Zoledronic acid: an unending tale for an antiresorptive agent.
BACKGROUND
Therapy with zoledronic acid (ZOL) is a standard for patients with malignant bone disease. However, the antitumor effects of ZOL are demonstrated only in the preclinical setting and, therefore, they require pharmacological and molecular optimization. ZOL blocks protein isoprenylation, a pleiotropic and basic biochemical process within the cells regulating the activity of several proteins involved in survival and proliferating pathways.


METHODS
The present review will cover different areas of research from pharmacology to cell biology and molecular biology regarding both direct and indirect anticancer effects of ZOL in humans. The challenge in demonstrating the clinical activity of ZOL is mainly based on its pharmacokinetic properties, which are discussed in detail.


RESULTS
New data about the modes to overcome the limitations of ZOL and the following therapeutic strategies to implement its anticancer activity are described: i) development of pharmacological combinations; ii) finding of new molecular targets of ZOL; and iii) development of new pharmacological formulations of ZOL.


CONCLUSIONS
In conclusion, ZOL has still underestimated anticancer properties that require further investigation in both preclinical and clinical settings.
Caraglia
Michele
M
II University of Naples, Department of Biochemistry and Biophysics, Via S. M. Costantinopoli 16, 80138 Naples, Italy. michele.caraglia@unina2.it
Marra
Monica
M
Naviglio
Silvio
S
Botti
Gerardo
G
Addeo
Raffaele
R
Abbruzzese
Alberto
A
D000970:Antineoplastic Agents / Q000627:therapeutic use; D015519:Bone Density / Q000187:drug effects*; D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004164:Diphosphonates / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D006801:Humans; D006878:Hydroxides / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D010087:Oxides / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D017368:Protein Prenylation / Q000187:drug effects; D000077211:Zoledronic Acid
D000970:Antineoplastic Agents; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D006878:Hydroxides; D007093:Imidazoles; D010087:Oxides; D000077211:Zoledronic Acid