Important note: Information in this article was accurate in 1996. The state of the art may have changed since the publication date.
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The studies in Science report that certain cells are more resistant to TNF's signal for cell death because it also activates a nuclear transcription factor (NF-kB) which prevents or inhibits apoptosis, thus undermining TNF's ability to kill cells. When the researchers introduced inhibitors of NF-kB, the tumor cells lost their ability to survive and underwent cell death. These studies illuminate the workings of NF-kB and can prove helpful in designing more effective strategies for the treatment of cancerous tumors and chronic inflammation. In one of the papers, Dr. Albert Baldwin of the University of North Carolina demonstrated that combining an NF-kB inhibitor with the chemotherapeutic drugs daunorubicin or vincristine led to a more potent killing in tumor cells.
The research was reported independently by three teams of researchers. The first two papers were led by Inder M. Verma, Ph.D., Professor in Molecular Biology and Virology Laboratory at The Salk Institute, and Chairman and Scientific Founder of Signal Pharmaceuticals and Albert S. Baldwin, Jr., Ph.D., Lineberger Comprehensive Cancer Center, Curriculum in Genetics and Molecular Biology, and Department of Biology, University of North Carolina. Dr. Baldwin is a collaborator of Signal Pharmaceuticals. A third paper was co-authored by Dr. David Baltimore of the Massachusetts Institute of Technology.
"These findings open new windows toward understanding tumor cell survival, and a new chapter in the search for improved cancer therapeutics," said David Anderson, Vice-President for Discovery at Signal Pharmaceuticals. "Inhibitors of NF-kB will have broad potential not only as anti-cancer agents, but also in other conditions where uncontrolled cellular proliferation leads to diseases such as autoimmunity, including rheumatoid arthritis, multiple sclerosis and psoriasis, and possibly in artherosclerosis and retenosis. Cells are normally programmed to divide in a controlled fashion. In cancer and autoimmune disease, the cells do not die and lead to pathogenic consequences. Therefore, blocking NF-kB may help treat these conditions by enhancing the clearance of these cells."
"This is an important study towards elucidating the fundamental pathway by which apoptosis occurs," said Dr. Verma. "As chemotherapy becomes less effective in killing tumors due to resistance, we need other therapies which will trigger cancer cell death. We found that by introducing an inhibitor of NF-kB, termed IkBM, into cancer cells in culture, made them more susceptible to killing by TNF. Our research also demonstrates that it may be possible to use natural and synthetically derived inhibitors of NF-kB in combination with existing drugs to greatly improve tumor killing and that NF-kB inhibitors may allow the use of lower doses of chemotherapy, thus limiting toxic side effects."
Dr. Verma's paper, titled "Suppression of TNF-a-Induced Apoptosis by NF- kB" explains how TNF-a sends chemical signals that helps induce apoptosis. This paper shows that certain cells are more resistant to the apoptotic signal because TNF-a also stimulates the production of the previously identified protein NF-kB.
Dr. Baldwin's paper, titled "Apoptosis: A Life-Death Balance With the Cell" demonstrated that not only TNF, but other forms of cancer therapy, such as radiation and chemotherapy drugs, activate NF-kB to enhance cell survival. Using an inhibitor similar to Dr. Verma's, Dr. Baldwin showed that blocking NF-kB led to enhanced tumor cell killing.
"Drs. Verma and Baldwin and their collaborators have identified how TNF acts as a double agent by simultaneously sending signals to kill tumors and also activating a protein that promotes cell survival," said Alan Lewis, Ph.D., President and CEO of Signal. "Currently at Signal, we are developing inhibitors of NF-kB and other transcription factors which regulate gene expression for use in inflammatory, viral, and bone diseases, as well as neurologic disorders and cancer."
A third paper by Dr. Baltimore, titled "An essential role for NF-kB in Preventing TNF-a-Induced Cell Death" showed that cells derived from NF-kB- deficient animals were more sensitive to killing agents such as TNF. They found that mice with part of the NF-kB molecule deleted dies in the fetal stage from massive cell death in the liver. Replacing the missing NF-kB by gene transfer made the cells resistance to TNF killing.
The Salk Institute for Biological Studies, located in La Jolla, California, is an independent non-profit institution conducting basic science research dedicated to the improvement of human health. Its two main fields of concentration are neuroscience and molecular biology/genetics. The Salk Institute was recently ranked the top research institution worldwide in both of these areas by the Philadelphia-based Institute for Scientific Information. The Institute was founded in 1960 by polio vaccine pioneer Jonas Salk, M.D., with a gift of land from the City of San Diego and the financial support of the March of Dimes Birth Defects Foundation.
Signal Pharmaceuticals, founded in 1993, is an integrated target and drug discovery company focused on small molecule drugs that regulate gene expression for the treatment of inflammatory, bone metabolism, viral and neurological diseases. These drugs represent a new class of pharmaceuticals targeting key signaling molecules that regulate genes and the production of disease-causing proteins. Signal's approach combines genomics, whole cell and biochemical assays, robotics-based high throughput screening and combinatorial chemistry to rapidly screen large compound libraries for activity against specific cell signaling targets. The Company has corporate alliances with Tanabe Seiyaku, Akzo Nobel and Roche Bioscience.
NOTE TO EDITORS: This release and accompanying Science papers are also available on the Internet at: http://www.noonanrusso.com and http://www.signalpharm.com/
CONTACT: Inder Verma, Ph.D., Professor, of The Salk Institute, 619-453-4100; Alan J. Lewis, Ph.D., President and CEO of Signal Pharmaceuticals, 619-558-7500; or Anthony J. Russo, ext. 202, or Neil M. Cohen, ext. 205, both of Noonan/Russo Communications, 212-696-4455
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