Review Cancer relapse under chemotherapy: Why TLR2/4 receptor agonists can help Ricardo P. Garay a, ⁎ , Patrice Viens b , Jacques Bauer c , Gérard Normier c , Marc Bardou d , Jean-François Jeannin e , Carlo Chiavaroli c a EA2381, Université Paris 7, Paris, France b Institut Paoli-Calmettes, UMR 599, Université de la Méditerranée, Marseille, France c OM Pharma, Meyrin/Geneva, Switzerland d Département de Médicine, Unité de Pharmacologie Clinique, Faculté de Médecine de Dijon, Université de Bourgogne, Dijon, France e EPHE/INSERM/Laboratoire d'Immunologie et Immunothérapie des Cancers, Unité 517 et IFR 100, Université de Bourgogne, Dijon, France Received 6 November 2006; received in revised form 7 February 2007; accepted 8 February 2007 Available online 17 February 2007 Abstract 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 TLR2/4 agonists, alone or in combination with chemotherapy. It appears that TLR2/4 agonists induce a well controlled tumor necrosis factor-alpha (TNF-α) secretion, at plasma levels known to permeabilize neoangiogenic tumor vessels to the passage of cytotoxic drugs. Moreover, TLR2/4 agonists induce inducible nitric oxide synthase (iNOS) expression, and nitric oxide is able to induce apoptosis of chemotherapy-resistant tumor cell clones. Finally, TLR2/4-stimulation activates dendritic cell traffic and its associated tumor-specific, cytotoxic T-cell responses. Therefore, parenteral TLR2/4 agonists seem promising molecules to prolong survival in cancer patients who relapse under chemotherapy. © 2007 Elsevier B.V. All rights reserved. Keywords: Toll-like receptor; TLR agonist; TNF; OM-174; Chemotherapy Contents 1. Introduction ............................................................... 2 2. TLR2 and TLR4 signaling ........................................................ 2 3. Microbes and microbial products: a long history of anticancer efficacy accompanied by high toxicity ................. 3 3.1. Lipopolysaccharide ........................................................ 3 3.2. BCG for bladder cancer ...................................................... 3 3.2.1. BCG, a TLR2/4 agonist ................................................. 3 3.2.2. TLR2/4-induced dendritic cells' anticancer mechanisms ................................. 3 4. TNF-α as neoadjuvant of local chemotherapy .............................................. 4 4.1. TNF-α and tumor penetration of chemotherapeutic agents .................................... 4 4.2. Tasonermin/melphalan combination for limb sarcoma ...................................... 5 5. Chemically pure TLR agonists ...................................................... 5 5.1. TLR2 agonists .......................................................... 5 5.2. TLR4 agonists .......................................................... 5 European Journal of Pharmacology 563 (2007) 1 – 17 www.elsevier.com/locate/ejphar ⁎ Corresponding author. 46bis rue du Maréchal Galliéni, 91360 Villemoisson-sur-Orge, France. Tel.: +33 1 6904 8034; fax: +33 1 6904 3251. E-mail address: ricardo.garay@wanadoo.fr (R.P. Garay). 0014-2999/$ - see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.ejphar.2007.02.018