, combined with wide surgical resection. While these treatments have significantly improved prognosis in localized osteosarcoma, their clinical utility is limited by substantial systemic toxicity. These limitations underscore the urgent need for novel, more tolerable therapeutic options. Our research was designed to investigate the antiproliferative potential of hellebrigenin, a naturally derived bufadienolide-type cardiac glycoside, against osteosarcoma cells. The cytotoxicity of hellebrigenin was quantified with the MTT assay in human osteosarcoma MG63 cells and non-cancerous Vero epithelial cells. MG63 cells were treated with 7.5 µM hellebrigenin for 24 h, followed by a series of assays to delineate its antiproliferative effects. Lipid peroxidation (TBARS) and antioxidant assays were conducted to assess hellebrigenin-induced oxidative stress. ROS generation was confirmed using DCFH-DA staining. Apoptotic induction was examined through nuclear, mitochondrial membrane potential, and dual AO/EtBr staining, with further validation by quantifying key apoptotic proteins. To evaluate anti-inflammatory effects, pro-inflammatory cytokine levels were measured. The compound’s anti-metastatic potential was assessed via analysis of the PI3K/AKT signaling axis. Hellebrigenin markedly reduced cell viability in MG63 cells, while showing minimal cytotoxicity in Vero cells. Biochemical and fluorescence-based assays confirmed hellebrigenin-induced oxidative stress and apoptosis in MG63 cells, corroborated by ELISA data on apoptotic markers. Moreover, hellebrigenin significantly downregulated pro-inflammatory cytokines and suppressed PI3K/AKT signaling, indicating strong anti-inflammatory and anti-metastatic properties. Collectively, these findings suggest that hellebrigenin exhibits marked antiproliferative potential in osteosarcoma cells through triggering apoptosis alongside reducing inflammation and metastasis-associated signaling pathways. Further animal model studies are necessary to confirm its therapeutic efficacy as a natural antiproliferative agent for osteosarcoma treatment.

Graphical Abstract