Protein Kinase G Activation Directly Triggers Cell Suicide Mechanisms.

Business Editors/Health & Medical Writers

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HORSHAM, Pa.--(BW HealthWire)--May 14, 2001

Report in the Journal of Biological Chemistry Expands

Understanding of Mechanism of Action for a New Class

of Anti-Cancer Drugs

A new finding that activation of cyclic GMP-dependent protein kinase G (PKG) leads to effects in multiple downstream pathways that regulate cancer cell survival may further explain what appears to be the broad anti-cancer activity of exisulind (Aptosyn(TM)), CP461, and other compounds that are members of a family of selective apoptotic antineoplastic drugs (SAANDs) under development by Cell Pathways, Inc. (Nasdaq:CLPA). Scientists at Columbia University and their collaborators at Cell Pathways previously reported that activation of PKG in cells led to the degradation of beta-catenin and the activation of the signaling molecule JNK1 culminating in programmed cell death or apoptosis. This report now provides evidence that PKG acts upstream from JNK1 by directly turning-on an important series of steps in the apoptosis pathway, the MEKK1-SEK1-JNK1 cascade. The activation of PKG and the setting in motion of this cell suicide mechanism appears to be initially triggered in precancerous and cancerous cells by inhibiting certain cyclic GMP phosphodiesterases (cGMP-PDEs), the drug targets for Cell Pathways' SAANDs.

The new research appears in the May 11 issue of the Journal of Biological Chemistry. Columbia University scientists, led by Dr. Bernard Weinstein, director emeritus of the Herbert Irving Comprehensive Cancer Center, senior author Dr. Jae-Won Soh and their collaborators at Cell Pathways co-authored the paper.

"The results reported in this paper are the first demonstration that PKG directly activates the MEKK1-SEK1-JNK1 cascade. While earlier studies have indicated that JNK1 can play a critical role in inducing apoptosis, the precise proteins that act upstream from MEKK1, causing its activation and thus triggering the subsequent cascade, have not previously been described. The appreciation of how the cGMP PDEs, PKG and the downstream apoptotic pathways interact will further the development of drugs that selectively target cancer," said Dr. Weinstein.

Cell Pathways and its collaborators have previously described a drug target consisting of certain cyclic GMP phosphodiesterases of the PDE5, PDE2 and PDE1 gene families. The scientists have found these molecules to be overexpressed in cancerous and precancerous cells of the colon, and in cancers of the lung, prostate, breast and pancreas. Researchers have shown that the inhibition of these cGMP-PDE proteins appears to trigger a chain of events that result in the apoptosis of cancerous and precancerous cells, but not normal cells. Cell Pathways researchers reported (Cancer Research July 1, 2000) that exisulind and other SAANDs appear to induce apoptosis in colon tumor cells by inhibiting the different forms of cGMP PDE in these cell lines. This activity results in a sustained increase in cGMP in the cells and the induction of PKG activity. Increased PKG activity appears to cause an important regulatory protein, beta-catenin, to be degraded, thus enhancing cell death by apoptosis.

"We are very excited about the results of this study, which expand upon our earlier research findings," said Rifat Pamukcu, M.D., chief scientific officer of Cell Pathways, Inc. "The observation that PKG activation, as seen with the SAANDs, appears to lead to multiple downstream effects on apoptotic pathways and cancer cell survival is a very important one. As they become cancerous, cells accumulate a diverse complement of mutations that increase their proliferation rate and interfere with apoptosis. The simultaneous effects of the SAANDs on multiple downstream pathways controlling cell survival may increase our opportunity to selectively kill cancer cells with such diverse mutations."

Research with exisulind, CP461 and other SAANDs has shown the ability of these drugs to inhibit the growth of a broad variety of malignant tumor cells in both cell culture and animal models of human cancers. Exisulind and CP461 are currently in human clinical development as potential treatments for a variety of cancer types. Among the ongoing trials is a 600 patient, multi-center Phase III study of Aptosyn(TM) (exisulind) and Taxotere(R) (docetaxel) in patients with advanced non-small cell lung cancer, initiated in March 2001.

Apoptosis and SAANDs

Apoptosis is the body's response to a normal, orderly sequence of biochemical or physical signals by which damaged or "worn out" cells are eliminated to make way for healthy, new cells. When the mechanism of apoptosis goes awry, cells continue to multiply and grow inappropriately, forming a mass of tissue -- a cancerous tumor. In colon cancer, excessive cell growth occurs as the result of the accumulation of a regulatory protein, beta-catenin, usually caused by mutations in the adenomatous polyposis coli (APC) gene.

Cyclic nucleotide PDEs consist of 11 gene families, each having one or more different members or "isoforms." Each family of PDEs is characterized by its ability to bind and degrade cyclic AMP (cAMP) and/or cGMP, but differs in its immunological, physical and kinetic properties. Only a limited number of the known PDE isoforms are expressed and used by any single type of cell or tissue to regulate cGMP or cAMP levels. Historically, PDE inhibition has not been a target for drug development in cancer. Moreover, the majority of PDE inhibitors investigated to date do not induce apoptosis in tumor cells. Thus, exisulind, CP461 and SAANDs represent a unique class of PDE inhibitors.

Cell Pathways, Inc., headquartered in Horsham, Pa., is a development stage pharmaceutical company focused on the research, development and commercialization of novel and unique medications to prevent and treat cancer. For additional information on Cell Pathways, Inc., visit the company's web site at http://www.cellpathways.com.

Note to editors: Aptosyn(TM) is a trademark of Cell Pathways, Inc. Taxotere(R) is a registered trademark of Aventis Pharmaceutical Inc.

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