Enhancement of ovarian cancer chemotherapy by delivery of multidrug-resistance gene small interfering RNA using tumor targeting Salmonella

Abstract

Aim The aim of this study was to observe the effect of attenuated Salmonella typhi as a tumor-targeting delivery vector for multidrug-resistance gene (MDR1) small interfering RNA (siRNA). Material and Methods The cisplatin (DDP)-resistant ovarian cancer cell line SKOV-3/DDP was established by treatment with gradually increasing concentrations of cisplatin. MDR1â€'siRNA expression plasmid containing short hairpin RNA (shRNA) of MDR1 gene was constructed and transformed into attenuated Salmonella typhi strainâ€'SL7207. SKOV-3/DDP cells were incubated with recombinant Salmonella and then subjected to analysis of MDR1 expression by real-time polymerase chain reaction and Western blot. SKOV-3/DDP tumor-bearing mice were established by subcutaneously injecting BALB/c nude mice with SKOV-3/DDP cells, and were orally inoculated with Salmonella carrying MDR1â€'siRNA plasmid and simultaneously injected intraperitoneally with cisplatin. Tumor growth and mouse survival were observed. Results Compared with parental cell line, the DDP-resistant SKOV-3/DDP cells expressed a much higher level of MDR1. The expression of MDR1 in SKOV-3/DDP cells infected with the Salmonella strain bearing MDR1â€'siRNA plasmid in vitro was detected to be downregulated and DDP tolerance of these cells was reversed. Tumor-bearing nude mice that were orally receiving recombinant Salmonella experienced a slow tumor growth and became more sensitive to DDP. Conclusion Attenuated Salmonella typhi may represent a promising vector for in vivo administration of RNA interference therapy against malignant tumors.