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 TLR2/4 agonists, alone or in combination with chemotherapy. It appears that TLR2/4 agonists induce a well controlled tumor necrosis factor-alpha (TNF-alpha) 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.
Garay
Ricardo P
RP
EA2381, Université Paris 7, Paris, France. ricardo.garay@wanadoo.fr
Viens
Patrice
P
Bauer
Jacques
J
Normier
Gérard
G
Bardou
Marc
M
Jeannin
Jean-François
JF
Chiavaroli
Carlo
C
D000818:Animals; D000970:Antineoplastic Agents / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001500:BCG Vaccine / Q000276:immunology; D017024:Chemotherapy, Adjuvant; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D004790:Enzyme Induction / Q000187:drug effects; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D016753:Interleukin-10 / Q000378:metabolism; D008050:Lipid A / Q000031:analogs & derivatives / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D020360:Neoadjuvant Therapy; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D012008:Recurrence; D015398:Signal Transduction / Q000187:drug effects*; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000819:agonists* / Q000276:immunology / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000819:agonists* / Q000276:immunology / Q000378:metabolism; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology
D000970:Antineoplastic Agents; C087507:BCG Connaught; D001500:BCG Vaccine; D008050:Lipid A; D008070:Lipopolysaccharides; C086889:ONO 4007; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D052247:Nitric Oxide Synthase Type II; C400105:defoslimod