Apatinib exhibits cytotoxicity toward leukemia cells by targeting VEGFR2-mediated prosurvival signaling and angiogenesis.

OBJECTIVE:Vascular permeability contributes to disease progression and drug resistance in hematological malignancies, including AML. Thus, targeting angiogenic signaling is a promising treatment strategy, especially for relapsed and resistant AML. The aim of this study was to evaluate the efficacy of apatinib, a novel receptor tyrosine kinase inhibitor that selectively targets VEGFR2. METHODS:Several AML cell lines were exposed to various concentrations of apatinib, and then CCK8 and Annexin V/PI assays were performed to determine IC50 values and apoptosis, respectively. The effect of apatinib against primary AML cells from 57 adult patients and 11 normal controls was also analyzed utilizing an apoptosis assay. Next, we tested the underlying mechanism of apatinib in AML using western blotting and mass cytometry (CyTOF). Finally, the activity of apatinib against tumor growth and angiogenesis was further evaluated in vivo in xenograft models. RESULTS:We found apatinib significantly inhibited growth and promoted apoptosis in AML cell lines in vitro. Similarly, apatinib showed cytotoxicity against primary AML cells but didn't affect normal BMMCs. Its effect was highly correlated with several clinical features, such as NPM1 mutation, extramedullary infiltration, relapsed/refractory disease, and M2 and M5 FAB subtypes. In addition, apatinib suppressed AML growth and attenuated angiogenesis in xenograft models. Mechanistically, apatinib-induced cytotoxicity was closely associated with inhibition of the VEGFR2-mediated Src/STAT3 and AKT/mTOR pathways and induction of mitochondria-mediated apoptosis. CONCLUSION:Apatinib exerts antileukemia effects by targeting VEGFR2-induced prosurvival signaling and angiogenesis, thus providing a rationale for the application of apatinib in AML.