Tributyrin has been shown to be
cytostatic to
tumor cells by inducing differentiation and apoptosis. On the other hand, immunological NK cells can kill
tumor cells, particularly when stimulated with
interleukin-2 (IL-2) and/or interleukin-12(IL-12). However, little is known about whether and how both antitumor mechanisms act together, although in vivo such an interaction must exist. Here we demonstrate in vitro, that pretreatment of human LS 174T
colon cancer cells with nontoxic concentrations of
tributyrin augments the sensitivity to spontaneous NK cell activity two-fold. However, when NK cells have been activated with an optimized combination of
IL-2 and
IL-12, the immunocytotoxicity increases up to five-fold (from 14% to 70%), versus a 3.8-fold increase against untreated
cancer cells. These effects are accompanied by increased IFN-gamma secretion and decreased
TGF-beta1 secretion.
Tributyrin is found to be a potent inducer of
ICAM-1,
LFA-3 and Fas on target cells corresponding to an increase of the FasL expression by IL-2/
IL-12 on the effector cells. Our data suggest a synergistic link between induction of
tumor cell differentiation and immunological defense mechanisms that may provide a rational basis for the improvement of clinical protocols, especially for
colon cancer.