title: Chemotherapy sensitivity recovery of prostate cancer cells by functional inhibition and knock down of multidrug resistance proteins.
abstract: BACKGROUND
  In several cancer types, expression of multidrug resistance (MDR) proteins has been associated with lack of chemotherapy response. In advanced prostate cancer (PCa) the use of chemotherapy is mainly palliative due to its high resistance. Previously, we described that MDR phenotype in PCa could be related with high basal and drug-induced expression of MDR proteins P-Glycoprotein (P-Gp), MRP1, and LRP.
  
  
  METHODS
  Using primary cell cultures from PCa patients, we evaluated the effect of function and expression inhibition of P-Gp, MRP1, and LRP, on cell survival after chemotherapy exposure. Cells were treated with specific MDR protein substrates (docetaxel and mitoxantrone for P-Gp, methotrexate for MRP1 and cisplatin for LRP) and pharmacological inhibitors (cyclosporine A, genistein and 3-aminobenzamide), and cell survival was evaluated trough 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and cell cycle analysis. MRP1 activity was evaluated by FACS using the specific inhibitor MK571. Cells were transfected with MDR proteins siRNAs and treated with the corresponding substrates.
  
  
  RESULTS
  PCa cell resistance to MDR protein substrates was partially reversed, decreasing cell survival in around 20%, by treating primary cell cultures with specific pharmacological inhibitors. PCa cells transfected with siRNAs against MDR proteins decreased cell survival when treated with the corresponding drugs. Docetaxel was the most effective chemotherapeutic drug to induce cell death and decrease survival.
  
  
  CONCLUSIONS
  Low chemotherapy response in PCa could be explained, in part, by over-expression of functional MDR proteins. Expression and function of these proteins should be evaluated to enhance efficacy of docetaxel-based therapies of patients with hormone-resistant PCa.
authors.affiliation: Laboratory of Molecular and Cellular Andrology, Physiology and Biophysics Department, Faculty of Medicine, University of Chile, Santiago, Chile.
authors.forename: Catherine
authors.initials: C
authors.lastname: Sánchez
authors.forename: Alejandro
authors.initials: A
authors.lastname: Mercado
authors.forename: Héctor R
authors.initials: HR
authors.lastname: Contreras
authors.forename: Patricia
authors.initials: P
authors.lastname: Mendoza
authors.forename: Juan
authors.initials: J
authors.lastname: Cabezas
authors.forename: Cristian
authors.initials: C
authors.lastname: Acevedo
authors.forename: Christian
authors.initials: C
authors.lastname: Huidobro
authors.forename: Enrique A
authors.initials: EA
authors.lastname: Castellón
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D003131:Combined Modality Therapy; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D006801:Humans; D008297:Male; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D010641:Phenotype; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D034741:RNA, Small Interfering / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D020394:Vault Ribonucleoprotein Particles / Q000235:genetics; D000099187:Major Vault Protein
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D034741:RNA, Small Interfering; D020394:Vault Ribonucleoprotein Particles; D000099187:Major Vault Protein; C421109:multidrug resistance-associated protein 1