Growth and Trophic Factors, pH and the Na+/H+ Exchanger in Alzheimers Disease, Other  Neurodegenerative Diseases and Cancer: New Therapeutic Possibilities and Potential Dangers

Salvador      Harguindey; Stephan   J.   Reshkin; Gorka      Orive; Jose      Luis Arranz; Eduardo      Anitua

Abstract

Abnormalities in the intricate intracellular signalling pathways play a key role in the deregulation of either spontaneous (normal or pathological) or induced (therapeutic) cell death mechanisms. Some of these pathways are increasingly becoming molecular therapeutic targets in different processes, ranging from neurodegenerative diseases to cancer. Recent discoveries in research and treatment have shown that failure to induce selective cell apoptosis in hyperproliferative processes, like neoplastic diseases, and the failure to prevent spontaneous cell death in neurodegenerative diseases (HNDDs) such as Alzheimers disease (AD), multiple sclerosis (MS), amyothrophic lateral sclerosis (ALS), Huntingtons disease (HD), and retinitis pigmentosa (RP), can be interpreted as problems stemming from the same basic mechanisms but moving in diametrically opposed directions. The integrated approach advanced here represents an interdisciplinary attempt to stimulate an integrated vision of two otherwise widely separated areas of research, experimental neurology and oncology. This kind of approach to the prevention of apoptosis (therapeutic antiapoptosis) and/or other forms of cell death in HNNDs, as well as to resistance to therapeutic apoptosis in cancer (pathological antiapoptosis), has the scope to improve the understanding of the dualistic nature of the basic abnormalities underlying the pathological deregulation of cell death. In this context, an intracellular pH (pHi)-related approach to these opposed situations is advanced to provide a unified theory of the apoptosis-antiapoptosis machinery. Some potential therapeutic possibilities opened by these lines of research, regarding the utilization of human growth factors and/or cellular anti-acidification measures directed to sustain cellular acid-base homeostasis in different HNNDs are considered because of their potential therapeutic benefit. Finally, we advance some possible dangers and side-effects raised by these very same treatment efforts.

Keywords: Apoptosis and antiapoptosis, cancer and Alzheimer's disease, neurodegenerative diseases, pH and Na+/H+ exchanger, p53, growth factors and tissue repair, trophic factor withdrawal

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