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The Active Components in Whole Grain Wheat for Colon Cancer Prevention: Synergistic Effects Between Phytochemical Alkylresorcinols and Fiber Microbial Metabolite Butyrate


 
 
 Wheat bran (WB) is a rich source of dietary fiber and phytochemicals with health-promoting properties. However, the active components especially the interaction between different components in whole grain (WG) wheat have not been fully explored. This study aimed to investigate whether WB phytochemicals, alkylresorcinols (ARs), and the active intestinal microbial metabolite of fiber, butyrate, could synergistically suppress human colon cancer cells.
 
 
 
 Cell viability was determined by MTT assay in HCT-116 and HT-29 cells after the treatments of the combination of ARs, C21 and C19, and NaB, respectively. Apoptosis was determined by Cell Death ELISA Kit. The further mechanism was investigated by western blot associated with apoptosis, autophagy, and ER stress pathways. The C21 levels in gastrointestinal tract were measured by HPLC in mice treated with human-relevant doses of C21. Isobologram analysis was employed for the determination of synergistic or additive anticancer effects of the co-treatments of AR and NaB.
 
 
 
 The combination of C21 or C19 and butyrate synergistically inhibited the growth of colon cancer cells and induced apoptosis. Further mechanistic studies demonstrated that the co-treatment of C21 and butyrate induced significant upregulations in cleaved Poly(ADP-ribose) polymerase (PARP), cleaved caspase 3, p53 upregulated modulator of apoptosis (PUMA), cytochrome C, lipid-conjugated membrane-bound form of microtubule-associated protein 1A/1B-light chain 3 (LC3-II), and C/EBP homologous protein (CHOP) expressions. Notably, the C21 concentrations in the large intestinal tract of mice treated with human-relevant doses of C21, were from 0.86 to 1.78 μmol/g, suggesting the C21 doses used in vitro may be achievable after daily WG wheat intake.
 
 
 
 We demonstrated for the first time that phytochemical component ARs and the microbial metabolites of WB fiber exhibit synergistic anticancer effects in human colon cancer cells, which may be associated with the induction of apoptosis, autophagy, and ER stress pathways. The present study provides novel insights into the understanding of the chemo-preventive effects of WG wheat against CRC. However, the mechanism of the synergistic anticancer effect of phytochemicals and fiber is complicated and still needs to be further investigated in vivo.
 
 
 
 USDA NIFA R01.
