The pharmacologic inhibition of the xc- antioxidant system improves the antitumor efficacy of COX inhibitors in the in vivo model of 3-MCA tumorigenesis.

The chemopreventive and therapeutic efficacy of the cyclooxygenase (COX) inhibitor ibuprofen (IB) and of sulfasalazine (SASP), a drug that targets the antioxidant xc- system, were exploited in the experimental model of 3-methylcholantrene (3-MCA)-induced mouse sarcoma. The chemopreventive treatments gave unsatisfactory results because administration of IB one day after the 3-MCA injection only slightly delayed the tumor development, whereas SASP dispensed under the same conditions resulted in accelerated tumorigenesis. Similarly, the therapeutic treatment with either drug, administrated daily from the tumor detection, decreased the proliferation rate of tumor cells and increased the survival of treated mice only at a low extent. Remarkably, the combined chemopreventive treatment with IB and therapeutic treatment with SASP displayed a better efficacy, with strong delay of sarcoma growth, reduced tumor size and increased survival of treated mice. The two drugs target not only tumor cells but also tumor-associated macrophages that were dramatically decreased in the tumor infiltrate of mice subjected to the combined treatment. The synergistic effects of the association between a broad anti-inflammatory compound, such as IB, and a redox-directed drug, such as SASP, shed new light in the role of inflammation and of the redox response in chemical tumorigenesis and point to the combined chemopreventive plus therapeutic treatment with IB and SASP as a promising novel approach for antitumor therapy.

[1]  P. Kalinski.  Regulation of Immune Responses by Prostaglandin E2 , 2012, The Journal of Immunology.

[2]  M. Netea,et al.  Interplay between redox status and inflammasome activation. , 2011, Trends in immunology.

[3]  M. Karin,et al.  Tumor promotion via injury- and death-induced inflammation. , 2011, Immunity.

[4]  M. Ciriolo,et al.  The cystine/cysteine cycle and GSH are independent and crucial antioxidant systems in malignant melanoma cells and represent druggable targets. , 2011, Antioxidants & redox signaling.

[5]  A. Castiglioni,et al.  High-mobility group box 1 release and redox regulation accompany regeneration and remodeling of skeletal muscle. , 2011, Antioxidants & redox signaling.

[6]  Scott E. Kern,et al.  Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis , 2011, Nature.

[7]  M. Cantwell,et al.  A systematic review to establish the frequency of cyclooxygenase-2 expression in normal breast epithelium, ductal carcinoma in situ, microinvasive carcinoma of the breast and invasive breast cancer , 2011, British Journal of Cancer.

[8]  P. Castellani,et al.  CIITA‐driven MHC‐II positive tumor cells: Preventive vaccines and superior generators of antitumor CD4+ T lymphocytes for immunotherapy , 2010, International journal of cancer.

[9]  R. Sitia,et al.  Redox remodeling allows and controls B-cell activation and differentiation. , 2010, Antioxidants & redox signaling.

[10]  C. Low,et al.  Potential use of the anti-inflammatory drug, sulfasalazine, for targeted therapy of pancreatic cancer. , 2010, Current oncology.

[11]  S. Wakana,et al.  xCT deficiency accelerates chemically induced tumorigenesis , 2010, Proceedings of the National Academy of Sciences.

[12]  A. Rubartelli,et al.  DAMPs and inflammatory processes: the role of redox in the different outcomes , 2009, Journal of leukocyte biology.

[13]  E. Podack,et al.  A critical analysis of the tumour immunosurveillance controversy for 3-MCA-induced sarcomas , 2009, British Journal of Cancer.

[14]  M. Ciriolo,et al.  Pathogen-Induced Interleukin-1β Processing and Secretion Is Regulated by a Biphasic Redox Response1 , 2009, The Journal of Immunology.

[15]  H. Sontheimer,et al.  Sulfasalazine inhibits the growth of primary brain tumors independent of nuclear factor‐κB , 2009, Journal of neurochemistry.

[16]  J. Estrela,et al.  Oxidative stress in environmental-induced carcinogenesis. , 2009, Mutation research.

[17]  Srinivas Nagaraj,et al.  Myeloid-derived suppressor cells as regulators of the immune system , 2009, Nature Reviews Immunology.

[18]  S. Ferrini,et al.  The redox state of the lung cancer microenvironment depends on the levels of thioredoxin expressed by tumor cells and affects tumor progression and response to prooxidants , 2008, International journal of cancer.

[19]  Michelle Collazo,et al.  Subsets of Myeloid-Derived Suppressor Cells in Tumor-Bearing Mice1 , 2008, The Journal of Immunology.

[20]  A. Rubartelli,et al.  The thiol redox state of lymphoid organs is modified by immunization: Role of different immune cell populations , 2008, European journal of immunology.

[21]  Yuzhuo Wang,et al.  The xc− cystine/glutamate antiporter: a mediator of pancreatic cancer growth with a role in drug resistance , 2008, British Journal of Cancer.

[22]  P. Allavena,et al.  Cancer-related inflammation , 2008, Nature.

[23]  A. Vickers,et al.  Should supplemental antioxidant administration be avoided during chemotherapy and radiation therapy? , 2008, Journal of the National Cancer Institute.

[24]  V. Bronte,et al.  Tumor‐induced tolerance and immune suppression by myeloid derived suppressor cells , 2008, Immunological reviews.

[25]  S. Akira,et al.  Demonstration of inflammation-induced cancer and cancer immunoediting during primary tumorigenesis , 2008, Proceedings of the National Academy of Sciences.

[26]  G. Wondrak,et al.  Experimental therapeutics: targeting the redox Achilles heel of cancer. , 2007, Current opinion in investigational drugs.

[27]  J. Talmadge.  Pathways Mediating the Expansion and Immunosuppressive Activity of Myeloid-Derived Suppressor Cells and Their Relevance to Cancer Therapy , 2007, Clinical Cancer Research.

[28]  D. Nie,et al.  Cyclooxygenases, prostanoids, and tumor progression , 2007, Cancer and Metastasis Reviews.

[29]  A. Holmgren,et al.  Targeting thioredoxin reductase is a basis for cancer therapy by arsenic trioxide , 2007, Proceedings of the National Academy of Sciences.

[30]  Wan-Wan Lin,et al.  A cytokine-mediated link between innate immunity, inflammation, and cancer. , 2007, The Journal of clinical investigation.

[31]  Yoichiro Iwakura,et al.  Interleukin-1beta-driven inflammation promotes the development and invasiveness of chemical carcinogen-induced tumors. , 2007, Cancer research.

[32]  A. Buckley,et al.  Sulfasalazine‐induced cystine starvation: Potential use for prostate cancer therapy , 2007, The Prostate.

[33]  R. Issels,et al.  The cystine/cysteine cycle: a redox cycle regulating susceptibility versus resistance to cell death , 2006, Oncogene.

[34]  Alberto Mantovani,et al.  Tumour-associated macrophages are a distinct M2 polarised population promoting tumour progression: potential targets of anti-cancer therapy. , 2006, European journal of cancer.

[35]  Paolo Serafini,et al.  Myeloid suppressor cells in cancer: recruitment, phenotype, properties, and mechanisms of immune suppression. , 2006, Seminars in cancer biology.

[36]  Jeannette Bigler,et al.  Non-steroidal anti-inflammatory drugs for cancer prevention: promise, perils and pharmacogenetics , 2006, Nature Reviews Cancer.

[37]  Ying Huang,et al.  Cystine-glutamate transporter SLC7A11 in cancer chemosensitivity and chemoresistance. , 2005, Cancer research.

[38]  R. DuBois,et al.  COX-2: a molecular target for colorectal cancer prevention. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[39]  Hans Clevers,et al.  At the Crossroads of Inflammation and Cancer , 2004, Cell.

[40]  Michael T. Lotze,et al.  Inflammation and necrosis promote tumour growth , 2004, Nature Reviews Immunology.

[41]  C. Harris,et al.  Radical causes of cancer , 2003, Nature Reviews Cancer.

[42]  G. Filomeni,et al.  Antigen-presenting dendritic cells provide the reducing extracellular microenvironment required for T lymphocyte activation , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[43]  N. Bruchovsky,et al.  Sulfasalazine, a potent suppressor of lymphoma growth by inhibition of the xc− cystine transporter: a new action for an old drug , 2001, Leukemia.

[44]  A. Holmgren,et al.  Widespread expression of thioredoxin and thioredoxin reductase in non-small cell lung carcinoma. , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[45]  R. Schreiber,et al.  IFNγ and lymphocytes prevent primary tumour development and shape tumour immunogenicity , 2001, Nature.

[46]  L. G. García Rodríguez,et al.  Reduced Risk of Colorectal Cancer among Long-Term Users of Aspirin and Nonaspirin Nonsteroidal Antiinflammatory Drugs , 2001, Epidemiology.

[47]  E. Giovannucci.  The prevention of colorectal cancer by aspirin use. , 1999, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[48]  R. Schreiber,et al.  Demonstration of an interferon γ-dependent tumor surveillance system in immunocompetent mice , 1998 .

[49]  C. Fletcher,et al.  Soft Tissue Tumors , 1995, Current Topics in Pathology.

[50]  N. Bruchovsky,et al.  Increased cystine uptake capability associated with malignant progression of Nb2 lymphoma cells , 1997, Leukemia.

[51]  R. White,et al.  Prostaglandin H synthase 2 is expressed abnormally in human colon cancer: evidence for a transcriptional effect. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[52]  R. Cawson.  Soft tissue tumors, 3rd edition, 1995: F.M. Enzinger and S.W. Weiss. Mosby, St Louis, £160 , 1995 .

[53]  R. Coffey,et al.  Up-regulation of cyclooxygenase 2 gene expression in human colorectal adenomas and adenocarcinomas. , 1994, Gastroenterology.

[54]  F. Enzinger,et al.  Soft tissue tumors , 1988 .

[55]  P. Cerutti.  Prooxidant states and tumor promotion. , 1985, Science.

[56]  Hideyo Sato,et al.  The oxidative stress-inducible cystine/glutamate antiporter, system xc−: cystine supplier and beyond , 2011, Amino Acids.

[57]  P. Sinha,et al.  Myeloid-derived suppressor cells inhibit T-cell activation by depleting cystine and cysteine. , 2010, Cancer research.

[58]  J. Baron,et al.  Nonsteroidal anti-inflammatory drugs and cancer prevention. , 2000, Annual review of medicine.

[59]  R. Schreiber,et al.  Demonstration of an interferon gamma-dependent tumor surveillance system in immunocompetent mice. , 1998, Proceedings of the National Academy of Sciences of the United States of America.