wYeloma. The combination of proteasome inhibition with novel targeted therapies is an emerging field of oncology. ERAD inhibitors as part of the mechanism of ER quality of t embroidered, misfolded proteins Or remain in separate parts in the ER and then ERAD degraded end. The ERAD pathway as molecular chaperones and lectin proteins In the identification of misfolded proteins are involved. ERresident cleave disulfide reductases in these proteins Easier to retrograde transport into the cytosol. In addition, they removed adenosinetriphosphatase AAA by means of the chain retrotranslocation into the cytosol, where they. By ubiquitin-proteasome system Defects in ERAD Cyt387 cause the accumulation of misfolded proteins in the ER and thus foreign sen ER stress and UPR. I Eeyarestatin, a chemical inhibitor, ERAD can block, has been shown to preferentially cytotoxic activity of t Have against cancer cells. EERI target p97 complex to deubiquitination of p97 YEARS Ring ERAD substrates that inhibit the degradation process required. PDI inhibitors of protein disulfide isomerase is one of the h Most common occurring proteins Aufrechterh ER Lt and a W Daughters function in organizing accurate protein folding. PDIs are important catalysts of protein folding w During the UPR activated. Treatment of cells with O 1 1 ium diazene 1.2 diolate entered Born causes a dose–Dependent increase in intracellular Ren nitric S glutathionylation and therefore inhibition of PDI.
NON PABA active UPR and causes D Cushioning translational phosphorylation and activation of PERK and its downstream effector eIF2a in human leukemia Mie cells and ovarian cancer. There was also evidence of XBP1 mRNA splicing S and transcriptional activation of the ER resident chaperones GRP78 and GRP94. Stimulation of the UPR may be associated with the cytotoxic potential of NO PABA in cancer cells. 4.2. Targeting heat shock ER chaperones HSP90 inhibitor proteins Under conditions of cellular Ren regulate cell stress chaperones to prevent protein misfolding and degradation. The three ER membrane sensors statements are highly Ma S dependent Ngig chaperone proteins HSP90 complex functions. The interaction between the family of heat shock proteins And important proteins Into the path of the UPR may be mediated in part by the destabilizing effect on proteins The UPR and increased Hte accumulation of misfolded proteins folded. Study of myeloma cells demonstrated that inhibitors of HSP90, 17AAG, and radicicol Similar tunicamycin and thapsigargin able to be activate three branches of the UPR. All drugs inhibit the proliferation and increased FITTINGS expression levels of the molecular chaperones BiP and GRP94. Unlike TG and TM, HSP90 inhibitors activate a caspase-dependent-Dependent pathway of cell death. 17AAG k Can the formation, intracellular Re inclusions in the cells of inducing breast cancer. In myeloma cells, these inclusions are composed of combinations of each Nes misfolded immunoglobulin light and analysis of protein samples from cells treated 17AAG suggest that exposure to ver HSP90 inhibitors LC3 expression changed in compliance with the autophagosome formation. Study showed Indicating similar effects of HSP90 inhibitor, 17AAG in HCT116 colon cancer cell line, that they use the UPR in a way Similar to multiple myeloma. A recent phase II study