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Autophagy embraces three major intracellular pathways in eukaryotic cells, macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA), which share a common destiny of lysosomal degradation, but are mechanistically different from one another. During macroautophagy, intact organelles (such as mitochondria) and portions of the cytosol are sequestered into a double-membrane vesicle, termed an autophagosome. Afterwards, the completed autophagosome matures by fusing with an endosome and/or lysosome, thereby forming an autolysosome. This latter step exposes the cargo to lysosomal hydrolases to allow its breakdown, and the resulting macromolecules are transported back into the cytosol through membrane permeases for reuse. By comparison, microautophagy involves the direct engulfment of cytoplasm at the lysosome surface, whereas CMA translocates unfolded, soluble proteins directly across the limiting membrane of the lysosome. Macroautophagy is thought to be the major type of autophagy, and it has been studied most extensively.
The basal, constitutive level of autophagy plays a vital role in cellular homeostasis through the elimination of damaged/old organelles as well as the turnover of long-lived proteins and protein aggregates, and therefore maintains quality control of essential cellular components. In addition, when cells encounter environmental stresses, such as nutrient starvation, oxidative stress, hypoxia, radiation, pathogen infection, or anticancer drug treatment, the level of autophagy can be dramatically augmented as a cytoprotective response, leading to adaptation and survival; however, dysregulated or excessive autophagy may result in cell death. Therefore, defective autophagy has been implicated in the pathogenesis of multiple diseases, such as certain types of neuronal degeneration and cancer, and also in aging.
Figure 1. Physiological and Pathological Roles of Autophagy
Pharmacologic enhancement of autophagy promises to benefit certain diseases (i.e., infectious or neurodegenerative diseases). Sirolimus, a clinically approved immunosuppressive and anticancer drug which inhibits mTOR and thereby exerts pleiotropic effects, including the activation of autophagy, has been used to enhance autophagy in experimental models. Cytosolic or histone deacetylases (i.e., HDAC1, HDAC2, HDAC6, and sirtuin-1) may work as regulators of autophagic initiation and of autophagic flux. Therefore, HDAC inhibitors, or inhibitors of lysosomal acidification, may represent useful pharmacologic strategies for modulating autophagy. Current clinical trials are examining the usefulness of autophagy as a target in disease. Chloroquine and its derivative, hydroxychloroquine, are being tested for enhancement of chemotherapeutic efficacy, including therapies for ductal carcinoma, breast cancer, pancreatic adenocarcinoma, and non–small-cell lung cancer. The design of therapeutic agents is complicated by the fact that many autophagy proteins, as well as pharmacologic inhibitors, may also affect biologic processes independently of autophagy activation.
An improved understanding of the mechanism by which autophagy can prevent pathogenesis may result in the identification of new targets for both diagnostic and therapeutic approaches. Drug screening for agonists or antagonists of autophagic activity, including upstream regulators and downstream targets of autophagy, could yield additional therapeutic targets. If the advances in autophagy continue at an accelerated pace, agents acting on autophagy may eventually provide useful therapies for human diseases.
Creative Biogene is able to offer a variety of autophagy-related products including stable cell lines, viral particles and clones for your drug discovery projects.
Autophagy Product Panel
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