Abstract
The survival of patients with non-Hodgkin's lymphoma (NHL) has substantially improved with current treatments. Nevertheless, the appearance of drug-resistant cancer cells leads to patient relapse. It is therefore necessary to find new antitumor therapies that can completely eradicate transformed cells. Chemotherapy-resistant cancer cells are characterized by the overexpression of members of the anti-apoptotic B-cell lymphoma 2 (Bcl-2) protein family, such as Bcl-XL, Bcl-2, and Mcl-1. We have recently shown that peptides derived from the BH3 domain of the pro-apoptotic Bax protein may antagonize the anti-apoptotic activity of the Bcl-2 family proteins, restore apoptosis, and induce chemosensitization of tumor cells. In this study, we investigated the feasibility of releasing this peptide into the tumor microenvironment using live attenuated Salmonella enterica, which has proven to be an ally in cancer therapy due to its high affinity for tumor tissue, its ability to activate the innate and adaptive antitumor immune responses, and its potential use as a delivery system of heterologous molecules. Thus, we expressed and released the cell-permeable Bax BH3 peptide from the surface of Salmonella enterica serovar Typhimurium SL3261 through the MisL autotransporter system. We demonstrated that this recombinant bacterium significantly decreased the viability and increased the apoptosis of Ramos cells, a human B NHL cell line. Indeed, the intravenous administration of this recombinant Salmonella enterica elicited antitumor activity and extended survival in a xenograft NHL murine model. This antitumor activity was mediated by apoptosis and an inflammatory response. Our approach may represent an eventual alternative to treat relapsing or refractory NHL.
Highlights
Cancer is a worldwide primary health problem, with an annual mortality rate of over 8 million individuals [1]
We evaluated the feasibility for the cell-permeable Bax BH3 peptide [Tag peptide (T) bound to Bax BH3 peptide (X) and the fusogenic peptide (P)] expressed and released from the surface of Salmonella enterica serovar Typhimurium strain SL3261 through the MisL autotransporter system [34] (Salmonella enterica L-STXP) to promote apoptosis signaling and the death of non-Hodgkin’s lymphoma (NHL) tumor cells
Determination of Inflammatory Cytokines by Cytometric Bead Array (CBA) After the antitumor activity assays of the murine model of NHL xenotransplantation induced by different recombinant strains of Salmonella enterica, as it was previously described, the mice were euthanized, and the serum samples obtained were analyzed by means of the CBA in order to characterize the profile of inflammatory cytokines induced along the treatment
Summary
Cancer is a worldwide primary health problem, with an annual mortality rate of over 8 million individuals [1]. Structural analysis of proteins in the Bcl-2 family has shown an interaction between them via a hydrophobic groove formed by the BH domains [17,18,19], and the overexpression of anti-apoptotic proteins promotes binding to the pro-apoptotic effector proteins Bax or Bak and inhibits their polymerization on the mitochondrial membrane, precluding the release of cytochrome c and the initiation of apoptosis [20, 21] Interaction of these proteins has led to the proposal of eliminating tumor cells that are resistant to apoptosis by blocking the activity of anti-apoptotic proteins with peptides derived from the BH3 domain of pro-apoptotic proteins such as Bak, Bax, Noxa, and Bid that once bound to the Bcl-XL, Bcl-2, and Mcl-1 proteins, antagonizing their function [22,23,24]. Our results suggest that the live attenuated Salmonella enterica serovar Typhimurium strain SL3261 expressing and releasing cell-permeable Bax BH3 peptide through the MisL autotransporter system may represent an eventual alternative to treat relapsing or refractory NHL
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