Apatinib Combined With Chidamide Induces Apoptosis In T-cell Acute Lymphoblastic Leukemia Cells Via Disrupting Energy Metabolism And Induction Of Mitochondrial Apoptotic Pathway

T-cell acute lymphoblastic leukemia(T-ALL)is one of the most deadly and aggressive hematological malignancies.Although the combination of high dose and long course of chemotherapy has significantly improved the prognosis of T-ALL,the success of the treatment is limited with 30～40%of paediatric and over 50%of adult patients with T-ALL exhibiting resistance to therapy and relapse.Enhanced molecular understanding of T-ALL biology will ultimately facilitate a targeted therapy driven approach that can improve survival of refractory T-ALL patients.The VEGFR-2 inhibitor Apatinib could inhibit cell growth and promote apoptosis in T-ALL cell lines in a dose-and time-dependent manner,but it requires the much higher dose than the clinical proposed dosage,and recent study demonstrated that VEGFR2 signaling decreases the sensitivity of leukemia cells to chemotherapy by reprogramming mitochondrial bioenergetic and apoptotic functions.Based on the findings,we speculate whether clinical dose VEGFR-2 inhibitor Apatinib could increase the apoptotic response of T-ALL cells to conventional agents by altering the mitochondrial metabolism.Chidamide,a novel HDAC inhibitor has been approved for the treatment of T-cell lymphoma,which is used as a single agent or in combination with other conventional agents to treat leukemia.However,it was not as good as expected regarding the clinical response of HDAC inhibitors in T-ALL patients.Therefore,this study mainly explored the synergistic effect and mechanism of clinical dose Apatinib combined with Chidamide in T-ALL cells.The results showed that Apatinib combined with Chidamide can significantly induce apoptosis in T-ALL cells.Also can reduce Oxygen Consumption Rate(OCR),ATP and activate proteins involved in the mitochondrial apoptotic pathway to induce apoptosis.Furthermore,the mechanism of combination strategies can decrease the function of mitochondrial aerobic metabolism and inhibit the anti-apoptotic signaling pathway by reduce the key enzyme of pyruvate metabolism including PDHA1 and MPC1 in T-ALL cells.In conclusion,we confirmed that the VEGFR-2 inhibitor Apatinib enhances chidamide induced apoptosis in T-cell acute lymphoblastic leukemia.Moreover,the mechanism of co-operation could be associated with apoptotic signaling pathway regulation with energy restriction.