NO-donating nonsteroidal antiinflammatory drugs (NSAIDs) inhibit colon cancer cell growth more potently than traditional NSAIDs: a general pharmacological property?
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.
Yeh
Raymond K
RK
American Health Foundation Cancer Center, Institute for Cancer Prevention, Valhalla, NY 06595, USA.
Chen
Jie
J
Williams
Jennie L
JL
Baluch
Mehdi
M
Hundley
Thomas R
TR
Rosenbaum
Raphael E
RE
Kalala
Srinivas
S
Traganos
Frank
F
Benardini
Francesca
F
del Soldato
Piero
P
Kashfi
Khosrow
K
Rigas
Basil
B
D000704:Analysis of Variance; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D003110:Colonic Neoplasms / Q000473:pathology; D019073:HT29 Cells; D006801:Humans; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D020030:Nitric Oxide Donors