Abstract
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.
Highlights
Multiple myeloma (MM) is an aggressive tumor characterized primarily by the accumulation of abnormal plasma cells in the bone marrow
In order to evaluate the anti-myeloma effects of GBT, cell viability was tested in MM cell lines, CD138+ cells separated from MM patients, and in normal B-cells
We have found that GBT suppressed cell growth in several human lung cancer cell lines with IC50 less than 100 nM, while had no obvious cytotoxicity on human normal cell lines [25, 26]
Summary
Multiple myeloma (MM) is an aggressive tumor characterized primarily by the accumulation of abnormal plasma cells in the bone marrow. MM is the second most prevalent hematologic neoplasm in the world, accounting for approximately 1% of neoplastic diseases and 13% of hematological malignancies [1,2,3] It is considered a progressive and incurable disease with a poor prognosis in the majority of patients. Patients with MM frequently develop severe complications, including infection, anaemia, thrombocytopenia, renal failure, and bone disease. This destructive bone disease, which is primarily attributed to enhanced activation of osteoclasts and the infiltration of MM cells in the bone marrow, reduces mobility and increases risk of pathological fractures and paralysis
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