Homoharringtonine enhances bortezomib antimyeloma activity in myeloma cells adhesion to bone marrow stromal cells and in SCID mouse xenografts

Despite the great progress in the treatment, multiple myeloma (MM) still remains incurable. Bortezomib (BTZ), a reversible inhibitor of the 26S proteasome, is very effective against MM but unable to eradicate the MM cells in bone marrow niche eventually causing the disease relapse. Homoharringtonine (HHT) is a known anti-leukemia drug that inhibits MM both in vitro and in vivo. This study aimed to investigate whether HHT could potentiate the anti-tumor activity of BTZ in MM cells cocultured with bone marrow stromal cells and in vivo xenograft models. We found that coculture of myeloma cells with a human stroma cell line significantly decreased the sensitivity of myeloma cells to BTZ treatment. HHT inhibited the proliferation of MM cells and potentiated the anti-myeloma effects of BTZ by inhibition of both canonical and noncanonical NF-κB pathways. HHT also enhanced the anti-myeloma effect of BTZ in vivo xenograft models. Taken together, our data suggest that HHT can enhance the anti-myeloma activity of BTZ both in vitro and in vivo, which may represent a new clinical treatment in MM.