Cyclic GMP mediates apoptosis induced by sulindac derivatives via activation of c-jun NH2-terminal kinase 1

Sulindac sulfone (Exisulind) induces apoptosis and exhibits cancer chemopre ventive activity, but in contrast to sulindac, it does not inhibit cyclooxy genases 1 or 2, We found that sulindac sulfone and two potent derivatives, CP248 and CP461, inhibited the cyclic GMP (cGMP) phosphodiesterases (PDE) 2 and 5 in human colon cells, and these compounds caused rapid and sustained activation of the c-Jun NH2-terminal kinase 1 (JNK1), Rapid activation of stress-activated protein/ERK kinase 1 (SER1) and mitogen-activated protein kinase kinase kinase (MEKK1), which are upstream of JNK1, was also observed . Other compounds that increase cellular levels of cGMP also activated JNK1 , and an inhibitor of protein kinase G (PKG), Rp-8-pCPT-cGMPS, inhibited JN K1 activation by the sulindac sulfone derivatives, Expression of a dominant -negative JNK1 protein inhibited CP248-induced cleavage of poly(ADP-ribose) polymerase, a marker of apoptosis, Thus, it appears that sulindae sulfone and related compounds induce apoptosis, at least in part, through activatio n of PKG, which then activates the MEKK1-SEK1-JNK1 cascade, These studies a lso indicate a role for cGMP and PKG in the JNK pathway.