Nonsteroidal anti-inflammatory drugs attenuate epidermal growth factor-induced proliferation independent of prostaglandin synthesis inhibition.
BACKGROUND
The mechanism(s) whereby nonsteroidal anti-inflammatory drugs (NSAIDs) attenuate colorectal tumor growth remains poorly understood. This study determined if NSAIDs decreased epidermal growth factor (EGF)-induced proliferation in human colonic tumor (Caco-2) cells and whether this process involved the inhibition of prostaglandin (PG) synthesis.


METHODS
Caco-2 cells were serum-starved (48 h) and subsequently treated (48 h) with either serum-free media or EGF (10 ng/ml) +/- physiologic and noninjurious (as determined by LDH release) concentrations of aspirin, indomethacin, and ibuprofen. PG synthesis was measured by EIA. Proliferation was quantitated with two assays: cellular protein and nucleic acid content.


RESULTS
NSAID treatment did not inhibit growth in cells treated with only serum-free media. Cells exposed to EGF demonstrated a significant increase in PGE2, protein, and nucleic acid. Levels of other eicosanoids (PGI2, TXA2) were minimal both before and after EGF treatment. Despite varying degrees of PGE2 inhibition, each NSAID group equally attenuated EGF-induced protein and nucleic acid synthesis. The correlation between PGE2 levels and protein (R2 = 0.56) or nucleic acid (R2 = 0.54) was poor. Finally, the addition of a physiologically appropriate concentration of exogenous PGE2 failed to reverse NSAID-induced growth inhibition.


CONCLUSIONS
These data suggest that NSAIDs, independent of PG synthesis inhibition, attenuate EGF-induced proliferation in Caco-2 cells. This may provide one explanation for how NSAIDs limit colonic neoplasia.
Kokoska
E R
ER
Department of Surgery, Saint Louis University Health Sciences Center, St. Louis, Missouri, 63104, USA.
Smith
G S
GS
Wolff
A B
AB
Deshpande
Y
Y
Miller
T A
TA
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D018938:Caco-2 Cells; D002118:Calcium / Q000378:metabolism; D002277:Carcinoma / Q000378:metabolism / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology*; D015777:Eicosanoids / Q000096:biosynthesis; D004815:Epidermal Growth Factor / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D006801:Humans; D011448:Prostaglandin Antagonists / Q000494:pharmacology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D015777:Eicosanoids; D011448:Prostaglandin Antagonists; D004815:Epidermal Growth Factor; D002118:Calcium