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

OBJECTIVE： To test the hypothesis that modified Shenlingbaizhu decoction （MSD） attenuates the for- mation of intestinal adenomas by regulating activa- tion of CD4＋CD25＋ forkhead box P3 （FoxP3） regu- latory T cells （Tregs） by downregulation of hypox- ia-inducible factor la （HIF-la）. METHODS： Chemical fingerprints of ginsenoside Rbl, ginsenoside Rc, paeoniflorin, and dioscin in standard extractions were used as material bases of MSD. Adenomatous polyposis coli multiple intesti- nal neoplasia （ApcM＇n/＋） mice, which harbor a muta- tion in adenomatous polyposis coil, were used to host intestinal adenomas. Peripheral blood and spleen Tregs were analyzed by flow cytometry. Pro- tein expression was analyzed by immunohisto- chemistry 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 Apc^min/＋ mice resembled that of human colorectal cancer. Molecular markers of neoplasms, such as 13-catenin, cyclooxygenase-2, prolif- erating cell nuclear antigen, and p53, were substantially ameliorated by MSD treatment. Moreover, MSD downregulated peripheral and spleen CD4＋ CD25＋FoxP3＋ Tregs and reduced in situ expression of CD4, CD25, and FoxP3 in intestinal adenomas. MSD also suppressed HIF-la expression in the intestinal adenomas, and HIF-la inhibition decreased expression of FoxP3 in Jurkat T cells under hypoxic conditions. CONCLUSION： MSD is a valid prescription to control the formation of intestinal adenomas in Apc^min/＋mice. It exerts anti-cancer effects partially through suppression of HIF-la that induced activation of CD4＋CD25＋FoxP3＋ Tregs in vivo and in vitro.