Anti-proliferative activity of CGK012 against multiple myeloma cells via Wnt/β-catenin signaling attenuation.

The aberrant activation of Wnt/β-catenin signaling is involved in the development of multiple myeloma; thus, this signaling pathway is a potential target for the development of therapeutics for this malignancy. Here, we performed cell-based chemical screening and found that CGK012, a pyranocoumarin compound, suppressed the Wnt3a-CM-mediated activation of β-catenin response transcription. CGK012 induced β-catenin phosphorylation at Ser33/Ser37/Thr41, leading to proteasomal degradation and reducing the level of intracellular β-catenin. Furthermore, CGK012 consistently decreased the amount of β-catenin and repressed the expression of cyclin D1, c-myc, and axin-2 (downstream target genes of β-catenin) in RPMI-8226 multiple myeloma cells. In addition, CGK012 inhibited the proliferation of RPMI-8226 cells and promoted apoptosis, as indicated by the increase in the population of Annexin V-FITC-stained cells and caspase-3/7 activity. These findings suggest that CGK012 could exert antiproliferative activity against multiple myeloma cells by attenuating the Wnt/β-catenin pathway; thus, it may have potential as a therapeutic agent for multiple myeloma treatment.

Pubmed ID: 28772205