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Clinical Cancer Research Vol. 6, 4136-4141, October 2000
© 2000 American Association for Cancer Research

Experimental Therapeutics, Preclinical Pharmacology

Cyclic GMP Mediates Apoptosis Induced by Sulindac Derivatives via Activation of c-Jun NH2-Terminal Kinase 11

Jae-Won Soh, Yuehua Mao, Min-Gab Kim, Rifat Pamukcu, Han Li, Gary A. Piazza, W. Joseph Thompson and I. Bernard Weinstein2

Department of Medicine and Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, New York, New York 10032 [J-W. S., Y. M., M-G. K., B. W.], and Cell Pathways, Inc., Horsham, Pennsylvania 19044 [R. P., H. L., G. A. P., W. J. T.]

Sulindac sulfone (Exisulind) induces apoptosis and exhibits cancer chemopreventive activity, but in contrast to sulindac, it does not inhibit cyclooxygenases 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 (SEK1) 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 JNK1 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 sulindac sulfone and related compounds induce apoptosis, at least in part, through activation of PKG, which then activates the MEKK1-SEK1-JNK1 cascade. These studies also indicate a role for cGMP and PKG in the JNK pathway.




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