Cancer relapse under chemotherapy: why TLR2/4 receptor agonists can help.

Liver or lung metastases usually relapse under chemotherapy. Such life-threatening condition urgently needs new, systemic anticancer compounds, with original and efficient mechanisms of action. In B16 melanoma mice treated with cyclophosphamide, D'Agostini et al. [D'Agostini, C., Pica, F., Febbraro, G., Grelli, S., Chiavaroli, C., Garaci, E., 2005. Antitumour effect of OM-174 and Cyclophosphamide on murine B16 melanoma in different experimental conditions. Int. Immunopharmacol. 5, 1205-1212.] recently found that OM-174, a chemically defined Toll-like receptor(TLR)2/4 agonist, reduces tumor progression and prolongs survival. Here we review 149 articles concerning molecular mechanisms of TLR2…

Tumour-derived and host-derived nitric oxide differentially regulate breast carcinoma metastasis to the lungs.

To study the role of nitric oxide (NO) in lung metastasis of breast carcinoma, we isolated two cell clones (H and J) from the parental EMT-6 murine breast carcinoma cell line, based on their differential NO production. In vitro, EMT-6 J cells, but not EMT-6H cells, constitutively expressed inducible NO synthase (NOS II) and secreted high levels of NO. IL-1beta increased NO production in both clones, and TNF-alpha had a synergistic effect on IL-1beta-induced NO production, but NO production by EMT-6 J cells was always higher than by EMT-6H cells. Proliferation, survival and adhesion to lung-derived endothelial cells of both clones were similar and were not affected by NO. In vivo, both clone…

Preface: First International Conference on Nitrosylation in Oncology and Immunology; Speakers' Presentations

Nitric Oxide Is a Promising Enhancer for Cancer Therapy

This report summarizes the present state of our knowledge pertaining to the nitric oxide (NO)-induced sensitization of tumor cell death. The effects of NO and its synergy with ionizing radiations, with members of the TNF family, and with chemotherapy have been investigated. The effect of NO-induced sensitization and the underlying molecular mechanisms are discussed.

Phase I study of OM-174, a lipid A analogue, with assessment of immunological response, in patients with refractory solid tumors.

International audience; BACKGROUND: Lipids A, the lipophilic partial structure of lipopolysaccharides, induce regression of several tumor types in animal models. Rather than exerting direct cytotoxic effect, these compounds trigger the immune system which in turn stimulates secretion of cytokines, and activates the inducible nitric oxide synthase, as well as immune cell infiltration of tumors. OM-174 is an analogue of lipid A with dual action on toll-like receptors 2 and 4. In an experimental model of peritoneal carcinomatosis induced in BDIX rats by intraperitoneal injection of syngeneic PROb colon cancer cells, it induced a complete regression of tumors. The present phase I trial was cond…

Toll-like Receptor 2 and 4 in Cancer Immunotherapy: Is Nitric Oxide a Mediator?

Post-Translational Regulation of Fas/CD95 in Cell Death and Survival: Role of Nitric Oxide

Lipid A-Induced Responses In Vivo

The lipid A analogs used in preclinical studies and clinical trials are not naturally-occurring forms of lipid A; they are synthetic molecules produced to be less toxic than lipid A itself and they do not reproduce the effects of natural lipid A molecules especially in vivo. The responses induced by lipid A analogs are summarized in this chapter: their fate in the blood stream and their toxicity as well as the lipid A tolerance and the tumor immune responses they induce. Lipid A is not found in the mammalian organism under normal circumstances so its use in cancer therapy raises important questions as to its different effects in vivo and its toxicity, particularly in cancer patients. Lipid …

S-nitrosylation of the death receptor fas promotes fas ligand-mediated apoptosis in cancer cells.

International audience; BACKGROUND & AIMS: Fas belongs to the family of tumor necrosis factor receptors which induce apoptosis. Many cancer cells express Fas but do not undergo Fas-mediated apoptosis. Nitric oxide reverses this resistance by increasing levels of Fas at the plasma membrane. We studied the mechanisms by which NO affects Fas function. METHODS: Colon and mammary cancer cell lines were incubated with the NO donor glyceryl trinitrate or lipid A; S-nitrosylation of Fas was monitored using the biotin switch assay. Fas constructs that contained mutations at cysteine residues that prevent S-nitrosylation were used to investigate the involvement of S-nitrosylation in Fas-mediated cell…

Innate immune response triggered by triacyl lipid A is dependent on phospholipid transfer protein (PLTP) gene expression

Hexaacyl lipopolysaccharide (LPS) aggregates in aqueous media, but its partially deacylated lipid A moiety forms monomers with weaker toxicity. Because plasma phospholipid transfer protein (PLTP) transfers hexaacyl LPS, its impact on metabolism and biological activity of triacyl lipid A in mice was addressed. Triacyl lipid A bound readily to plasma high-density lipoproteins (HDLs) when active PLTP was expressed [HDL-associated lipid A after 4.5 h: 59.1+/-16.0% of total in wild-type (WT) vs. 32.5+/-10.3% in PLTP-deficient mice, P0.05]. In the opposite to hexaacyl LPS, plasma residence time of lipid A was extended by PLTP, and proinflammatory cytokines were produced in higher amounts in WT th…

H89 enhances the sensitivity of cancer cells to glyceryl trinitrate through a purinergic receptor-dependent pathway

// Marion Cortier 1, 2, 3 , Rahamata Boina-Ali 1, 2, 3 , Cindy Racoeur 1, 2, 3 , Catherine Paul 1, 2, 3 , Eric Solary 2, 4, 5 , Jean-Francois Jeannin 1, 2, 3 , Ali Bettaieb 1, 2, 3 1 EPHE, Tumor Immunology and Immunotherapy Laboratory, Dijon, F-21000, France 2 Inserm U866, Dijon, F-21000, France 3 EA7269, University of Burgundy, Dijon, F-21000, France 4 Inserm UMR1009, Gustave Roussy Institute, Villejuif F-94805, France 5 University Paris-Sud, Faculty of Medicine, Le Kremlin-Bicetre, F-94800, France Correspondence to: Ali Bettaieb, e-mail: ali.bettaieb@u-bourgogne.fr Keywords: H89, GTN, cancer, purinergic receptors, cGMP Received: October 08, 2014      Accepted: January 09, 2015      Publis…

Lipid A in Cancer Therapies Preclinical Results

Studies in animal models showed that the antitumoral effect of LPS and of their biologically active moiety, lipid A, is indirect and relies on the induction of an immune response both innate and specific, leading to cytokine production. They also affect tumor development by inhibiting tumor blood flow and induce necrosis as well as apoptosis of tumor cells. Lipids A have been tested in animals, either alone or as adjuvant in therapeutic vaccines. The efficacy of treatments depends on the type of molecule and on the protocol. In general, increased survival was obtained, accompanied in some cases by tumor regression and cure.

Conclusion