%A Yu,Zanyang %A Li,Li %A Wang,Chengqiang %A He,Hui %A Liu,Gen %A Ma,Haoyue %A Pang,Lei %A Jiang,Mingdong %A Lu,Qianwei %A Li,Pan %A Qi,Hongyi %D 2020 %J Frontiers in Pharmacology %C %F %G English %K Cantharidin,Nur77,AML,differentiation,Apoptosis %Q %R 10.3389/fphar.2020.01321 %W %L %M %P %7 %8 2020-August-28 %9 Original Research %+ Hongyi Qi,College of Pharmaceutical Sciences, Southwest University,China,hongyiqi@swu.edu.cn %# %! Cantharidin induces apoptosis and differentiation %* %< %T Cantharidin Induces Apoptosis and Promotes Differentiation of AML Cells Through Nuclear Receptor Nur77-Mediated Signaling Pathway %U https://www.frontiersin.org/articles/10.3389/fphar.2020.01321 %V 11 %0 JOURNAL ARTICLE %@ 1663-9812 %X BackgroundAcute myeloid leukemia (AML) is a hematopoietic malignancy characterized by uncontrolled proliferation and accumulation of myeloblasts in the bone marrow (BM), blood, and other organs. The nuclear receptors Nur77 is a common feature in leukemic blasts and has emerged as a key therapeutic target for AML. Cantharidin (CTD), a main medicinal component of Mylabris (blister beetle), exerts an anticancer effect in multiple types of cancer cells.PurposeThis study aims to characterize the anti-AML activity of CTD in vitro and in vivo and explore the potential role of Nur77 signaling pathway.Study Design/MethodsThe inhibition of CTD on cell viability was performed in different AML cells, and then the inhibition of CTD on proliferation and colony formation was detected in HL-60 cells. Induction of apoptosis and promotion of differentiation by CTD were further determined. Then, the potential role of Nur77 signaling pathway was assessed. Finally, anti-AML activity was evaluated in NOD/SCID mice.ResultsIn our study, CTD exhibited potent inhibition on cell viability and colony formation ability of AML cells. Moreover, CTD significantly induced the apoptosis, which was partially reversed by Z-VAD-FMK. Meanwhile, CTD promoted the cleavage of caspases 8, 3 and PARP in HL-60 cells. Furthermore, CTD obviously suppressed the proliferation and induced the cell cycle arrest of HL-60 cells at G2/M phase. Meanwhile, CTD effectively promoted the differentiation of HL-60 cells. Notably, CTD transiently induced the expression of Nur77 protein. Interestingly, CTD promoted Nur77 translocation from the nucleus to the mitochondria and enhanced the interaction between Nur77 and Bcl-2, resulting in the exposure of the BH3 domain of Bcl-2, which is critical for the conversion of Bcl-2 from an antiapoptotic to a proapoptotic protein. Importantly, silencing of Nur77 attenuated CTD-induced apoptosis, reversed CTD-mediated cell cycle arrest and differentiation of HL-60 cells. Additionally, CTD also exhibited an antileukemic effect in NOD/SCID mice with the injection of HL-60 cells into the tail vein.ConclusionsOur studies suggest that Nur77-mediated signaling pathway may play a critical role in the induction of apoptosis and promotion of differentiation by CTD on AML cells.