Mevastatin is an inhibitor of
3-hydroxy-3-methylglutaryl-coenzyme A (
HMG-CoA) reductase, the rate-limiting
enzyme in
cholesterol synthesis.
Butyrate, a
short-chain fatty acid, reduces proliferation and induces differentiation of human
colon cancer cells. The aim of our study was to determine the effect of
mevastatin, alone or in combination with
butyrate, on proliferation, the cell cycle and apoptosis in the human
colorectal carcinoma cell line Caco-2. In this report we show that
mevastatin combined with
butyrate synergistically suppressed growth of Caco-2 cells in a dose- and time-dependent manner. In addition, incubation with
mevastatin arrested cells in the G1 phase of the cell cycle after 24 h with a switch to the G2/M phase after 72 h. This was accompanied by a down-regulation of
cyclin-dependent kinases (cdk) 4 and cdk 6 as well as
cyclin D1, while cdk 2 and
cyclin E protein levels remained unchanged during
mevastatin treatment. Cell cycle inhibitors p21 and p27 were significantly upregulated by
mevastatin. The proapoptotic properties of
mevastatin were further enhanced by co-incubation with
butyrate. Lastly, the effects of
mevastatin could be reversed by addition of
mevalonate, but not farnesyl- or geranylgeranylpyrophosphate, intermediate products of
cholesterol synthesis, to the medium. These results suggest that
HMG-CoA reductase inhibitors like
mevastatin may enhance the antiproliferative effect of
butyrate in
colon cancer cells via induction of apoptosis together with a G0/G1 cell cycle arrest.