Pharmacologic control of intracellular signaling pathways: from research to therapy

Intracellular signaling pathways mediate the main events in a cell's life cycle, such as growth, proliferation, differentiation, performance of specialized functions, and apoptosis. Intracellular signaling is initiated either by extracellular signals or by intracellular gene products, e.g., those resulting from appropriately or inappropriately activated oncogenes. Extracellular signals either are generated by the general environment or are secretory products of other cells (e.g., growth factors, cytokines, hormones). Both act on specific receptors and, with some similarities to endogenous products, activate intracellular signaling and cell functional responses. Extracellular and intracellular signals coordinate the activities of the various cells in multicellular organisms. Dysregulation of signaling pathways by extracellular stimuli such as pathogens, or by gene abnormalities such as oncogene activation or loss of tumor suppressor gene activity, induces disease. The usual therapeutic targets of drugs are the stimuli and, in cancer, the oncogene or its direct product, the mRNA. Molecular components of cell signaling pathways are candidate targets for therapy. This approach may itself be sufficient to modify the positive or negative effects of a molecule in the signaling pathway. Drugs targeting cell signaling molecules can be combined with drugs acting on oncogenes, extracellular stimuli, or receptors. The main molecules involved in intracellular signaling are those of the transduction pathways and the second messengers and transcription factors. These molecules and their interactions are first recalled and are then analyzed to determine how, by the use of "specific" inhibitors, antisense methods, and directed mutagenesis, their functionality has been established. Finally, we will consider whether or not these methods can be adapted to clinical use.