Bone Abstracts

The skeleton is a preferred site of metastasis in patients with advanced breast cancer, and bone loss is one of the major complications of breast cancer metastasis. Therefore, prevention of bone metastasis is clinically important. Our previous observation of an anti-osteoclastic activity of Trolox, a vitamin E analogue, led us to investigate whether Trolox could inhibit bone metastasis and bone destruction induced by breast cancer. I.P. administration of Trolox markedly inhibited osteolytic lesions and preserved bone volume in intracardially injected breast tumor-bearing mice. Histological analysis revealed decreased tumor burden as well as reduced osteoclast number by Trolox treatment. In vitro, Trolox inhibited breast tumor-induced prostaglandin E₂ (PGE₂) synthesis and mRNA expression of RANKL in primary osteoblasts. This reduction of RANKL expression was attributed to a decrease in PGE₂ production, because exogenous addition of PGE₂ to the osteoblasts restored the RANKL expression inhibited by Trolox. Also, we found that Trolox decreased the invasiveness of breast cancer cells through down-regulation of the PGE₂ level. The inhibitory effect of Trolox on PGE₂ synthesis as well as osteoclast formation was confirmed in triple cell co-cultures of breast cancer cells, osteoblasts, and bone marrow cells. In line with the in vitro results, in bone marrow fluid, breast tumor-induced PGE₂ production was decreased by Trolox treatment, which resulted in a reduction of osteolysis and preservation of bone volume in an intra-tibial injection experiment. We have identified that Trolox has anti-metastatic and anti-osteolytic activities on breast cancer metastasis to bone through the suppression of PGE₂ production. Therefore, Trolox may be a potent therapeutic agent for patients with bone metastasis of advanced breast cancer.