Cimetidine and Ibuprofen Modulate TCell Responses in a Mouse Model of Breast Cancer

Cimetidine and ibuprofen exhibit immunomodulatory effectsas an antagonist of histamine H۲ receptor, and a cyclooxygenaseinhibitor, respectively. Here, the effects of cimetidine andibuprofen on some effector T cell-related parameters were investigatedusing a breast cancer (BC) model. BC was establishedin Balb/c mice using the ۴T۱ cell line. On day ۱۰ aftertumor induction, the BC-bearing mice were classified into fourgroups and treated with PBS, cimetidine (۲۰ mg/kg), ibuprofen(۲۰ mg/kg) or a combination of “cimetidine + ibuprofen” viaintraperitoneal injection (daily from days ۱۱ to ۳۰). The micewere sacrificed on day ۳۱ and the frequency of splenic Th۱ andTreg cells, plasma IFN-γ and TGF-β levels, and intra-tumoralT-bet, GATA۳, FOXP۳ and RORγt expressions were detectedusing flowcytometry, ELISA and real-time-PCR, respectively.In untreated cancerous mice, the percentage of splenic Th۱ cellsand plasma IFN-γ levels were lower (P<۰.۰۰۳ and P<۰.۰۱, respectively),whereas the percentage of splenic Treg cells andplasma TGF-β levels were higher than in healthy mice (P<۰.۰۴and P<۰.۰۰۵, respectively). Treatment of BC-bearing mice withcimetidine, ibuprofen or both drugs promoted the frequency ofTh۱ cells (P<۰.۰۵, P<۰.۰۰۷ and P<۰.۰۰۵, respectively) as wellas IFN-γ levels (P<۰.۰۰۴, P<۰.۰۰۰۱ and P<۰.۰۳, respectively),while reduced the frequencies of Treg cells (P<۰.۰۲, P<۰.۰۳and P<۰.۰۱, respectively), TGF-β levels (P<۰.۰۰۶, P<۰.۰۲ andP<۰.۰۰۲, respectively), intra-tumoral expression of FOXP۳(P<۰.۰۰۶, P<۰.۰۰۵ and P<۰.۰۰۵, respectively), and intra-tumoralexpression of RORγt (P<۰.۰۴, P<۰.۰۳ and P<۰.۰۵, respectively)compared with untreated BC mice. The “cimetidineibuprofen”-treated mice displayed greater T-bet expression thanthe un-treated mice (P<۰.۰۰۶). Cimetidine and/or ibuprofentreatedBC-bearing mice exhibited reduced intra-tumoral expressionof GATA۳ compared with the untreated BC mice, butthe differences were not significant. Cimetidine and ibuprofencorrect some effector T cell-related parameters in cancerousmice. Immunotherapeutic potentials cimetidine and ibuprofenin cancers need investigations