The NFκB pathway plays an important role in inflammation and bone remodelling. The sesquiterpene lactone parthenolide (PTN) is a potent NFκB inhibitor, and previous studies showed that PTN reduces osteolysis associated with breast cancer (Idris et al. 2009). Here, we took advantage of an in vivo supracalvarial injection, ex vivo mouse calvarial organ and in vitro co-culture models to assess the cell-autonomous effects of PTN on cancer cell-induced osteolysis. MicroCT analysis of calvarial bone showed that human MDA-231, mouse 4T1 and rat MLL cancer cells caused osteolysis when co-cultured with mouse calvaria, and these effects were significantly reduced by PTN (1 μM; MDA-231, 56%; 4T1, 62%; MLL, 36%, increase in BV/TV, P<0.05). Treatment of osteoblasts with PTN (1 μM) increased alkaline phosphatase levels (62% increase, P<0.01), enhanced bone nodule formation (42% increase, P<0.01) and reduced the ability of MDA-231 and 4T1 conditioned medium to enhance osteoblast support for osteoclastogenesis (MDA-231, 38% and 4T1, 24%; reduction, P<0.05) and induce mRNA expression of RANKL (85% reduction, P<0.01) and OPG (76% reduction, P<0.01). Moreover, PTN also inhibited RANKL (IC50; 1.6 μM), MDA-231 (IC50; 1.1 μM), 4T1 (IC50; 1.2 μM), and MLL (IC50; 1.4 μM) induced osteoclast formation in a dose dependent manner. Finally, intraperitoneal administration of PTN (1 mg/kg per day) in adult immune-competent mice prior to supracalvarial injection of MDA-231 conditioned medium caused a significant reduction of osteolysis (37% increase in BV/TV, P<0.05). This effect was found to be strongly associated with inhibition of NFκB-mediated pro-inflammatory actions of the bone- and tumour-derived factors RANKL, TGFβ, IL8, and CXCL1 that alter the balance of osteoblasts and osteoclasts in bone metastatic microenvironment. Collectively, our findings suggest that, due to the combined anti-resorptive and osteoanabolic effects, PTN, or similar sesquiterpene lactones currently in clinical trials for advanced solid tumors, has potential as a promising therapeutic agent for the treatment of osteolytic bone disease.
Disclosure: The authors declared no competing interests.