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

Abstract

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). The cisplatin (DDP)-resistant ovarian cancer cell line SKOV-3/DDP was established by treatment with gradually increasing concentrations of cisplatin. MDR1 siRNA expression plasmid containing short hairpin RNA (shRNA) of MDR1 gene was constructed and transformed into attenuated Salmonella typhi strain 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 MDR1 siRNA plasmid and simultaneously injected intraperitoneally with cisplatin. Tumor growth and mouse survival were observed. 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 MDR1 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. Attenuated Salmonella typhi may represent a promising vector for in vivo administration of RNA interference therapy against malignant tumors.