Umbelliprenin induced production of IFN-γ and TNF-α, and reduced IL-10, IL-4, Foxp3 and TGF-β in a mouse model of lung cancer

Umbelliprenin is a member of the 7-prenyloxycoumarins with potential therapeutic properties such as cytotoxic effects on various cancer cells. The present study investigates the effect of umbelliprenin on predominance of Th1 and Th2 responses in Lewis lung cancer (LLC) mouse model. The cytotoxic effect of umbelliprenin was explored on LLC cells and mouse splenocytes by MTT assay. Mice into which LLC had been transplanted were treated with umbelliprenin on alternate days, at 2.5 mg/200 mu l intraperitoneally. Foxp3, TNF-alpha and TGF-beta mRNA expressions were assessed in tumor and lung tissues of LLC mice. In addition, IL-10, IFN-gamma and IL-4 levels were determined in sera and also in splenocyte culture supernatants at the presence of tumor cell lysate (10 mu g/ml) and Con A (3 mg/ml) after 72 h. Results showed the cytotoxic effects of umbelliprenin on LLC cells (IC50 = 51.6 +/- 5.4 mu M) while no adverse effect was seen at this concentration on normal splenocytes. TNF-alpha mRNA expression in both lung and tumor tissues was increased. However, Foxp3 and TGF-beta expressions were decreased in tumor tissues. Serum level of IFN-gamma was elevated in the umbelliprenin treated cancerous mice compared to the control group while IL-10 and IL-4 secretions were reduced. Tumor size was also decreased in umbelliprenin treated group. In summary, umbelliprenin has shown a partially Th1 bias with a reduction of regulatory immune response. Although the mechanism behind this action is not known, it is speculated that upon changing the Th1/Th2 balance in favour of Th1, umbelliprenin induces its antitumor activity.