Metformin, an inexpensive, well-tolerated oral agent that is a commonly used first-line treatment for
type 2 diabetes, has become the focus of intense research as a potential
anticancer agent. In this study, we describe the inhibitory effect of
metformin in
interleukin 8 (IL-8) upregulation by
lithocholic acid (LCA) in HCT116
colorectal cancer (CRC) cells. Pharmacological inhibition studies indicated that
reactive oxygen species (ROS) were involved in LCA-induced
IL-8 upregulation through activation of the
transcription factor NF-κB.
Metformin was demonstrated to block LCA-stimulated ROS production, in turn suppressing NF-κB signaling that was critical for
IL-8 upregulation. An
NADPH oxidase assay proved that the inhibitory effect of
metformin on ROS production was derived from its strong suppression of
NADPH oxidase, a key producer of ROS in cells. Compared with
conditioned media (CM) derived from HCT116 cells treated with LCA, CM derived from HCT116 cells pretreated with
metformin and then treated with LCA lost all stimulatory effect on endothelial cell proliferation and tubelike formation. In conclusion,
metformin inhibited
NADPH oxidase, which in turn suppressed ROS production and NF-κB activation to prevent
IL-8 upregulation stimulated by LCA; this prevention thus obstructed endothelial cell proliferation and tubelike formation.