The Effect of Glucuronidation on Curcumin Bioactivity in Bone Metastatic Breast Cancer

Abstract

Breast cancer bone metastasis is characterized by the formation of osteolytic lesions via a TGFβ-dependent vicious cycle. Although there is currently no cure for these lesions, previous studies show that turmeric-derived curcuminoids (CURC) may inhibit this pathway in estrogen receptor negative (ER–) breast cancers. However, most circulating CURC exists in its glucuronidated form (G-CURC), so this study sought to determine the effects of glucuronidation on CURC bioactivity in multiple ER– breast cancer cell lines. The results reveal that CURC decreases phosphorylation of Smad proteins, a key step in the TGFβ signaling pathway, in multiple ER– breast cancer cell lines, while G-CURC has no effect. Furthermore, secretion of TGFβ-induced parathyroid hormone-related protein (PTHrP), a key osteolytic factor in bone metastasis, was inhibited in ER– cells lines following CURC treatment and subsequent TGFβ stimulation. These data suggest that aglycone CURC inhibits the Smad-dependent TGFβ signaling pathway involved in the breast cancer bone metastases and may prevent release of osteolytic factors that aid in bone resorption, while G-CURC is not biologically active. Since GCURC is the predominate form in circulation, future studies are necessary to characterize the means through which G-CURC may be converted to CURC, systematically and/or within the bone microenvironment.