Hsp90ย (heat shock protein 90) is aย chaperone proteinย that assists other proteins toย foldย properly, stabilizes proteins againstย heat stress, and aids inย protein degradation. It also stabilizes a number of proteins required for tumor growth, which is whyย Hsp90 inhibitorsย are investigated as anti-cancer drugs.
Heat shock proteins, as a class, are among the most highly expressedย cellularย proteins across all species.[3]ย As their name implies, heat shock proteins protect cells when stressed by elevated temperatures. They account for 1โ2% of total protein in unstressed cells. However, when cells are heated, the fraction of heat shock proteins increases to 4โ6% of cellular proteins.[4]
Heat shock protein 90 (Hsp90) is one of the most common of the heat-related proteins. The โ90โ comes from the fact that it weighs roughly 90ย kiloDaltons. A 90ย kDa protein is considered fairly large for a non-fibrous protein. Hsp90 is found inย bacteriaย and all branches ofย eukarya, but it is apparently absent inย archaea.[5]ย Whereas cytoplasmic Hsp90 is essential for viability under all conditions inย eukaryotes, the bacterial homologueย HtpGย is dispensable under non-heat stress conditions.[6]
This protein was first isolated by extracting proteins from cells stressed by heating, dehydrating or by other means, all of which caused the cellโs proteins to begin toย denature.[7]ย However it was later discovered that Hsp90 also has essential functions in unstressed cells. -wiki
Aging is the main risk factor for many chronic degenerative diseases and cancer. Increased senescent cell burden in various tissues is a major contributor to aging and age-related diseases. Recently, a new class of drugs termed senolytics were demonstrated to extending healthspan, reducing frailty and improving stem cell function in multiple murine models of aging. To identify novel and more optimal senotherapeutic drugs and combinations, we established a senescence associated ฮฒ-galactosidase assay as a screening platform to rapidly identify drugs that specifically affect senescent cells. We used primary Ercc1 โ/โ murine embryonic fibroblasts with reduced DNA repair capacity, which senesce rapidly if grown at atmospheric oxygen. This platform was used to screen a small library of compounds that regulate autophagy, identifying two inhibitors of the HSP90 chaperone family as having significant senolytic activity in mouse and human cells. Treatment of Ercc1 โ/โ mice, a mouse model of a human progeroid syndrome, with the HSP90 inhibitor 17-DMAG extended healthspan, delayed the onset of several age-related symptoms and reduced p16INK4a expression. These results demonstrate the utility of our screening platform to identify senotherapeutic agents as well as identified HSP90 inhibitors as a promising new class of senolytic drugs.
SCIENTIFIC STUDIES
Mandatory FDA Disclaimer: Not intended to diagnose, treat, cure or prevent any disease.
Mandatory FDA Disclaimer: Not intended to diagnose, treat, cure or prevent any disease.