Synergistic Activity And Mechanism Of Cytarabine And Mcl-1 Inhibitor AZD5991 Against Acute Myeloid Leukemia

Acute myeloid leukemia(AML)is a malignant proliferative disease of immature myeloid precursor cells.The median age of onset of AML patient is 67 years.The conventional treatment for AML is "7+3" therapy with cytarabine(Ara-C)and daunorubicin and hematopoietic stem cell transplantation.However,most patients relapse.The 5-year survival rate for AML patients under 60 years is about 26%,and for patients over 60 years is about 8%.Therefore,there is an urgent need to find new treatment for AML to improve the prognosis and quality of life of patients.The main anti-AML mechanism of Ara-C is induction of DNA damage.Additionally,Ara-C can downregulate the anti-apoptotic protein Mcl-1.Mcl-1 is a member of the Bcl-2 family of anti-apoptotic proteins,which is highly expressed in AML cells.Mcl-1 plays an important role in AML cell survival and is considered as a potential target for the treatment of AML.On the other hand,Mcl-1 also plays an important role in DNA damage repair.Accordingly,we propose to use Ara-C and Mcl-1 inhibitors in combination.Ara-C can increase the activity of Mcl-1 inhibitors by decreasing Mcl-1 levels,while Mcl-1 inhibitors can also enhance the activity of cytarabine by interfering with DNA damage repair.To test the above hypothesis,we first investigated the effect of AZD5991,an Mcl-1 inhibitor with clinical application potential,and Ara-C on apoptosis of AML cells when used alone or in combination.Results in AML cell lines as well as in AML clinical sample cells showed that AZD5991 and Ara-C were able to synergistically induce apoptosis in AML cells.The combination of AZD5991 and Ara-C-induced apoptosis is partially caspase and Bak/Bax dependent.Further results showed that Mcl-1 levels had an important effect on AZD5991 activity.AZD5991 was able to upregulate Mcl-1 levels,while Ara-C inhibited AZD5991-induced upregulation of Mcl-1.On the other hand,the combination of AZD5991 and Ara-C was able to induce more DNA damage compared to the single treatments.This study improved the molecular mechanism of Mcl-1 inhibitor synergizing with Ara-C against AML,and provided theoretical and experimental basis for the combination of AZD5991 and Ara-C in the treatment of AML.