title: The in vitro anti-tumour activity of zoledronic acid and docetaxel at clinically achievable concentrations in prostate cancer.
abstract: Bisphosphonates and chemotherapy have increasingly gained favour in the treatment of metastatic hormone resistant prostate cancer. We investigated whether zoledronic acid, at a concentration found at the bone, would enhance the anti-tumour activity of docetaxel in the hormone resistant prostate cancer cell line PC-3. Cells were exposed to zoledronic acid (1 mM) in combination or in sequence with docetaxel (3 nM). Cell viability, apoptosis and markers for inhibition of the mevalonate pathway were analyzed 48 or 72 hours after drug treatment. Reduction in cell viability and increased apoptosis levels were most pronounced with single agent zoledronic acid. Western blot analysis showed an overall reduction in the proliferation marker Mini chromosome maintenance protein 2 (MCM2) and reduction in caspase-3 precursor for all drug treatments and a marked reduction in Rho A levels with single agent zoledronic acid and zoledronic acid-docetaxel sequence. This study highlights the potency of zoledronic acid, when used at concentrations similar to those found at the bone, in reducing cell viability and causing apoptosis. Clinically, these findings suggest that in patients with bone metastases due to hormone resistance prostate cancer, who are not fit enough for systemic chemotherapy, single agent zoledronic acid may have a direct effect on viability of prostate cancer epithelial cells.
authors.affiliation: Human Cancer Studies Group, School of Medicine, Swansea University, UK. Claire_Morgan70@hotmail.com
authors.forename: Claire
authors.initials: C
authors.lastname: Morgan
authors.forename: Paul D
authors.initials: PD
authors.lastname: Lewis
authors.forename: Rachel M
authors.initials: RM
authors.lastname: Jones
authors.forename: Gianfilippo
authors.initials: G
authors.lastname: Bertelli
authors.forename: Gerry A
authors.initials: GA
authors.lastname: Thomas
authors.forename: Robert C F
authors.initials: RC
authors.lastname: Leonard
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000556:secondary*; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004164:Diphosphonates / Q000494:pharmacology*; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D064111:Minichromosome Maintenance Complex Component 2; D009376:Neoplasms, Hormone-Dependent / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000473:pathology*; D043823:Taxoids / Q000494:pharmacology*; D000077211:Zoledronic Acid
chemical_list: D000970:Antineoplastic Agents; D050071:Bone Density Conservation Agents; D018797:Cell Cycle Proteins; D004164:Diphosphonates; D007093:Imidazoles; D009687:Nuclear Proteins; D043823:Taxoids; D000077143:Docetaxel; D000077211:Zoledronic Acid; C084859:MCM2 protein, human; D064111:Minichromosome Maintenance Complex Component 2