RT Journal Article
SR Electronic
T1 siRNA Targeting of <em>MDR1</em> Reverses Multidrug Resistance in a Nude Mouse Model of Doxorubicin-resistant Human Hepatocellular Carcinoma
JF Anticancer Research
JO Anticancer Res
FD International Institute of Anticancer Research
SP 2675
OP 2682
VO 36
IS 6
A1 HAITAO YANG
A1 RUI DING
A1 ZHONG TONG
A1 JUN HUANG
A1 LEI SHEN
A1 YU SUN
A1 JING LIAO
A1 ZHIJIAN YANG
A1 ROBERT M. HOFFMAN
A1 CHENGHONG WANG
A1 XIANGLING MENG
YR 2016
UL http://ar.iiarjournals.org/content/36/6/2675.abstract
AB Aim: To investigate the effects of vector-based small interfering RNA (siRNA) targeting MDR1 on the reversal of multidrug resistance in a mouse model of doxorubicin (DOX)-resistant human hepatocellular carcinoma. Materials and Methods: Three siRNAs plasmid vectors (MDR1 siRNA1, MDR1 siRNA2 and MDR1 siRNA3) targeting MDR1 were constructed and transfected into DOX-resistant human hepatocellular carcinoma Bel-7402/ADM cells. The expression of MDR1 mRNA and P-glycoprotein (P-gp) was detected with RT-PCR and western blotting, respectively. A nude mouse model of DOX-resistance was established with untransfected Bel-7402/ADM or Bel-7402/ADM transfected with MDR1 siRNA (Bel-7402/ADMsi). The nude mice with tumors from untransfected Bel-7402/ADM cells were treated with either saline (Group 1); intravenous DOX (Group 2); or the combination of intra-tumoral MDR1 siRNA and intravenous DOX (Group 3). The nude mice with tumors from Bel-7402/ADMsi cells were treated with intravenous DOX (Group 4). DOX and MDR1 siRNA were administered twice a week at 20 mg/kg/dose and 9.8 mg/kg/dose, respectively. Tumor growth was measured to assess reversal of multidrug resistance by MDR1 siRNA. Results: MDRl mRNA and P-gp expression of Bel-7402/ADM cells was reduced by transfection of three siRNAs with different silencing efficiency (p&lt;0.05). DOX treatment (Group 4) resulted in significant reduction in tumor size in the Bel-7402/ADMsi tumor model (p&lt;0.05), indicating reversal of multidrug resistance in tumor by MDR1 siRNA. However, the combination treatment of intratumoral MDR1 siRNA and DOX (Group 3) showed no significant anti-tumor efficacy in the untransfected Bel-7402/ADM (p&gt;0.05) tumor model, suggesting poor in vivo transfection efficiency of MDR1 siRNA. Analysis of the tumor samples showed the reduced expression level of MDR1 mRNA and P-gp was due to efficacy of MDR1 siRNA. Conclusion: In vitro transfection of siRNAs' vectors targeting the MDR1 gene can effectively silence MDR1 mRNA and P-gp expression in DOX-resistant human hepatocellular carcinoma Bel-7402/ADM cells that resulted in reversal of multidrug resistance to DOX in the xenograft tumor model.