Signal Transduction Inhibitors
Signal transduction is defined as any biochemical communication from one part of the cell to another. It is essential for normal functioning of the cell, and is highly regulated. The process begins with a specific protein called a receptor that is bound in the cell surface membrane. 2 The portion of the receptor that faces the exterior of the cell contains a ligand or site that can bind to a signaling molecule. This binding results in the activation of the receptor. The interior portion of the receptor is either a functional enzyme, or can combine with and activate an enzyme. Enzymes catalyze reactions, but are not themselves used up in the process. Receptors for most growth factors are enzymes called tyrosine kinases. Signal transduction can be described as a cascade of reactions, in which a chemical change in one molecule leads to change in another molecule (mostly proteins). The signaling process begins when the enzyme receives a phosphate group from ATP, an energy generating molecule present in the cell. The phosphate group is then transferred to a series of protein kinase molecules in turn. The process continues until an activated molecule enters the nucleus, where it results in the activation of genes responsible for functioning of the cell cycle and cell division. The cancer state is typically characterized by a signaling process that is unregulated and in a continuous state of activation. This may be due to the action of oncogenes, or genes that code for abnormal proteins that are themselves kinase enzymes or otherwise activate the signaling process. Gene mutations of cancer could also alter the receptor molecule in a manner that it remains active without regulation.
Ras protein
The signal transduction pathways are very complex and still not completely understood. All proteins in the pathways are potential candidates for inhibition. My article of March 2001 focused on inhibition of ras protein, since this protein occupies a prominent position in signaling pathways. Ras protein normally functions by relaying a signal from receptor protein kinases to proteins further down the pathway. A mutation in the ras gene can leave its protein product in a permanently activated state. Unfortunately, clinical trials on ras inhibitors have not been particularly promising to date. Oncolytics Biotech has developed a product (Reolysin) that selectively kills cancer cells that have an activated ras pathway. However, this product is a reovirus, not an inhibitor. The reovirus is able to infect and kill cancer cells because the ras pathway inactivates the cellular PKR protein that normally prevents virus multiplication.
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