Abstract
Cisplatin is one of the most effective anticancer drugs, but its severe toxic effects, including depletion of immune-competent cells, limit its efficacy. We combined the systemic treatment with cisplatin with intratumor delivery of dendritic cells (DC) previously treated ex vivo with a pulse of nitric oxide (NO) released by the NO donors (z)-1-[2-(2-aminoethyl)-N-(2-ammonioethyl)amino]-diazen-1-ium-1,2-diolate or isosorbide dinitrate. We found that this chemoimmunotherapy, tested in the B16 mouse model of melanoma, was significantly more efficacious than cisplatin alone, leading to tumor regression and animal survival at low doses of cisplatin that alone had no effect. Tumor cure was not observed when combining cisplatin with DCs not exposed to NO donors, indicating the key role of the pretreatment with NO. We investigated the mechanisms responsible for the synergic effect of NO-treated DCs and cisplatin and found that NO-treated DCs were protected both in vitro and in vivo from cisplatin-induced cytotoxicity. Cisplatin triggered DC apoptosis through increased expression and activation of acid sphingomyelinase; pretreatment of DCs with NO donors prevented such activation and inhibited activation of the downstream proapoptotic events, including generation of ceramide, activation of caspases 3 and 9, and mitochondrial depolarization. The effects of NO were mediated through generation of its physiologic messenger, cyclic GMP. We conclude that NO and NO generating drugs represent promising tools to increase the efficacy of chemoimmunotherapies in vivo, promoting the survival and increasing the function of injected cells by targeting a key pathway in cisplatin-induced cytotoxicity.
Highlights
Delivery of cytotoxic chemotherapeutic agents in the treatment of human cancer is often accompanied by acute and cumulative toxicities to normal tissues that limit the dose and duration of treatment
In this study we show that intratumor delivery of dendritic cell (DC) briefly exposed ex vivo to nitric oxide (NO) enhances significantly the therapeutic efficacy of cisplatin
The effect of the combined chemoimmunotherapy is significantly greater than that of NO-treated DCs alone [8] and opens the way to possible therapeutic strategies that minimize the toxic effects of the chemotherapeutic while enhancing their efficacy
Summary
Delivery of cytotoxic chemotherapeutic agents in the treatment of human cancer is often accompanied by acute and cumulative toxicities to normal tissues that limit the dose and duration of treatment. One promising strategy to reduce the toxicity of chemotherapy maintaining its efficacy is the combination of chemotherapy with immunotherapy. Such strategy could exploit the debulking effects of chemotherapy to treat cancers, because. Approaches based on dendritic cell (DC) vaccines are promising. These professional antigen-presenting cells can exploit chemotherapy-induced apoptosis of tumor cells to elicit improved antitumor immunity through the acquisition of tumor-associated antigens from apoptotic tumor cells; in addition, they have direct cytotoxic effects on cancer cells [1, 2]
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