Preventive Effects Of Lactobacillus Salivarius FDB86 On Colorectal Cancer And The Underling Mechanism

Colorectal cancer is the most commonly diagnosed cancer in digestive system.In China,colorectal cancer is the third common cancer and the fifth cause of cancer death in men and women.The current available treatments include surgery,radiotherapy and chemotherapy,but they have serious side-effects.Therefore.alternative prevention treatment is necessary.Probiotics have potential anti-cancer properties,and are cheaper and safer in comparison with chemoprevetion drugs.Lactobacillus salivarius FDB86(LS)was recently isolated from centenarians lived in Bama village.LS was shown to inhibit 4-Nitroquinoline-l-oxide induced oral cancer in the previous studies.In the present study.the prevention effect of LS on colorectal cancer was evaluated in dimethylhydrazine(DMH)induced rat model and the mechanisms by which LS inhibited the tumorgenesis were investigated in both in vivo and in vitro tests.This study provided new evidence for exploring probiotics with anti-cancer properties.Firstly,inhibitory effect of LS on formation of colonic precancerous lesions,aberrant crypt foci(ACF)was determined.Inoculation of LS significantly decreased the numbers of ACFs,especially the numbers of large ACFs,showing potentials of anti-cancer abilities.Secondly,the effect of LS on prevention of colorectal cancers was investigated.Inoculation of LS significantly decreased the incidence,multiplicities and the malignant degrees of colorectal tumors.The decreased incidence of colorectal tumors in LS treated group at high dose arrived to 26.2%.Furthermore,after the formation of ACFs,orally intake of LS still decreased the incidence and multiplicities of colorectal tumors during promotion phases.Results also showed that orally intake of LS significantly reduced the proliferation and enhanced the apoptosis in colorectal tumors,which may lead to inhibited progressions of colorectal cancers.In vitro studies compared the effects of LS metabolites and heat-killed LS on proliferation and apoptosis activities of colon cancer cells.LS metabolites significantly inhibited the proliferation activities of colon cancer cells in a dose dependent manner,and induced apoptosis in colon cancer cells.Heat-killed LS has lower effect on inhibiting the proliferation of cancer cells than LS metabolites,and has no effect on apoptosis.Therefore,LS metabolites confirmed to be the major active ingredients in modulating proliferation and apoptosis of colon cancer cells.Further studies investigated the signaling pathways by which LS metabolites regulated proliferation and apoptosis in colon cancer cells.Results showed that LS metabolites down-regulated AKT activity and the downstream proteins of cyclinDl and COX-2(cyclooxygenase-2)in colon cancer cells.Inhibition of cyclinD1 by LS metabolites induced G0/G1 arrest in cell cycle.which lead to inhibited proliferation of colon cancer cells.Orally intake of LS also down-regulated AKT activity and the expression levels of cyclinD1 and COX-2 in DMH induced colorectal tumors.Taken together,LS regulated the proliferation and apoptosis levels in colorectal tumors by secreting metabolites,which down regulated AKT signaling pathway and the downstream proteins of cyclinD1 and COX-2.