Study On The Role Of Traditional Chinese Medicine Or Its Derivative In The Treatment Of Hematological Malignancies And The Associated Molecular Mechanisms

The studies of the effectiveness and the associated mechanism of traditional Chinese medicines promote the emergence of new medicines and new therapeutic strategies.Our group works on the anti-tumor effect of anti-malarial medicine Artemisinin and anti-Acute Promyelocytic Leukemia(APL)“megic bullet”Arsenic Trioxide(ATO)for a long time.Recently,our group synthesized a new water-soluble anti-malarial drug artemisinin derivative,SM1044,and proved its effectiveness on diffuse large B-cell lymphoma(DLBCL).Moreover,when we combined ATO with Tyrosine Kinase Inhibitor(TKI),Philadelphia chromosome positive acute lymphoblastic leukemia(Ph~+ALL)cells were triggered to apoptosis.In this study,we focused on studying the role of SM1044 on DLBCL,as well as ATO combined with second TKI Dasatinib in the treatment of Ph~+ALL.DLBCL is the most common form of non-Hodgkin's lymphoma.R-CHOP is currently the standard therapy for DLBCL,but the prognosis of refractory or recurrent patients remains poor.In this study,we found that the treatment of DLBCL cell lines with SM1044 induces autophagy-dependent apoptosis,which is directed by an accelerated degradation of the anti-apoptosis protein Survivin,via its acetylation-dependent interaction with the autophagy-related protein LC3-?.Additionally,SM1044 also stimulates the de novo synthesis of ceramide,which in turn activates the CaMKK2/AMPK/ULK1 axis,leading to the initiation of autophagy.TKIs have significantly improved the prognosis of Ph~+ALL,one of the most common and aggressive forms of hematological malignancies.However,TKI resistance has remained an unsolved issue.In this study,we investigated the impact of adding ATO on the action of Dasatinib,a second generation TKI,in Ph~+ALL.We showed that ATO cooperates with Dasatinib in both TKI-sensitive and resistant Ph~+ALL cell lines to increase apoptosis and we unraveled the underlying mechanisms.Indeed,combining ATO and Dasatinib leads to severe cell apoptosis by activating the UPR apoptotic IRE1/JNK/PUMA axis,while neutralizing the UPR ATF4-dependent anti-apoptotic axis,activated by ATO alone.Additionally,ATO and Dasatinib in combination repress the expression of several genes,which we previously showed to be associated with shorter survival probability in ALL patients.In conclusion,on one hand,our findings elucidated the mechanism of autophagy-dependent apoptosis in DLBCL cells induced by SM1044,on the other hand,we clarified the mechanism of the combination effect of ATO plus Dasatinib on treating Ph~+ALL.Our study not only provides theoretical basis for treating DLBCL with SM1044 and Ph~+ALL with ATO plus Dasatinib,but also open a new area for the further study of our group.