Nonsteroidal anti-inflammatory drugs (
NSAIDs) have been widely reported to inhibit
tumor growth by a COX-independent mechanism, although alternative targets have not been well defined or used to develop improved drugs for
cancer chemoprevention. Here, we characterize a novel
sulindac derivative referred to as
sulindac benzylamine (SBA) that does not inhibit COX-1 or COX-2, yet potently inhibits the growth and induces the apoptosis of human colon
tumor cells. The basis for this activity appears to involve cyclic
guanosine 3',5',-monophosphate
phosphodiesterase (cGMP PDE) inhibition as evident by its ability to inhibit cGMP hydrolysis in colon
tumor cell lysates and purified cGMP-specific PDE5, increase intracellular cGMP levels, and activate
cGMP-dependent protein kinase G at concentrations that suppress
tumor cell growth. PDE5 was found to be essential for colon
tumor cell growth as determined by
siRNA knockdown studies, elevated in colon
tumor cells as compared with normal colonocytes, and associated with the
tumor selectivity of SBA. SBA activation of PKG may suppress the oncogenic activity of β-
catenin as evident by its ability to reduce β-
catenin nuclear levels, Tcf (
T-cell factor) transcriptional activity, and
survivin levels. These events preceded apoptosis induction and appear to result from a rapid elevation of intracellular cGMP levels following cGMP PDE inhibition. We conclude that PDE5 and possibly other cGMP degrading
isozymes can be targeted to develop safer and more efficacious
NSAID derivatives for
colorectal cancer chemoprevention.