Every Thing Around Finding Less Costly Wnt Pathway small molecule library research

We have also tested the effect of celecoxib on daf 2 mutants and found no significant lifespan extension. Again, this supports the idea that celecoxib may extends lifespan by modulating the IIS pathway activity. Although, celecoxib was originally developed as a potent COX 2 inhibitor, our finding that celecoxib extends lifespan in a daf 16 dependent manner raises the possibility that the longevity effect of celecoxib may be independent of its COX 2 inhibitory activity. The reason is two fold.


First, in mammalian models, celecoxib is known to have additional cellular targets. For instance, several studies suggested that celecoxib might inhibit tumor growth, mGluR at least in part, by acting on a COX 2 independent mechanism, when treated at a higher dosage. More importantly, no COX isoforms have been identified in unicellular organisms, the plant kingdom, insects and nematodes, including C. elegans. To investigate whether the longevity activity of celecoxib can be dissociated from its COX 2 inhibitory activity, we analyzed the lifespan of animals exposed to OSU 03012, a close structural analog of celecoxib that exhibits no detectable COX 2 inhibitory activity up to 50 uM. Treatment with OSU 03012 significantly extends worm lifespan to an extent similar to celecoxib when initiated from hatching. Wild type animals treated with 0.

5 uM OSU 03012 displayed the largest lifespan small molecule library extension. Adult only treatment of 0. 5 uM OSU 03012 displayed an even greater lifespan extension. Similar to what we have observed with celecoxib, exposure to OSU 03012 further extends the lifespan of eat 2 and cyc 1 mutants, but not the lifespan of daf 16 and daf 2 mutants. Since OSU 03012 exhibits no detectable COX 2 inhibitory activity, our findings strongly suggest that celecoxib and its derivative OSU 03012 act on a target other than COX 2 to modulate longevity in C. elegans. It should be noted that we couldnt rule out the possibility that different mutants may exhibit varied sensitivity to the drugs. However, this is unlikely to be the case, as daf 16 mutants failed to respond to all three different concentrations of OSU 03012 we have examined.

Among all the potential secondary targets reported to date ), inhibition of PDK 1, a known IIS pathway component upstream of DAF 16, by celecoxib is particularly VEGF intriguing. It has been reported that celecoxib and a number of its derivatives exhibit different degrees of inhibitory activity against human PDK 1. Given the strong antagonistic activity of OSU 03012 on human PDK 1 both in vitro and in vivo, we have also tested the effect of OSU 03012 on pdk 1 mutants lifespan. Treatment with OSU 03012 failed to extend the lifespan of either the long lived loss offunction pdk 1 mutants, or the short lived gain of function pdk 1 mutants. To determine whether the activity of C.

elegans PDK 1 could indeed be inhibited by celecoxib and OSU 03012 in vivo, we analyzed the phosphorylation status Wnt Pathway of SGK 1, a known substrate of PDK 1, in animals exposed to both drugs.