Antitumor effects of Stat3-siRNA and endostatin combined therapies, delivered by attenuated Salmonella, on orthotopically implanted hepatocarcinoma

Abstract

Hepatocellular carcinoma (HCC) is one of the most aggressive carcinomas. Limited therapeutic options, mainly due to a fragmented genetic understanding of HCC, and major HCC resistance to conventional chemotherapy are the key reasons for a poor prognosis. Thus, new effective treatments are urgent and gene therapy may be a novel option. Signal transducer and activator of transcription 3 (Stat3) is a highly studied member of the STAT family. Inhibition of Stat3 signaling has been found to suppress tumor growth and improve survival, providing a molecular target for cancer therapy. Furthermore, HCC is a hypervascular tumor and angiogenesis plays a crucial role in tumor growth and metastasis. Thus, anti-angiogenic therapy, combined with inhibition of Stat3, may be an effective approach to combat HCC. We tested the effect that the combination therapy consisting of endostatin (a powerful angiogenesis inhibitor) and Stat3-specific small interfering RNA, using a DNA vector delivered by attenuated S. typhimurium, on an orthotopic HCC model in C57BL/6 mice. Although antitumor effects were observed with either single therapeutic treatment, the combination therapy provided superior antitumor effects. Correlated with this finding, the combination treatment resulted in significant alteration of Stat3 and endostatin levels and that of the downstream gene VEGF, decreased cell proliferation, induced cell apoptosis and inhibited angiogenesis. Importantly, combined treatment also elicited immune system regulation of various immune cells and cytokines. This study has provided a novel cancer gene therapeutic approach.

Nifuroxazide prompts antitumor immune response of TCL-loaded DC in mice with orthotopically-implanted hepatocarcinoma

“…We found that combined application of nifuroxazide and TCL-loaded DC significantly inhibited the expression of p-STAT3 compared with PBS group and nifuroxazide group. Inhibition of the expression of STAT3 increased the T cell infiltration and proliferation (32). Moreover, application of nifuroxazide inhibited the proliferation of MDSC that had an immunosuppressive effect on antitumor responses (17).…”

Delivery of the co-expression plasmid pEndo-Si-Stat3 by attenuated Salmonella serovar typhimurium for prostate cancer treatment

“…Our previous experimental findings and those of other reports (Tian et al 2012; Pawelek et al 1997; Low et al 1999) show that attenuated S. typhimurium can specifically home to tumor cells, possibly via tumor-associated macrophages. The Endostatin and Si-Stat3 combination therapy also activates anti-tumor immune responses (Jia et al 2012). Interestingly, in the current study, combined treatment with Endostatin and siRNA specific to Stat3 also activated various immune cells and cytokines (data not shown).…”

Combined nifuroxazide and SAT05f therapy reduces graft-versus-host disease after experimental allogeneic bone marrow transplantation

“…Immunoblotting was performed as previously described. 52 For immunoblotting, cell lysates were obtained after cell debris discarded. Proteins were separated in 12% SDS-PAGE gels, transferred to polyvinylidene difluoride (PVDF) membranes (Millipore Corp, Billerica, MA, USA) and immunoblotted with appropriate primary antibodies specific for total Stat3, p-Stat3, β -antin (Cell Signaling Technology, Danvers, MA, USA) or TLR-9 (Santa Cruz Biotechnology, Delaware Ave Santa Cruz, CA, USA).…”