New Organ-Specific Pharmacological Strategies Interfering With Signaling Pathways In Inflammatory Disorders/Autoimmune Disorders

Bradley      A. Wisler; James      E. Dennis; Charles      J. Malemud

doi:10.2174/157436211795659883

Abstract

Pro-inflammatory cytokine and anabolic growth factor-mediated activation of the Janus kinase/Signal Transducers and Activators of Transcription (JAK/STAT), Stress-activated protein kinase/Mitogen-activated protein kinase (SAPK/MAPK) and Phosphatidylinositide-3-kinase/Phosphatase and TENsin homolog/Akt/mammalian Target Of Rapamycin (PI3K/PTEN/Akt/mTOR) pathways occurs in several autoimmune-mediated inflammatory disorders, such as primary Sjogrens syndrome, inflammatory bowel diseases, Crohns disease and ulcerative colitis and rheumatoid arthritis. JAK/STAT pathway activation has been implicated in maintaining the high level of pro-inflammatory cytokine gene transcription in these disease states. Furthermore, activation of JAK/STAT can result in the ‘cross-talk’ activation of SAPK/MAPK and PI3K/PTEN/Akt/mTOR leading to the destruction of tissues and organs as well as the abnormal level of survival of immune cells which perpetuates the inflammatory response. Small molecule inhibitors (SMIs) of these intracellular signaling pathways are now being tested in animal models and in clinical trials with the view that SMIs will join the armamentarium of disease-modifying drugs that have shown clinical efficacy by virtue of their ability to neutralize pro-inflammatory cytokine/cytokine receptor binding. Although systemic administration of SMIs have long been considered the benchmark for predicting successful use in medical therapy, novel organ-specific drug delivery systems have now been shown to deliver drugs only to tissues and organs affected in these disease processes.

Keywords: Autoimmunity, inflammatory bowel diseases, JAK/STAT, organ-specific drug delivery, P13K/PTEN/Akt/mTOR, rheumatoid arthritis, SAPK/MAPK, Sjogren's syndrome, Cancer cell motility, Hepatocyte growth factor/scatter factor, Rho, ROCK, GTPase, c-Met, metastasis, actin cytoskeleton, EMT, ribozyme, amoeboid cell motility, Y27632, lamellipodia, cancer cell invasion, RhoC, stress fibres, motility signals, Ras, doxycycline, mitogen, breat cancer, MDA-MB-231, MCF-7, Rho/rac pathway