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    Oxidative stress, cell proliferation and inflammation.

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    Team leader


    Research topics


    Since 2000, our group studied the role of cellular reactive oxygen species (ROS) level deregulation in the pathogenesis of human diseases characterized by excessive proliferation and/or inflammation, e.i. cancer, hepatitis, endometriosis and systemic sclerosis. We have demonstrated that depending on their molecular targets and the basal level of ROS, anti-oxidative molecules could have pro-apoptotic (Malassagne, Gastroenterology 2001, Ferret, Hepatology 2001, Bedda, Hepatol, 2003, Laurent, Hepatology, 2004) or pro-proliferative properties (Laurent, Cancer Res, 2005, Alexandre, JNCI, 2006). We found that cancer cells display increase sensitivity to oxidative burst, providing a rational for a new strategy of targeted therapy. The discovery that several chemotherapeutic drugs also exert their antitumoral effects through ROS generation has prompted us to investigate whether ROS modulation in that context could be appropriate or not (Alexandre, Int J Cancer, 2006). We have showed that Mangafodipir an original anti-oxidative molecule was particularly able to synergize with chemotherapeutic drugs both in vitro and in vivo in mouse (Alexandre, JNCI 2006) and to prevent in the same time the side-effects of the chemotherapeutic drugs like the peripheral neuropathy (Coriat, JCI 2014). Three patents have been obtained by the University Paris Descartes and a spin off company created to support clinical trial with mangafodipir. So far, three trials have been performed with this compound, one on hepatitis and two on cancer.




    To discover, synthetize and evaluate new oxidative stress modulator with potential medical application we have created with 10 European labs of chemistry and of biology, the REDCAT consortium (www.redcat-itn.eu). This consortium, founded by the European council, has so far tested 40 original molecules with some of them, especially the organotelluride (Coriat, Cell Death Dis 2011 ; Doering, J Med Chem, 2010) or coumarins, showing remarkable anti-tumoral activities.

    The role of ROS on tumor progression is not only restricted to the promotion of cancer cell proliferation and we have shown that ROS can also favour tumor spreading through the increase of ADAM 9 protease expression (Montgaret et al, Int J Cancer, 2011). Moreover, the production of ROS by tumor cells despite a very short half-life can diffuse outside the cancer cells and have an impact on the viability of surrounding cells. This bystander effect has been described by J Alexandre during his fellowship at the MD Anderson Cancer center at Houston showing that tumor cells stimulated by chemotherapeutic agent overproduced ROS that can kill surrounding tumor cells (Alexandre, Cancer Res, 2007). We have extended this notion to the immune system since ROS produced by tumor cells can kill immunocompetent cells compromising the anti-tumoral immune response (Thomas-Schoemann, Int J Cancer, 2011).





    Our group is also involved in investigating the role of ROS in non-tumoral inflammatory pro-proliferative disorders like endometriosis, connective tissue disorders (systemic sclerosis and SLE) and infectious diseases (acne, polyomavirus and herpes infection).

     

     

    Publications

    1. Coriat R, Alexandre J, Nicco C, Quinquis L, Benoit E, Chéreau C, Lemaréchal H, Mir O, Borderie D, Tréluyer JM, Weill B, Coste J, Goldwasser F, Batteux F. Treatment of oxaliplatin-induced peripheral neuropathy by intravenous mangafodipir. J Clin Invest. 2014 Jan. 124(1):262-72
    2. Thomas-Schoemann A, Batteux F, Mongaret C, Nicco C, Chéreau C, Annereau M, Dauphin A, Goldwasser F, Weill B, Lemare F, Alexandre J. Arsenic trioxide exerts  antitumor activity through regulatory T cell depletion mediated by oxidative stress in a murine model of colon cancer. J Immunol. 2012 Dec 1;189(11):5171-7.
    3. Coriat R, Nicco C, Chéreau C, Mir O, Alexandre J, Ropert S, Weill B, Chaussade S, Goldwasser F, Batteux F. Sorafenib-induced hepatocellular carcinoma cell death depends on reactive oxygen species production in vitro and in vivo. Mol Cancer Ther. 2012 Oct;11(10):2284-93
    4. Coriat R, Marut W, Leconte M, Ba LB, Vienne A, Chéreau C, Alexandre J, Weill  B, Doering M, Jacob C, Nicco C, Batteux F. The organotelluride catalyst LAB027 prevents colon cancer growth in the mice. Cell Death Dis. 2011 Aug 11;2:e191
    5. Trachootham D, Alexandre J, Huang P. Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach? Nat Rev Drug Discov. 2009 Jul;8(7):579-91.