title: Anti-MDR1 siRNA restores chemosensitivity in chemoresistant breast carcinoma and osteosarcoma cell lines.
abstract: BACKGROUND
  Reversion of chemoresistance by inhibition of P-glycoprotein (P-gp) expression may overcome the chemoresistance observed in many cancer types and may allow for improved therapeutic ratio. We investigated whether siRNA specific for ABCB1 (MDR1) mRNA might restore sensitivity to chemotherapy in tumor cell lines known to overexpress the MDR1 gene.
  
  
  METHODS
  MDR1-expressing tumor cell lines were transiently transfected with anti-MDR1 silencing RNA (siRNA) before exposure to doxorubicin or methotrexate. The capacity of siRNA to reduce cell proliferation and increase the IC₅₀ of the tested chemotherapies was investigated.
  
  
  RESULTS
  siRNA down-regulated MDR1 mRNA expression by 50% in breast carcinoma and osteosarcoma cell lines, and significantly inhibited tumor cell proliferation up to 90% (p<0.01), when co-administered with doxorubicin or methotrexate, despite the known chemoresistance of the cell lines. siRNAs reduced the IC₅₀ of doxorubicin and methotrexate by more than 10-fold (p<0.01).
  
  
  CONCLUSIONS
  These results suggest the potential clinical application of anti-MDR1 siRNA to restore chemosensitivity and possibly improve the therapeutic ratio of these cytotoxic drugs.
authors.affiliation: Research Center in Cancerology in Lyon-CRCL, Centre Leon Berard, Lyon, France.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Perez
authors.forename: Christine
authors.initials: C
authors.lastname: Bardin
authors.forename: Chantal
authors.initials: C
authors.lastname: Rigal
authors.forename: Besse
authors.initials: B
authors.lastname: Anthony
authors.forename: Raphaël
authors.initials: R
authors.lastname: Rousseau
authors.forename: Aurelie
authors.initials: A
authors.lastname: Dutour
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001483:Base Sequence; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004317:Doxorubicin / Q000494:pharmacology / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D008727:Methotrexate / Q000494:pharmacology / Q000627:therapeutic use; D012516:Osteosarcoma / Q000188:drug therapy* / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics*
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D034741:RNA, Small Interfering; D004317:Doxorubicin; D008727:Methotrexate