Modified Shenlingbaizhu decoction reduces intestinal adenoma formation in adenomatous polyposis coli multiple intestinal neoplasia mice by suppression of hypoxia-inducible factor 1α-induced CD4+CD25+forkhead box P3 regulatory T cells

OBJECTIVE: To test the hypothesis that modified Shenlingbaizhu decoction(MSD) attenuates the formation of intestinal adenomas by regulating activation of CD4+CD25+ forkhead box P3(Fox P3) regulatory T cells(Tregs) by downregulation of hypoxia-inducible factor 1α(HIF-1α).METHODS: Chemical fingerprints of ginsenoside Rb1, ginsenoside Rc, paeoniflorin, and dioscin in standard extractions were used as material bases of MSD. Adenomatous polyposis coli multiple intestinal neoplasia(ApcMin/+) mice, which harbor a mutation in adenomatous polyposis coli, were used to host intestinal adenomas. Peripheral blood and spleen Tregs were analyzed by flow cytometry. Protein expression was analyzed by immunohistochemistry and Western blotting.RESULTS: The number and size of intestinal adenomas were significantly reduced by MSD treatment.Mucosal thickening and the spleen size were also substantially decreased by MSD. The carcinogenesis process in ApcMin/+mice resembled that of human colorectal cancer. Molecular markers of neoplasms, such as β-catenin, cyclooxygenase-2, proliferating cell nuclear antigen, and p53, were substan-tially ameliorated by MSD treatment. Moreover,MSD downregulated peripheral and spleen CD4 +CD25+Fox P3+ Tregs and reduced in situ expression of CD4, CD25, and Fox P3 in intestinal adenomas.MSD also suppressed HIF-1α expression in the intestinal adenomas, and HIF-1α inhibition decreased expression of Fox P3 in Jurkat T cells under hypoxic conditions.CONCLUSION: MSD is a valid prescription to control the formation of intestinal adenomas in ApcMin/+mice. It exerts anti-cancer effects partially through suppression of HIF-1α that induced activation of CD4+CD25+Fox P3+ Tregs in vivo and in vitro.