Synergistic Effects Of Arsenic Trioxide Combined With Salmonella Typhimurium In Treating The Advanced Hepatocellular Carcinoma In Rat Models

Background: To evaluate the safety and efficacy of arsenic trioxide (ATO) combined with VNP20009 in treating the advanced hepatocellular carcinoma (HCC). Methods: The proliferation assay, migration assay and real-time PCR analyses were performed to assess the impact of ATO combined with VNP20009 on the McA-RH7777 cells. Forty Buffalo rats were orthotopically implanted with HCC in the livers and randomly divided into four groups: (A) ATO plus VNP20009; (B) ATO; (C) VNP20009; and (D) control. ATO (2 mg/kg) was administered by peritoneal injection once a day and continued for five days. VNP20009 (about 1x107 CFU) was directly injected into the tail vein. MRI examinations were performed to access the tumor responses one and 2 weeks later, respectively. Micro CT scans of chest were performed to assess the lung metastases. Hematoxylin-eosin (HE) staining and immunohistochemical analyses were performed to analyze the tumor tissues. Results: In the in vitro experiments, VNP20009 suppressed the proliferation of McA-RH7777 cells, attenuated their migration ability, and weakened the potential of metastases. MRI examinations showed that the mean residual tumor volumes of ATO plus VNP20009 group on the 7th day and 14th day after the administration of ATO combined with VNP20009 were significantly smaller than those of other groups. Micro CT scans revealed that the lung metastases rates of ATO plus VNP20009 group and VNP20009 group were significantly lower than those of other groups. Immunohistochemical analyses displayed that the levels of VEGF and Vimentin in the tumors of ATO plus VNP20009 group were obviously lower than those of other groups. The median survival of rats in the ATO plus VNP20009 group was longer than those of other groups. Conclusions: The strategy of ATO combined with VNP20009 was safe and had a potential to inhibit tumor growth, decrease the lung metastases, and prolong the overall survival in treating the advanced HCC. The two complementary interventions may have synergistic effects.