Review Bisphosphonates' antitumor activity: An unravelled side of a multifaceted drug class Philippe Clézardin ⁎ INSERM, Research Unit U664, University of Lyon-1, Faculty of Medicine Lyon-Est (domaine Laennec), rue Guillaume Paradin, 69372 Lyon Cedex 08, France abstract article info Article history: Received 12 June 2010 Revised 11 July 2010 Accepted 12 July 2010 Available online 22 July 2010 Edited by: T. Jack Martin Keywords: Bisphosphonate Metastasis Breast Gamma delta T Angiogenesis Bisphosphonates, especially nitrogen-containing bisphosphonates (N-BPs), are widely used to preserve and improve bone health in patients with cancer because they inhibit osteoclast-mediated bone resorption. In addition to their effects on bone, preclinical evidence strongly suggests that N-BPs exert anticancer activity without the involvement of osteoclasts by interacting with macrophages, endothelial cells and tumor cells, and by stimulating the cytotoxicity of γδ T cells, a subset of human T cells. This review examines the current insights and fronts of ongoing preclinical research on N-BPs' antitumor activity. © 2010 Elsevier Inc. All rights reserved. Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71 Effects of N-BPs on tumor cells in vitro . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72 Effects of N-BPs on experimental angiogenesis in vitro and in vivo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73 Effects of N-BPs in animal models of cancer and metastasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73 Animal models of cancer-induced bone lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73 Animal models of soft tissue tumors and visceral metastasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74 Effects of N-BPs on human Vγ9Vδ2 T cell cytotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76 Concluding comments and future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78 Introduction Bisphosphonates are degradation-resistant structural analogues of pyrophosphates, which are all characterized by two phosphonate groups linked to a central carbon atom, forming a P-C-P structure [1]. Two side chains (referred to as R 1 and R 2 ) are covalently bound to the carbon atom of the common P-C-P structure. The P-C-P backbone and the R 1 side chain (preferably a hydroxyl group) allow the bispho- sphonates to bind avidly to hydroxyapatite crystals [1]. Consistent with these data, studies in animals have shown that bisphosphonates are primarily deposited in newly formed bone and under osteoclasts [2], where they inhibit osteoclast-mediated bone resorption [1]. In this respect, the anti-resorptive potency of bisphosphonates may be broadly classified on the basis of whether or not they contain a nitrogen moiety in their R 2 side chain; nitrogen-containing bispho- sphonates (N-BPs) being more potent than non-N-BPs in inhibiting bone resorption [1]. Non-N-BPs (e.g., etidronate and clodronate) are metabolically incorporated into non-hydrolyzable analogues of ATP (AppCp) that leads to inhibition of mitochondrial ADP/ATP translocase and osteoclast apoptosis [3] (Fig. 1). N-BPs (e.g., pamidronate, alendro- nate, risedronate, ibandronate, zoledronate and minodronate) specif- ically interfere with farnesyl pyrophosphate synthase (FPPS), a key enzyme in the mevalonate pathway that catalyzes the condensation of isopentenyl pyrophosphate (IPP) to dimethylallyl pyrophosphate (DMAPP) to form farnesyl pyrophosphate (FPP) [4,5] (Fig. 1). In addition, N-BPs interfere with an enzyme that is downstream of FPPS in the mevalonate pathway, the geranylgeranyl pyrophosphate synthase (GGPPS) [6] (Fig. 1). As a consequence, the covalent Bone 48 (2011) 71–79 ⁎ Fax: +33 478 778 772. E-mail address: philippe.clezardin@inserm.fr. 8756-3282/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.bone.2010.07.016 Contents lists available at ScienceDirect Bone journal homepage: www.elsevier.com/locate/bone