title: The pharmacologic inhibition of the xc- antioxidant system improves the antitumor efficacy of COX inhibitors in the in vivo model of 3-MCA tumorigenesis.
abstract: 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.
authors.affiliation: Unit of Cellular Biology, IRCCS AOU San Martino-IST, Genoa 16132, Italy.
authors.forename: Enrica
authors.initials: E
authors.lastname: Balza
authors.forename: Patrizia
authors.initials: P
authors.lastname: Castellani
authors.forename: Laura
authors.initials: L
authors.lastname: Delfino
authors.forename: Mauro
authors.initials: M
authors.lastname: Truini
authors.forename: Anna
authors.initials: A
authors.lastname: Rubartelli
mesh_terms: D000328:Adult; D000368:Aged; D027182:Amino Acid Transport System y+ / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000975:Antioxidants / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007052:Ibuprofen / Q000494:pharmacology* / Q000627:therapeutic use; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D008297:Male; D008748:Methylcholanthrene; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism; D012513:Sarcoma, Experimental / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D012460:Sulfasalazine / Q000494:pharmacology* / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D027182:Amino Acid Transport System y+; D016588:Anticarcinogenic Agents; D000975:Antioxidants; D016861:Cyclooxygenase Inhibitors; D017382:Reactive Oxygen Species; C492255:Slc7a11 protein, mouse; D012460:Sulfasalazine; D008748:Methylcholanthrene; D007052:Ibuprofen