Wogonin reverses the drug resistance of chronic myelogenous leukemia cells to imatinib through CXCL12-CXCR4/7 axis in bone marrow microenvironment.

Abstract

BackgroundIn the current study, chronic myeloid leukemia (CML) cells (K562 and KU812) co-cultured with human bone marrow stromal cells (BMSCs) were significantly less sensitive to imatinib (IM). The activation of the CXCL12-CXCR4/7 axis plays an important role in the protective effect of the bone marrow microenvironment (BME) on CML cells. The aim of this study was to investigate whether Wogonin could increase the sensitivity of CML cells to IM when they were co-cultured with BME and explore its underlying mechanism.MethodsA model of CML cells co-cultured with BMSCs was applied in vitro. Flow cytometric, western blotting, immunofluorescence, and RT-PCR assays were used to explore the protective effects of BME on CML cells.ResultsThe results showed that Wogonin could reverse the resistance of CML cells to IM under co-culture conditions by inhibiting Transforming growth factor-β (TGF-β) secretion in the BME, preventing the translocation of Smad4 into nucleus and subsequently reducing the expression of CXCR4 and CXCR7 in CML cells. Moreover, the reverse effect of Wogonin was demonstrated by inhibiting the activation of CXCL12-CXCR4/7 axis via restraining the TGF-β/Smad4/Id3 pathway in vitro. In vivo studies also showed that Wogonin decreased the expression of CXCR4 and CXCR7 in mice bone marrow with low systemic toxicity, and the mechanism was consistent with the in vitro study.ConclusionsWogonin increases the sensitivity of CML cells to IM in BME by controlling the TGF-β/Smad4/Id3 pathway and decreasing the expression of CXCR4 and CXCR7. These results co-supported the point that Wogonin could be a potential candidate of reversal agents on treatment of IM-resistant CML.