Pharmacologic inhibitors of IκB kinase suppress growth and migration of mammary carcinosarcoma cellsin vitroand prevent osteolytic bone metastasisin vivo

Abstract

The NF-κB signaling pathway is known to play an important role in the regulation of osteoclastic bone resorption and cancer cell growth. Previous studies have shown that genetic inactivation of IκB kinase (IKK), a key component of NF-κB signaling, inhibits osteoclastogenesis, but the effects of pharmacologic IKK inhibitors on osteolytic bone metastasis are unknown. Here, we studied the effects of the IKK inhibitors celastrol, BMS-345541, parthenolide, and wedelolactone on the proliferation and migration of W256 cells in vitro and osteolytic bone destruction in vivo. All compounds tested inhibited the growth and induced apoptosis of W256 cells as evidenced by caspase-3 activation and nuclear morphology. Celastrol, BMS-345541, and parthenolide abolished IL1β and tumor necrosis factor α-induced IκB phosphorylation and prevented nuclear translocation of NF-κB and DNA binding. Celastrol and parthenolide but not BMS-345541 prevented the activation of both IKKα and IKKβ, and celastrol inhibited IKKα/β activation by preventing the phosphorylation of TAK1, a key receptor-associated factor upstream of IKK. Celastrol and parthenolide markedly reduced the mRNA expression of matrix metalloproteinase 9 and urinary plasminogen activator, and inhibited W256 migration. Administration of celastrol or parthenolide at a dose of 1 mg/kg/day suppressed trabecular bone loss and reduced the number and size of osteolytic bone lesions following W256 injection in rats. Histomorphometric analysis showed that both compounds decreased osteoclast number and inhibited bone resorption. In conclusion, pharmacologic inhibitors of IKK are effective in preventing osteolytic bone metastasis in this model and might represent a promising class of agents to the prevention and treatment of metastatic bone disease associated with breast cancer.

Celastrus and Its Bioactive Celastrol Protect against Bone Damage in Autoimmune Arthritis by Modulating Osteoimmune Cross-talk

“…In this context, our results showing the bone damage-protective effects of celastrus/celastrol in the AA model are supported by those of studies examining the effects of celastrol in tumor models. For example, celastrol was shown to suppress the osteolytic bone metastasis associated with experimentally induced breast cancer (61); celastrol suppressed trabecular bone loss and reduced the number and size of osteolytic bone lesions in rats (61). Furthermore, celastrol inhibited RANKL-induced signaling in osteoclasts, caused osteoclast apoptosis, and inhibited osteoclast formation (62).…”

Discovery of non-ETS gene fusions in human prostate cancer using next-generation RNA sequencing

“…Despite the growing body of literature showing that IKK-beta exerts crucial function in inflammation, immunity, and cancer, the role of IKK-beta in human prostate cancer cells remains largely elusive. Recent evidence using small molecule inhibitors of IKK such as BMS-345541, MLX 105, or PS1145 suggests IKK activity as a potential target for therapy in various malignancies (Lam et al 2005;Yang et al 2006;Yemelyanov et al 2006;Idris et al 2009;Jinawath et al 2010). Our analysis now provides evidence that IKK-beta activity is important for maintaining the integrity of prostate cancer cells.…”

Targeting Apoptosis Pathways in Cancer and Perspectives with Natural Compounds from Mother Nature

“…Thereupon, the natural compounds have been examined in human and recently reported. Parthenolide was found to inhibit the expression of matrix metalloproteinase-9 and urinary plasminogen activator and the migration of carcinoma cells in vitro, as well as osteolytic bone metastasis associated with breast cancer in vivo (149). At doses up to 4 mg daily by oral capsule to treat fever, it is barely detectable in the plasma (150) .…”