Emerging anti-cancer molecular mechanisms of aminobisphosphonates

Bone metastases are common in patients with many types of cancer, especially breast and prostatecancer — in which the incidence is approximately 70% among patients with advanced metastaticdisease. Aminobisphosphonates (NBPs) have entered clinical practice in the treatment of bonemetastases from several neoplasms, including breast and prostate adenocarcinoma, as a result oftheir anti-resorption properties. However, evidence has accumulated on the direct anti-tumoureffects of NBPs. This review describes the metabolic pathways that are putative molecular targets ofNBPs and that are involved in the prenylation processes of several intracellular small GTP-bindingproteins (ras family related proteins). The latter regulate the intracellular survival and proliferativepathways of tumour cells and could be the intracellular molecular targets of the NBPs responsiblefor the direct anti-cancer effects, even if definitive conclusions cannot be drawn at present. Differentmechanisms have been reported to account for the anti-neoplastic action of NBPs, including: theinduction of apoptosis; cell cycle perturbations; and anti-invasive, anti-migration and anti-angiogeniceffects. Moreover, this review describes the most important clinical studies that demonstrate theactivity of NBPs in preventing skeletal-related events induced by bone metastases. The mainpharmacokinetic pitfalls of NBPs are described, and methods of overcoming these pitfalls throughthe use of liposome vehicles are proposed. Finally, the principal pre-clinical studies on theinteraction between NBPs and other biological agents are also described; these studies may enablereductions in the in vivo NBP concentrations required to achieve anti-tumour activity. To date,however, the real molecular targets of NBPs are not completely known and new technologicalplatforms are required in order to detect them and to develop new anti-cancer strategies based onthe use of NBPs.