Deciding appropriate therapy for multiple myeloma (MM) is challenging because of 
the occurrence of multiple chromosomal changes and the fatal nature of the 
disease. In the current study, gamabufotalin (GBT) was isolated from toad venom, 
and its tumor-specific cytotoxicity was investigated in human MM cells. We found 
GBT inhibited cell growth and induced apoptosis with the IC50 values <50 nM. 
Mechanistic studies using functional approaches identified GBT as an inhibitor 
of c-Myc. Further analysis showed that GBT especially evoked the ubiquitination 
and degradation of c-Myc protein, thereby globally repressing the expression of 
c-Myc target genes. GBT treatment inhibited ERK and AKT signals, while 
stimulating the activation of JNK cascade. An E3 ubiquitin-protein ligase, WWP2, 
was upregulated following JNK activation and played an important role in c-Myc 
ubiquitination and degradation through direct protein-protein interaction. The 
antitumor effect of GBT was validated in a xenograft mouse model and the 
suppression of MM-induced osteolysis was verified in a SCID-hu model in vivo. 
Taken together, our study identified the potential of GBT as a promising 
therapeutic agent in the treatment of MM.