Novel small molecule inhibitor of Kpnβ1 induces cell cycle arrest and apoptosis in cancer cells

Karyopherin beta 1 (Kpn beta 1) is a major nuclear import receptor that mediates the import of cellular cargoes into the nucleus. Recently it has been shown that Kpn beta 1 is highly expressed in several cancers, and its inhibition by siRNA induces apoptotic cancer cell death, while having little effect on non-cancer cells. This study investigated the effect of a novel small molecule, Inhibitor of Nuclear Import-60 (INI-60), on cancer cell biology, as well as nuclear import activities associated with Kpn beta 1, and cancer progression in vivo using cervical and oesophageal cancer cell lines. INI-60 treatment resulted in the inhibition of cancer cell proliferation, colony formation, migration and invasion, and induced a G1/S cell cycle arrest, followed by cancer cell death via apoptosis. Non-cancer cells were minimally affected by INI-60 at concentrations that inhibited cancer cells. INI-60 treatment altered the localisation of Kpn beta 1 and its cargoes, NF kappa B/p65, NFAT and AP-1, and the overexpression of Kpn beta 1 reduced INI-60 cytotoxicity. INI-60 also inhibited KYSE 30 oesophageal cancer cell line growth in vivo. Taken together, these results show that INI-60 inhibits the nuclear import of Kpn beta 1 cargoes and interferes with cancer cell biology. INI-60 presents as a potential therapeutic approach for cancers of different tissue origins and warrants further investigation as a novel anti-cancer agent.