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Nitric Oxide Confers Therapeutic Activity to Dendritic Cells in a Mouse Model of Melanoma

¹ Department of Pharmaco-Biology, University of Calabria, Rende; ² Vita-Salute University and DIBIT H San Raffaele Scientific Institute, Milan; ³ Department of Preclinical Sciences, LITA Vialba, L. Sacco Hospital, University of Milano, Milan; and ⁴ E. Medea Scientific Institute, Bosisio Parini, Italy

Susceptibility of dendritic cells (DCs) to tumor-induced apoptosis reduces their efficacy in cancer therapy. Here we show that delivery within exponentially growing B16 melanomas of DCs treated ex vivo with nitric oxide (NO), released by the NO donor (z)-1-[2-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETA-NO), significantly reduced tumor growth, with cure of 37% of animals. DETA-NO-treated DCs became resistant to tumor-induced apoptosis because DETA-NO prevented tumor-induced changes in the expression of Bcl-2, Bax, and Bcl-xL; activation of caspase-9; and a reduction in the mitochondrial membrane potential. DETA-NO also increased DC cytotoxic activity against tumor cells and DC ability to trigger T-lymphocyte proliferation. All of the effects of DETA-NO were mediated through cGMP generation. NO and NO-generating drugs may therefore be used to increase the anticancer efficacy of DCs.

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