# Integration of _Salmonella_ into Combination Cancer Therapy
## 3 _Salmonella_ in Combination with Other Approaches to Cancer Therapy
### Combination with Chemotherapeutic Agents
Several potential mechanisms have been advanced to explain the demonstrably superior outcomes of _Salmonella_ and chemotherapeutic agents in combination. [PERSON] et al. showed that the anti-tumor effect of cisplatin was augmented when combined with _Salmonella cholerasuis_ due to the capacity of _Salmonella_ to increase the expression of connexin 43 (Cx43), therefore enhancing gap junction intercellular communication (GJIC) [106]. The expression of Cx43 is decreased in a variety of cancer cells and this may interfere with the response of tumor cells to treatments [107]. _Salmonella_ overcomes this limitation by upregulating and activating the expression of Cx43 [78; 106], thereby enhancing antigen presentation by dendritic cells [78] and facilitating the transmission of antitumor drugs and apoptosis signals between adjacent cancer cells [108]. Another study conducted by [PERSON] et al. reported that _Salmonella cholerasuis_ reduced the expression level of multi-drug resistance protein P-gp on tumor cells [59]. The decline in P-gp expression was accompanied by a decrease in its efflux capabilities and was attributed to the inhibition of p-AKT, p-P70S6K, and p-mTOR levels during _Salmonella_ infection [59]. Given that high levels of P-gp on tumor cells are associated with chemotherapeutic drug resistance [109], the ability of _Salmonella_ to regulate the expression of P-gp may enhance the sensitivity of tumor cells to chemotherapy. [PERSON]'s group demonstrated the ability of _Salmonella cholerasuis_ to enhance the susceptibility of B16F10 and 4T1 cells to 5-fluorouracil therapy, as illustrated by the improved therapeutic effect of the combination in tumor-bearing mice [59]. It has been suggested that _S. typhimurium_ could also improve the chemosensitivity of tumor cells by inducing the quiescent cancer cells from the G\({}_{0}\)/G\({}_{1}\) phase to the S/G\({}_{2}\)/M phase in the cell cycle [110; 111]. In one study, almost 90% of tumor cells in the center and 80% of the total cells in an established tumor were shown to be in G\({}_{0}\)/G\({}_{1}\) phase of the cell cycle [112]. Given that cytotoxic agents are only effective in killing proliferating cancer cells with minimal effect on quiescent cancer cells [112], _Salmonella_ could enhance the chemosensitivity of quiescent tumor cells by decoying them from a chemo-resistant G\({}_{0}\)/G\({}_{1}\) phase to a chemo-sensitive S/G\({}_{2}\)/M phase. This combination improved the therapeutic efficacy of cisplatin against the osteosarcoma PDOX lung metastasis model [45]. In this study, _Salmonella_ strain A1-R was utilized to enhance the sensitivity and push quiescent tumor cells to S/G\({}_{2}\) phase, while recombinant methionine was used to selectively trap the cells in this stage [45]. Finally, chemotherapy was administered to tumor-bearing mice, and this combination resulted in a remarkable tumor reduction compared to monotherapy and bitherapy [45]. In this context, the new paradigm in cancer therapy was referred to as \"decoy, trap and shoot (kill)\" chemotherapy [45; 111].