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Antitumor Effect of Il-2 and TRAIL Expressed by Salmonella: An Immunotherapeutic Proposal against Bladder Cancer In Vitro and In Vivo by iNOS, Caspase Activation, Immune System Modulation and Tumor Regression

Bruna Dias de Lima Fragelli, Joice Margareth de Almeida Rodolpho, Krissia Franco de Godoy, Luciana Camillo, Cynthia Aparecida de Castro, Patricia Brassolatti, Ricardo Carneiro Borra, Adilson José da Silva, André Vessoni Alexandrino, Maria Teresa Marques Novo-Mansur, Camila Tita Nogueira, Fernanda de Freitas Anibal

IL-2 and TRAIL are therapeutic agents known for their antitumor role, but they can be cleared quickly by the body or be cytotoxic, compromising their function. To reverse this impasse, the synthesis of these agents by live bacteria directly in the tumor is a viable approach, due to bacteria’s preference to colonize tumor tissue. It happens because of the high nutrient grid in this microenvironment and possible escape from the immune system since solid tumors are ischemic and have regions of hypoxia. In this context, attenuated Salmonella represents a promising live vector for delivery of antitumor molecules. The present study investigated the effects of IL-2, TRAIL and mixture of proteins expressed by recombinant Salmonella, strain SL3261, with unique and innovative construction with IL-2 and TRAIL proteins, on bladder cancer cells and in mice od C57BL/6. Human bladder cancer cell line RT4 was exposed for 24 and 48 hours to these proteins and were analyzed with flow cytometry, ELISA, dyes and fluorescent antibodies. In the animal model, tumor induction was performed with MB49 cells, followed by treatment with bacterial strains and collection of tissues and organs for analysis. The results demonstrated that both agents are cytotoxic to the tumor cells, as they cause a decrease in cell viability, modification of its proper morphology and induction of apoptosis. This effect is caused by the activation of the iNOS enzyme by IL-2, which leads to the production of Nitric Oxide (NO) with consequent activation of genes that lead to DNA degradation and by the activation of the Caspase family by TRAIL, causing apoptosis. In mice, there was an important regression of tumor progression and modulation of the immune system. Therefore, IL-2, TRAIL and MIX synthesized by recombinant Salmonella show promising potential in bladder cancer therapy.