Nonsteroidal anti-inflammatory drugs (
NSAIDs) are used to reduce
inflammation and as
analgesics by inhibition of
cyclooxygenase-2. At higher concentrations, some
NSAIDs inhibit proliferation and induce apoptosis of
cancer cells. Although several molecular mechanisms have been postulated to explain the anticancer effects of
NSAIDs, they do not involve merely the inhibition of
cyclooxygenase-2, and a more proximate initiator molecule may be regulated by
NSAIDs to inhibit growth. The
p75 neurotrophin receptor (p75NTR) is a proximate cell membrane receptor
glycoprotein that has been identified as a
tumor and
metastasis suppressor. We observed that
NSAID treatment of cell lines from bladder and other organs induced expression of the p75NTR
protein. Of the different types of
NSAIDs examined,
ibuprofen was more efficacious than
aspirin and
acetaminophen and comparable with (R)-
flurbiprofen and
indomethacin in induction of p75NTR
protein expression. This rank order
NSAID induction of the p75NTR
protein correlated with the ability of these
NSAIDs to reduce
cancer cell survival. To examine a mechanistic relationship between
ibuprofen induction of p75NTR
protein and inhibition of survival,
bladder cancer cells were transfected with
ponasterone A-inducible vectors that expressed a death domain-deleted (DeltaDD) or intracellular domain-deleted (DeltaICD) p75NTR product that acts as a dominant negative antagonist of the intact p75NTR
protein. Expression of DeltaDD and DeltaICD rescued cells from
ibuprofen inhibition of growth. These observations suggest that p75NTR is an important upstream modulator of the anticancer effects of
NSAIDs and that
ibuprofen induction of the p75NTR
protein establishes an alternate mechanism by which
ibuprofen may exert an anticancer effect.