Estrogen receptor transcription and transactivation: Antitumor potential of bisphosphonates

Abstract

Bisphosphonates (BPs), especially those with a nitrogen-containing substituent, are potent inhibitors of osteoclast-mediated bone resorption. They have found extensive clinical use for the treatment of both benign and malignant bone disease. BPs bind to hydroxyapatite and rapidly accumulate in bone where they inhibit the mevalonate biosynthetic pathway, thereby preventing the post-translational prenylation of small GTP-binding proteins and inducing apoptosis in osteoclasts. Recent in vitro studies indicate that BPs also inhibit proliferation, reduce viability and induce apoptosis in several human tumor cell lines. In addition, BPs reduce the invasion of tumor cells through extracellular matrix and impair the binding of tumor cells to bone in vitro. This growing body of evidence suggests that BPs may have the potential to exert direct antitumor effects in vivo, particularly in bone metastases where the local BP concentration is elevated by the enhanced osteoclastic resorption of BP-loaded bone. Several experiments with zoledronic acid (a highly potent BP with an imidazole substituent) administered to mice injected with mammary, prostate or myeloma cancer cells indicate not only inhibition of the tumor-induced osteolysis, but also a reduction in the growth of bone metastases, accompanied by the induction of tumor cell apoptosis. Moreover, zoledronic acid has recently been shown to potently inhibit endothelial cell proliferation in vitro and angiogenesis in mice bearing subcutaneous implants loaded with growth factors. Overall, these findings provide a rationale for testing the antitumor potential of the more potent nitrogen-containing BPs in pilot clinical trials.