Pharmacological strategies to enhance the response of hepatoblastoma to chemotherapy through MDR1 inhibition

Hepatoblastoma (HB) is the most common malignant liver tumor in children. One-fifth of patients exhibit a poor prognosis due to resistance to conventional chemotherapy, which typically includes doxorubicin. One of the underlying mechanisms is drug efflux through the MDR1 export pump. This study aims to explore pharmacological strategies for sensitizing HB by inhibiting MDR1. A panel of compounds, including established MDR1 inhibitors, natural products, clinically used drugs, and tyrosine kinase inhibitors (TKIs), was employed to inhibit MDR1 activity and enhance the response to doxorubicin. Wild-type (HepG2-WT) and doxorubicin-resistant (HepG2-DR) cells, with enhanced MDR1 expression, as well as murine xenograft models and patient-derived HB cells (HB-303) and organoids, were utilized. Curcumin did not sensitize HepG2-DR cells to doxorubicin, whereas verapamil and simvastatin enhanced doxorubicin cytotoxicity only at toxic concentrations. In contrast, several TKIs, including nilotinib, tivozanib, and, to a lesser extent, cabozantinib, exhibited synergistic effects with doxorubicin in HepG2-DR cells. These TKIs also improved the efficacy of doxorubicin in patient-derived HB organoids, a response that depended on MDR1 expression. Third-generation MDR1 inhibitors (tariquidar, elacridar, and zosuquidar) sensitized HepG2-DR and HB-303 cells at non-toxic nanomolar concentrations in vitro. Furthermore, the combination of doxorubicin and zosuquidar significantly reduced tumor growth even when these were generated from chemoresistant cells. In conclusion, we described pharmacological strategies to enhance HB response to chemotherapy. MDR1 inhibitors, such as zosuquidar, may enable dose reductions of chemotherapeutic agents, whereas the use of synergistic TKIs, such as tivozanib, may improve therapeutic outcomes and minimize adverse effects in children with HB.