A drawback of extensive
coxib use for antitumor purposes is the risk of life-threatening side effects that are thought to be a class effect and probably due to the resulting imbalance of
eicosanoid levels.
2,5-Dimethyl-celecoxib (DMC) is a close structural analogue of the selective
cyclooxygenase-2 inhibitor celecoxib that lacks cyclooxygenase-2-inhibitory function but that nonetheless is able to potently mimic the antitumor effects of
celecoxib in vitro and in vivo. To further establish the potential usefulness of DMC as an
anticancer agent, we compared DMC and various
coxibs and nonsteroidal anti-inflammatory drugs with regard to their ability to stimulate the endoplasmic reticulum (ER) stress response (ESR) and subsequent apoptotic cell death. We show that DMC increases intracellular free
calcium levels and potently triggers the ESR in various tumor cell lines, as indicated by transient inhibition of
protein synthesis, activation of ER stress-associated
proteins GRP78/BiP, CHOP/GADD153, and caspase-4, and subsequent
tumor cell death.
Small interfering RNA-mediated knockdown of the protective chaperone
GRP78 further sensitizes
tumor cells to killing by DMC, whereas inhibition of caspase-4 prevents
drug-induced apoptosis. In comparison,
celecoxib less potently replicates these effects of DMC, whereas none of the other tested
coxibs (
rofecoxib and
valdecoxib) or traditional nonsteroidal anti-inflammatory drugs (
flurbiprofen,
indomethacin, and
sulindac) trigger the ESR or cause apoptosis at comparable concentrations. The effects of DMC are not restricted to in vitro conditions, as this
drug also generates ER stress in xenografted
tumor cells in vivo, concomitant with increased apoptosis and reduced
tumor growth. We propose that it might be worthwhile to further evaluate the potential of DMC as a non-
coxib alternative to
celecoxib for anticancer purposes.