PPARγ-dependent anti-tumor and immunomodulatory actions of pioglitazone

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.