NO (
nitric oxide) biology has provided the impetus for the development of
anticancer agents based on their ability to release NO. NO-
NSAIDs (NO-donating non-steroidal anti-inflammatory drugs), consisting of a conventional
NSAID to which an NO-releasing moiety is covalently attached, are promising chemopreventive agents against
cancer. Compared with their parent compounds, NO-
NSAIDs are up to several hundred times more potent in inhibiting the growth of
cancer cell lines and prevent colon and
pancreatic cancer in animal models. Their chemopreventive effect is due to inhibition of proliferation, induction of cell death and inhibition of cell-cycle-phase transitions.
NO-ASA (
NO-aspirin), the best-studied NO-
NSAID, induces oxidative stress in target cells. Major downstream signalling effects involve the Wnt, NOS2 (
nitric oxide synthase 2), MAPK (
mitogen-activated protein kinase),
NF-kappaB (
nuclear factor kappaB) and Nrf2 (nuclear factor-erythroid 2 p45 subunit-related factor 2) pathways. NO-
NSAIDs, particularly
NO-ASA, appear to be safe compounds, as suggested by many animal and early human studies. An ongoing clinical trial is designed to determine whether
NO-ASA can inhibit early stages of colon
carcinogenesis in subjects at risk for
colon cancer. It is clinical trials that will ultimately determine the role of NO-
NSAIDs in
cancer prevention and perhaps treatment.