The novel
nitric oxide-donating nonsteroidal antiinflammatory drugs (NO-
NSAIDs), consisting of a traditional
NSAID to which a NO releasing moiety is covalently attached, may have an important role in
colon cancer prevention and/or treatment. Preclinical studies have shown that
NO-aspirin (
NO-ASA) is more potent than traditional ASA in preventing
colon cancer. Preclinical and clinical studies have also documented its superior safety, compared to traditional ASA. To evaluate the role of this structural modification on the
cancer cell growth inhibitory effect of
NSAIDs, we studied seven pairs of traditional
NSAIDs (ASA,
salicylic acid,
indomethacin,
sulindac,
ibuprofen,
flurbiprofen,
piroxicam) and their corresponding NO-
NSAIDs. All NO-
NSAIDs (except NO-
piroxicam which is a
salt and not a true NO-
NSAID) have greater potency in inhibiting HT-29 and HCT-15
colon cancer cell growth compared to their
NSAID counterparts: the IC(50)s of the NO-
NSAIDs were enhanced between 7- and 689-fold in HT-29 cells and 1.7- to 1083-fold in HCT-15 cells over those of the corresponding
NSAIDs. Their growth inhibitory effect is due to a profound cell kinetic effect consisting of reduced cell proliferation and enhanced cell death. Since HT-29 cells express
cyclooxygenases but HCT-15 do not, this effect appears independent of
cyclooxygenase in the
colon cancer cells. Thus the structural modification of these traditional
NSAIDs leading to NO-
NSAIDs enhances their potency in inhibiting
colon cancer cell growth. Our findings suggest that the enhanced potency imparted on
NSAIDs by this structural modification represents a pharmacological property that may be a general one for this class of compounds.