Luteolin attenuates the chemoresistance of osteosarcoma through inhibiting the PTN/β-catenin/MDR1 signaling axis by upregulating miR-384

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.