Cantharidin Induces Apoptosis and Promotes Differentiation of AML Cells Through Nuclear Receptor Nur77-Mediated Signaling Pathway

Abstract

Background Acute 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. Purpose This 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/Methods The 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. Results In 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. Conclusions Our 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.

Pharmacological mechanism of mylabris in the treatment of leukemia based on bioinformatics and systematic pharmacology

“…Recent studies have shown that NUR77 , which encodes nuclear receptor subfamily 4 group A member 1, plays an important role in tumor suppression in acute myeloid leukemia. Specifically, Zanyang et al [ 22 ]. reported that cantharidin induced NUR77 expression, significantly inhibiting viability and colony formation in acute myeloid leukemia cell lines.…”

Research Progress of Natural Small-Molecule Compounds Related to Tumor Differentiation

“…Cantharidin (CTD) is the main bioactive component of cantharidin. Recent studies have found that CTD and its derivatives, such as Cantharidic acid and norcantharidin, inhibit leukemia cell proliferation, induce apoptosis, cause cell cycle arrest and enhance the inhibitory effect of chemotherapeutic drugs [ 34 , 35 , 36 ]. Notopterol, a coumarin, is an active monomer extracted from N. incisum with antipyretic, analgesic, and anti-inflammatory properties.…”

Review targeted drug delivery systems for norcantharidin in cancer therapy

“…The molecular formula of CTD is C 10 H 12 O 4 , and the molecular weight is 196.2 g/mol. CTD has been confirmed to exert inhibitory effects on multiple types of cancers, such as liver cancer [ 3 ], acute myeloid leukemia [ 4 ], pancreatic cancer [ 5 ], gastric cancer [ 6 ], breast cancer [ 7 ], osteosarcoma [ 8 ] and lung cancer [ 9 ]. Moreover, it could recruit white blood cells, and may potentiate immune response [ 10 , 11 ].…”