title: PPARγ-dependent anti-tumor and immunomodulatory actions of pioglitazone.
abstract: Peroxisome proliferator-activated receptor-γ (PPARγ) has been reported to play important roles in carcinogenesis. The current study was carried out to assess the possible anti-tumor effects of pioglitazone (PIO), a PPARγ agonist, in a mouse mammary carcinoma model, i.e. a solid Ehrlich carcinoma (SEC). Effects of PIO on tumor-induced immune dysfunction, and the possibility that PIO may modulate the anti-tumor and immunomodulatory effects of doxorubicin (DOX) were also studied. The effects in tumor-bearing hosts of several doses of PIO (100 mg/kg, per os), with and without the added presence of DOX (2 mg/kg, IP), was investigated in vivo; end-points evaluated included assessment of tumor volume, splenic lymphocyte profiles/functionality, tumor necrosis factor (TNF)-α content, as well as apoptosis and expression of nuclear factor-κB (NF-κB) among the tumor cells. The data indicate that PIO induced significant anti-tumor activity against the SEC. PIO treatments also significantly mitigated both tumor- and doxorubicin-induced declines in immune parameters assessed here. Moreover, PIO led to decreased NF-κB nuclear expression, and, in doing so, appeared to chemo-sensitize these tumor cells to DOX-induced apoptosis. All pioglitazone-studied effects were antagonized by GW9662, a selective PPARγ antagonist.
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University , Tanta , Egypt and.
authors.forename: Alaa E
authors.initials: AE
authors.lastname: El-Sisi
authors.forename: Samia S
authors.initials: SS
authors.lastname: Sokar
authors.forename: Tarek A
authors.initials: TA
authors.lastname: Salem
authors.forename: Sally E
authors.initials: SE
authors.lastname: Abu Risha
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D002286:Carcinoma, Ehrlich Tumor / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D004317:Doxorubicin / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000276:immunology; D007155:Immunologic Factors / Q000494:pharmacology*; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D051379:Mice; D016328:NF-kappa B / Q000276:immunology; D009363:Neoplasm Proteins / Q000276:immunology*; D047495:PPAR gamma / Q000276:immunology*; D000077205:Pioglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: D007155:Immunologic Factors; D016328:NF-kappa B; D009363:Neoplasm Proteins; D047495:PPAR gamma; D045162:Thiazolidinediones; D014409:Tumor Necrosis Factor-alpha; D004317:Doxorubicin; D000077205:Pioglitazone
keywords: Doxorubicin; GW9662; NF-κB; immunity; mammary tumor; pioglitazone