title: Zoledronic acid cooperates with a cyclooxygenase-2 inhibitor and gefitinib in inhibiting breast and prostate cancer.
abstract: Biphosphonates (BPs) are widely used to inhibit osteoclastic activity in malignant diseases such as bone metastatic breast and prostate carcinoma. Recent studies reported that BPs could also cause a direct antitumor effect, probably due to their ability to interfere with several intracellular signalling molecules. The enzyme cyclooxygenase-2 (COX-2) and the epidermal growth factor receptor (EGFR) play an important role in the control of cancer cell growth and inhibitors of COX-2 and EGFR have shown antitumor activity in vitro and in vivo in several tumor types. We, and others, have previously shown that EGFR and COX-2 may be directly related to each other and that their selective inhibitors may have a cooperative effect. In the present study we have evaluated the combined effect of zoledronic acid, the most potent nitrogen-containing BP, with the COX-2 inhibitor SC-236 and the selective EGFR-tyrosine kinase inhibitor gefitinib, on breast and prostate cancer models in vitro and in xenografted nude mice. We show that combination of zoledronic acid with SC-236 and gefitinib causes a cooperative antitumor effect accompanied by induction of apoptosis and regulation of the expression of mitogenic factors, proangiogenic factors and cell cycle controllers both in vitro and in xenografted nude mice. The modulatory effect on protein expression and the inhibitory effect on tumor growth is much more potent when the three agents are used together. Since studies are ongoing to explore the antitumor effect of zoledronic acid, our results provide new insights into the mechanism of action of these agents and a novel rationale to translate this feasible combination treatment strategy into a clinical setting.
authors.affiliation: Cattedra di Oncologia Medica, Dipartimento di Endocrinologia e Oncologia Molecolare e Clinica, Università di Napoli Federico II, Naples, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Melisi
authors.forename: Rosa
authors.initials: R
authors.lastname: Caputo
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Damiano
authors.forename: Roberto
authors.initials: R
authors.lastname: Bianco
authors.forename: Bianca Maria
authors.initials: BM
authors.lastname: Veneziani
authors.forename: A Raffaele
authors.initials: AR
authors.lastname: Bianco
authors.forename: Sabino
authors.initials: S
authors.lastname: De Placido
authors.forename: Fortunato
authors.initials: F
authors.lastname: Ciardiello
authors.forename: Giampaolo
authors.initials: G
authors.lastname: Tortora
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D052246:Cyclooxygenase 2 Inhibitors / Q000627:therapeutic use*; D004164:Diphosphonates / Q000627:therapeutic use*; D005260:Female; D000077156:Gefitinib; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D011506:Proteins / Q000378:metabolism; D011720:Pyrazoles / Q000627:therapeutic use*; D011799:Quinazolines / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays; D000077211:Zoledronic Acid; D000096926:Benzenesulfonamides
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D004164:Diphosphonates; D000077156:Gefitinib; D007093:Imidazoles; D011506:Proteins; D011720:Pyrazoles; D011799:Quinazolines; D013449:Sulfonamides; D000077211:Zoledronic Acid; C119130:4-(5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide; D000096926:Benzenesulfonamides