Anti-Tumoral Effect of the Mitochondrial Target Domain of Noxa Delivered by an Engineered Salmonella typhimurium

Abstract

Bacterial cancer therapy relies on the fact that several bacterial species are capable of targeting tumor tissue and that bacteria can be genetically engineered to selectively deliver therapeutic proteins of interest to the targeted tumors. However, the challenge of bacterial cancer therapy is the release of the therapeutic proteins from the bacteria and entry of the proteins into tumor cells. This study employed an attenuated Salmonella typhimurium to selectively deliver the mitochondrial targeting domain of Noxa (MTD) as a potential therapeutic cargo protein, and examined its anti-cancer effect. To release MTD from the bacteria, a novel bacterial lysis system of phage origin was deployed. To facilitate the entry of MTD into the tumor cells, the MTD was fused to DS4.3, a novel cell-penetrating peptide (CPP) derived from a voltage-gated potassium channel (Kv2.1). The gene encoding DS4.3-MTD and the phage lysis genes were placed under the control of PBAD, a promoter activated by L-arabinose. We demonstrated that DS4.3-MTD chimeric molecules expressed by the Salmonellae were anti-tumoral in cultured tumor cells and in mice with CT26 colon carcinoma.

Solubility and Seeded Metastable Zone width of functional sugar L-arabinose

“…L-arabinose is the critical agent in the synthesis of antiviral drug clevudine (Choung et al, 2012) and telbivudine (Jia et al, 2014;Li et al, 2014), which are potent anti-hepatitis B (HBV) agents. It also has great usage in tumor therapy (Loessner et al, 2007;Jeong et al, 2014;Kaluzhny et al, 2009) and chemistry (Yamauchi & Kinoshita, 2001;EL-Farargy & Ghonium, 2008) and biology fields (Becker & Boles, 2003;Jeon et al, 2010). Although it has been known for a long time, the solubility and metastable zone width of L-arabinose in aqueous solution have not been reported before.…”

Salmonella-Mediated Cancer Therapy: Roles and Potential

“…A holin/lysine lysis phage system was deployed to deliver the toxin, and a novel cell-penetrating peptide (CPP) derived from a voltage-gated potassium channel (DS4.3) was conjugated to MTD for import into cancer cells [10].…”

“…Overcoming these obstacles is important to move BMCT closer to clinical application in the future. [7,10,71,72] pTet Tetracylin [30] RecA Radiation [12] Quorum sensing Bacterial density [72,73] Hypoxia-inducing promoters Low oxygen condition [11,20,72,74,75] …”

Engineered bacteria as therapeutic agents

“…Endostatin, Thrombospondin 1), and cytokines (e.g. IL-2, LIGHT) that induce the immune system against tumor cells [28,32]. These strategies are shown in Figure 2 Engineered bacteria in cancer therapies.…”