Tributyrin, a stable and rapidly absorbed prodrug of butyric acid, enhances antiproliferative effects of dihydroxycholecalciferol in human colon cancer cells

Tributyrin, a prodrug of natural butyrate, has been evaluated with an aim t o overcome pharmacokinetic drawbacks of natural butyrate as a drug, i.e., i ts rapid metabolization and inability to achieve pharmacologic concentratio ns in neoplastic cells. We studied the effects of tributyrin on growth, dif ferentiation and vitamin D receptor expression in Caco-2 cells, a human col on cancer cell line. Tributyrin was more potent in inhibiting growth and in ducing cell differentiation than natural butyrate. The effect was further e nhanced after addition of physiologic concentrations of dihydroxycholecalci ferol [(OH)(2)D-3]. The synergistic effect of tributyrin and (OH)(2)D-3 in Caco-2 cells was due to tributyrin-induced overexpression of the vitamin D receptor, as measured by reverse transcriptase-polymerase chain reaction. T reatment with tributyrin increased binding of (OH)(2)D-3 to its receptor 1. 5-fold, without any change in receptor affinity. We conclude that tributyri n may, at least in part, exert its growth-reducing and differentiation-indu cing effect in Caco-2 cells by an upregulation of the vitamin D receptor, t his may provide a useful therapeutic approach in chemoprevention and treatm ent of colorectal cancer by the two nutrients occurring naturally in human diet.