Tubulin binding small molecule PTC596 and proteasome inhibitor bortezomib cooperatively suppress the growth of myeloma cells

A novel small molecule PTC596 directly binds tubulin and inhibits microtubule polymerization. The clinical development of PTC596 was recently initiated for some cancers. We herein investigated the preclinical efficacies of PTC596 alone and in combination with the proteasome inhibitor bortezomib in the treatment of multiple myeloma (MM). PTC596 inhibited the proliferation of MM cell lines as well as primary MM samples in vitro, and this was confirmed with MM cell lines in vivo. PTC596 synergized with bortezomib to inhibit the growth of MM cells in vitro. This combination therapy exerted synergistic effects in a xenograft model of human MM cell lines in immunodeficient mice and exhibited sufficient tolerability. Mechanistically, treatment with PTC596 induced cycle arrest at G2/M phase followed by apoptotic cell death, associated with the inhibition of microtubule polymerization. RNA sequence analysis also revealed that PTC596 and the combination with bortezomib affected the cell cycle and apoptosis in MM cells. Importantly, endoplasmic reticulum stress induced by bortezomib was enhanced by PTC596, providing one of the underlying mechanisms of action of the combination therapy. Our results indicate that PTC596 alone and in combination with proteasome inhibition are potential novel therapeutic options to improve outcomes in patients with MM.