title: Zoledronic acid increases docetaxel cytotoxicity through pMEK and Mcl-1 inhibition in a hormone-sensitive prostate carcinoma cell line.
abstract: BACKGROUND
  In prostate cancer, the identification of drug combinations that could reduce the tumor cell population and rapidly eradicate hormone-resistant cells potentially present would be a remarkable breakthrough in the treatment of this disease.
  
  
  METHODS
  The study was performed on a hormone-sensitive prostate cancer cell line (LNCaP) grown in normal or hormone-deprived charcoal-stripped (c.s.) medium. Cell viability and apoptosis were assessed by SRB assay and Annexin-V/TUNEL assays, respectively. Activated caspase-3, p21, pMEK and MCL-1 expression levels were detected by western blotting.
  
  
  RESULTS
  The simultaneous exposure of zoledronic acid [100 microM] and docetaxel [0.01 microM] for 1 h followed by treatment with zoledronic acid for 72, 96 or 120 h produced a high synergistic interaction (R index = 5.1) with a strong decrease in cell viability. This cytotoxic effect was associated with a high induction of apoptosis in both LNCaP and in c.s. LNCaP cells. The induction of apoptosis was paralleled by a decrease in pMEK and Mcl-1 expression.
  
  
  CONCLUSIONS
  The zoledronic acid-docetaxel combination produced a highly significant synergistic effect on the LNCaP cell line grown in normal or hormone-deprived medium, the principal molecular mechanisms involved being apoptosis and decreased pMEK and Mcl-1 expression. This experimentally derived schedule would seem to prevent the selection and amplification of hormone-resistant cell clones and could thus be potentially used alongside standard androgen deprivation therapy in the management of hormone-sensitive prostate carcinoma.
authors.affiliation: Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), Meldola, Italy. francesco.fabbri@ausl.fo.it
authors.forename: Francesco
authors.initials: F
authors.lastname: Fabbri
authors.forename: Giovanni
authors.initials: G
authors.lastname: Brigliadori
authors.forename: Silvia
authors.initials: S
authors.lastname: Carloni
authors.forename: Paola
authors.initials: P
authors.lastname: Ulivi
authors.forename: Ivan
authors.initials: I
authors.lastname: Vannini
authors.forename: Anna
authors.initials: A
authors.lastname: Tesei
authors.forename: Rosella
authors.initials: R
authors.lastname: Silvestrini
authors.forename: Dino
authors.initials: D
authors.lastname: Amadori
authors.forename: Wainer
authors.initials: W
authors.lastname: Zoli
mesh_terms: D017304:Annexin A5 / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002277:Carcinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D004164:Diphosphonates / Q000008:administration & dosage; D000077143:Docetaxel; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D005456:Fluorescent Dyes / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage; D020287:In Situ Nick-End Labeling / Q000379:methods; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors*; D008297:Male; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009376:Neoplasms, Hormone-Dependent / Q000473:pathology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*; D012235:Rhodamines / Q000378:metabolism; D043823:Taxoids / Q000008:administration & dosage; D013997:Time Factors; D000077211:Zoledronic Acid
chemical_list: D017304:Annexin A5; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004164:Diphosphonates; D005456:Fluorescent Dyes; D007093:Imidazoles; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D012235:Rhodamines; D043823:Taxoids; D000077143:Docetaxel; C022027:lissamine rhodamine B; D000077211:Zoledronic Acid; D048369:MAP Kinase Kinase 1; D053148:Caspase 3