Differential Effects of a First-in-Class IKKα Inhibitor on Trabecular and Cortical Bone in a Human Prostate Cancer Xenograft Model

IKK α , a key component of canonical and non-canonical NFκB signalling, is implicated in prostate cancer and bone metabolism. Here, we validated the anti-proliferative effects of selected molecules from a series of first-in-class IKK α inhibitors against a panel of human prostate cancer models and then showed that the potent anti-tumour and highly IKK α -selective SU 1349 reduced the ability of human PC3 cells to migrate and invade in vitro, induce osteolysis ex vivo, and cause trabecular bone loss in mice. Paradoxically, mice treated with SU 1349 exhibited cortical bone loss. Histomorphometrical in vivo and functional in vitro studies confirmed that SU 1349 suppressed osteoclastogenesis, but both enhanced and reduced osteoblast number and activity. Mechanistically, despite SU 1349 being an inhibitor with a significant selectivity for IKK α over IKK β , it inhibited both canonical and non-canonical NFκB signalling in PC3 cells, osteoclasts, and osteoblasts, and reduced the levels of several PC3-secreted, NFκB-regulated factors. This study suggests that IKK α inhibitors could be of therapeutic value in the treatment of prostate cancer-induced osteolysis. However, osteoblast inhibition may limit their usefulness as osteoprotective agents.