Colorectal cancer (CRC) is a disease whose genesis may include metabolic dysregulation. Cancer stem cells are attractive targets for therapeutic interventions since their aberrant expansion may underlie tumor initiation, progression, and recurrence. To investigate the actions of metabolic regulators on cancer stem cell-like cells (CSC) in CRC, we determined the effects of soybean-derived bioactive molecules and the anti-diabetes drug metformin (MET), alone and together, on the growth, survival, and frequency of CSC in human HCT116 cells. Effects of MET (60 μM) and soybean components genistein (Gen, 2 μM), lunasin (Lun, 2 μM), β-conglycinin (β-con, 3 μM), and glycinin (Gly, 3 μM) on HCT116 cell proliferation, apoptosis, and mRNA/protein expression and on the frequency of the CSC CD133+CD44+ subpopulation by colonosphere assay and fluorescence-activated cell sorting/flow cytometry were evaluated. MET, Gen, and Lun, individually and together, inhibited HCT116 viability and colonosphere formation and, conversely, enhanced HCT116 apoptosis. Reductions in frequency of the CSC CD133+CD44+ subpopulation with MET, Gen, and Lun were found to be associated with increased PTEN and reduced FASN expression. In cells under a hyperinsulinemic state mimicking metabolic dysregulation and without and with added PTEN-specific inhibitor SF1670, colonosphere formation and frequency of the CD133+CD44+ subpopulation were decreased by MET, Lun and Gen, alone and when combined. Moreover, MET + Lun + Gen co-treatment increased the pro-apoptotic and CD133+CD44+-inhibitory efficacy of 5-fluorouracil under hyperinsulinemic conditions. Results identify molecular networks shared by MET and bioavailable soy food components, which potentially may be harnessed to increase drug efficacy in diabetic and non-diabetic patients with CRC.

The aim of this study was to examine the comparative hypocholesterolemic effect of soybean 7S fraction in rats fed a high-cholesterol diet. Soybean 7S globulin (β-conglycinin) was administered orally once a day to rats, and the effects were measured after 28 days. Wistar rats were divided into four groups: standard diet (STD) (casein alone), hypercholesterolemic (HC) diet (STD plus 1 g/100 g cholesterol and 0.5 g/100 g cholic acid), HC+7S(1) diet (HC diet plus 200 mg of 7S/kg of body weight/day), and HC+7S(2) diet (HC diet plus 300 mg of 7S/kg of body weight/day). Food intake, weight gain, animals' growth, and feeding efficiency ratio were similar among the STD and three HC groups, indicating that these parameters were not affected by treatments. Animals that had received different doses of soybean 7S globulin had lower total cholesterol (TC), triglycerides (TG), and low-density lipoprotein (LDL)/high-density lipoprotein (HDL) ratio in serum and lower levels of hepatic TC and TG than those fed only the HC diet. The atherogenic indexes of HC+7S(1) and HC+7S(2) groups were 40% and 55% lower than that of the HC group, respectively. The results showed that the oral daily administration of β-conglycinin in the diet to HC rats, at between 1.85% and 2.75% of total ingested protein, promotes the reduction of TC, LDL-cholesterol, and TG and an increase in HDL-cholesterol in the plasma, besides a small but significant reduction in cholesterol and TG levels in the liver of the animals as well as a reduced atherogenic index.