Apatinib Exhibits Cytotoxicity to Acute Myeloid Leukemia Cell Via Targeting VEGFR2-Mediated Pro-Survival Signaling and Angiogenesis

Objective:Vascular permeability contributes to disease progression and drug resistance in acute myeloid leukemia (AML). Thus, targeting angiogenetic signaling is a promising strategy for the treatment of AML, especially for relapsed and resistant diseases. The aim of the present study was to evaluate the potential efficacy of Apatinib, a novel receptor tyrosine kinase inhibitor selectively targeting VEGFR-2, in AML treatment. Method: CCK8 and Annexin V/PI assay were separately utilized to determine the IC50 value and apoptosis of AML cell lines. The cytotoxic efficacy of Apatinib against primary AML cells from 57 adult patients and 11 normal counterparts were then evaluated by analysis of apoptosis. Using JC-1 kit to detect the mitochondrial membrane potential, and western bolting and mass cytometry assay as well as immunohistochemistry to explore the underlying mechanism. Finally, the anti-leukemia activity was further evaluated in in vivo xenograft models. Results: Our findings demonstrated apatinib markedly inhibited proliferation and promoted apoptosis in AML cell lines. Similarly, apatinib showed cytotoxicity against primary AML cells while harmless to normal hematopoiesis. Its effect was correlated with several clinical features such as NPM1 mutation, extramedullary infiltration, relapse/refractory disease and FAB subtypes. Additionally, apatinib suppressed AML cells growth and attenuated angiogenesis in xenograft model. Mechanistically, apatinib-induced cytotoxicity was closely associated with the inhibition of VEGFR2-meidated Src/STAT3 and AKT/mTOR pathway and the induction of mitochondrial-mediated apoptosis. Conclusion: In summary, apatinib exerts anti-leukemia function via targeting VEGFR2-triggered pro-survival signaling and angiogenesis, providing a rationale for clinical trials of apatinib in the treatment of AML. Disclosures No relevant conflicts of interest to declare.