Multidrug resistance (MDR) remains a critical bottleneck in successful treatment of osteosarcoma (OS). Luteolin is a flavonoid compound that has been verified to increase the sensitivity to antineoplastic drugs in many tumors. However, its roles in reversing MDR of OS and the potential underlying mechanisms remain largely unknown. In this study, we demonstrated that luteolin enhances cellular chemosensitivity to doxorubicin and cisplatin both in OS cells and xenograft models, and it could increase the miR-384 level and downregulate the PTN expression. Additionally, target analysis confirmed that miR-384 directly modulates PTN expression, and subsequent mechanistic analysis verified that miR-384 could inhibit the MDR of OS cells through suppressing the PTN/β-catenin/MDR1 signaling axis. Further analysis revealed treatment of sensitive MG63 cells with luteolin effectively packaged miR-384 into secreted exosomes and the exosomes could improve doxorubicin response in doxorubicin-resistant MG63/DOX cells. Our study confirmed that luteolin exerts MDR reversal effect against OS cells by regulating PTN expression via miR-384 and it may be a promising therapeutic agent for chemoresistant OS via its targeting of the PTN/β-catenin/MDR1 axis.

多药耐药（MDR）仍然是成功治疗骨肉瘤（OS）的关键瓶颈。木犀草素是一种黄酮类化合物，已被证实可增加许多肿瘤对抗肿瘤药物的敏感性。然而，它在逆转 OS 的 MDR 中的作用和潜在的潜在机制仍然很大程度上未知。在这项研究中，我们证明了木犀草素在 OS 细胞和异种移植模型中增强了细胞对阿霉素和顺铂的化学敏感性，并且它可以增加 miR-384 水平并下调 PTN 表达。此外，靶点分析证实 miR-384 直接调节 PTN 表达，随后的机制分析证实 miR-384 可以通过抑制 PTN/β-catenin/MDR1 信号轴来抑制 OS 细胞的 MDR。进一步分析表明，用木犀草素处理敏感的 MG63 细胞可有效地将 miR-384 包装到分泌的外泌体中，并且外泌体可以改善多柔比星抗性 MG63/DOX 细胞中的多柔比星反应。我们的研究证实，木犀草素通过 miR-384 调节 PTN 表达对 OS 细胞发挥 MDR 逆转作用，它可能通过靶向 PTN/β-catenin/MDR1 轴成为一种有前途的化疗耐药 OS 治疗剂。