title: Zoledronic acid increases cytotoxicity by inducing apoptosis in hormone and docetaxel-resistant prostate cancer cell lines.
abstract: Our aim was to investigate the possible synergistic/additive cytotoxic and apoptotic effects of combination of docetaxel and zoledronic acid (ZA), in PC-3 hormone-refractory prostate cancer cells (HRPC), as well as their docetaxel-resistant sublines. We established a docetaxel-resistant cell line (PC-3R) from PC-3 prostate cancer cells, by intermittent exposure to increasing concentrations of docetaxel in vitro. We then examined the effect of ZA and docetaxel on cell proliferation in both PC-3 and PC-3R prostate cancer cells. XTT cell proliferation assay was used to assess the cytotoxicity, and DNA fragmentation and caspase 3/7 enzyme activity were measured to verify apoptosis. According to our results, docetaxel and ZA were found to be synergistically cytotoxic and apoptotic in both PC-3 and docetaxel-resistant PC-3R cells, in a dose- and time-dependent manner. Combined treatment with docetaxel and ZA synergistically inhibited PC-3 cell growth in vitro through an enhanced induction of cell death, compared with either agent alone; this result was also evident on PC-3R cells. Moreover, we have also demonstrated that apoptosis was induced in prostate cancer cells exposed to these drugs by a concentration-dependent increase in DNA fragmentation and caspase 3/7 enzyme activity. We concluded that ZA, either with docetaxel or not, might still exert some cytotoxicity even in docetaxel-resistant cells. From the clinical perspective, when the clinician decided to change the treatment in the post-docetaxel setting, continuing or combination with ZA may be an effective therapeutic approach for the treatment of HRPC patients.
authors.affiliation: Medical Oncology Clinic, Izmir Katip Celebi University Ataturk Training and Research Hospital, Izmir, Turkey, varolumut@yahoo.com.
authors.forename: Umut
authors.initials: U
authors.lastname: Varol
authors.forename: Mustafa
authors.initials: M
authors.lastname: Degirmenci
authors.forename: Burcak
authors.initials: B
authors.lastname: Karaca
authors.forename: Harika
authors.initials: H
authors.lastname: Atmaca
authors.forename: Asli
authors.initials: A
authors.lastname: Kisim
authors.forename: Selim
authors.initials: S
authors.lastname: Uzunoglu
authors.forename: Canfeza
authors.initials: C
authors.lastname: Sezgin
authors.forename: Ulus Ali
authors.initials: UA
authors.lastname: Sanli
authors.forename: Ruchan
authors.initials: R
authors.lastname: Uslu
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004164:Diphosphonates / Q000008:administration & dosage*; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage*; D008297:Male; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D043823:Taxoids / Q000008:administration & dosage*; D000077211:Zoledronic Acid
chemical_list: D004164:Diphosphonates; D007093:Imidazoles; D043823:Taxoids; D000077143:Docetaxel; D000077211:Zoledronic Acid