Cutting the limits of aminobisphosphonates: new strategies for the potentiation of their anti-tumour effects.

Therapy with aminobisphosphonate (N-BPs), and zoledronic acid (ZOL) especially, has become a standard of care for patients with malignant bone disease. In addition, preclinical and preliminary clinical data suggest that N-BPs exert their direct or indirect anti-tumour effects on cancer growth factor release, cancer cell adhesion, invasion and viability, cancer angiogenesis and cancer cell apoptosis. Here, we will discuss the molecular mechanisms of the antitumour effects induced by ZOL. Despite their well-established in vitro anti-tumour effects N-BPs have not clear in vivo anti-tumour activity in humans. The bases of these discrepancies will be discussed in the text with a special focus on the pharmacokinetic limits of N-BPs. Moreover, the following molecular and pharmacological strategies in order to overcome N-BPs limitations will be described: i) development of pharmacological combinations with other biological agents; ii) finding of new molecular targets of N-BPs; iii) development of new pharmacological formulations of N-BPs. Finally, a new scenario of integrated bio-medicine and pharmacology will be depicted in order to drive the optimization of anti-cancer activity of N-BPs.