Ginsenoside Rh4 reverses ABCB1-induced doxorubicin resistance via the PI3Kδ/AKT axis in osteosarcoma

Osteosarcoma (OS), the most common primary malignant bone tumor, notably impacts children and adolescents, presenting a considerable challenge to current therapeutic strategies. The complexity of OS treatment is exacerbated by its propensity for metastasis and the emergence of multidrug resistance (MDR), with resistance to doxorubicin mediated by the ATP-binding cassette transporter ABCB1 posing a significant barrier to effective treatment. This study introduces ginsenoside Rh4, a novel ginsenoside derivative, as a promising agent in reversing doxorubicin resistance in OS by targeting the PI3Kδ/AKT signaling pathway. Through comprehensive in vitro and in vivo assessments, we demonstrate that ginsenoside Rh4 not only effectively mitigates ABCB1-induced doxorubicin resistance by downregulating ABCB1 expression but also disrupts the PI3Kδ/AKT pathway. This dual mechanism enhances doxorubicin's cytotoxicity against resistant OS cells and inhibits cell migration and invasion, suggesting a broader therapeutic role for Rh4. Furthermore, in a xenograft OS model, Rh4, in combination with doxorubicin, significantly curtails tumor progression without augmenting doxorubicin-associated cardiotoxicity. These findings represent the first report of ginsenoside Rh4's ability to overcome MDR in OS, providing a reference for future research on ginsenosides and highlighting its potential as a multi-faceted therapeutic candidate with broader implications for cancer therapy beyond osteosarcoma.