{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:30:04Z","timestamp":1760059804886,"version":"build-2065373602"},"reference-count":70,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2025,7,12]],"date-time":"2025-07-12T00:00:00Z","timestamp":1752278400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["R03CA245780A","8BC11","I01-BX005051"],"award-info":[{"award-number":["R03CA245780A","8BC11","I01-BX005051"]}]},{"name":"Bankhead\u2013Coley Cancer Research Program","award":["R03CA245780A","8BC11","I01-BX005051"],"award-info":[{"award-number":["R03CA245780A","8BC11","I01-BX005051"]}]},{"name":"Veterans Affairs BLR&amp;D Distinguished Medical Research Scientist Award","award":["R03CA245780A","8BC11","I01-BX005051"],"award-info":[{"award-number":["R03CA245780A","8BC11","I01-BX005051"]}]},{"name":"Miami VA Geriatric Research and Clinical Center (GRECC)","award":["R03CA245780A","8BC11","I01-BX005051"],"award-info":[{"award-number":["R03CA245780A","8BC11","I01-BX005051"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Inhibitors of the ubiquitin\u2013proteasome system increase proteotoxic stress and have achieved clinical success for multiple myeloma but not for solid cancers such as hepatocellular carcinoma. Our objective is to identify a combination with proteasome inhibitors that enhances proteotoxic stress and apoptotic cell death in hepatocellular carcinoma but with less toxicity to non-cancer cells. We found that rencofilstat, a pan-cyclophilin inhibitor, combined with ixazomib, a proteasome inhibitor, increased apoptotic cell death in hepatocellular carcinoma but not in umbilical vein or dermal fibroblast non-cancer cells. We then analyzed the effects of rencofilstat + ixazomib on XBP1s and PERK, critical factors in the unfolded protein response used by cells to survive proteotoxic stress. Rencofilstat + ixazomib maintained higher expression of XBP1s and genetic models suggested that XBP1s was a pro-survival protein early and pro-death protein at later times. Simultaneously, decreased PERK expression prevented the block in protein synthesis via phospho-eIF2\u03b1 and likely further amplified proteotoxic stress. Rencofilstat + ixazomib did not have effects on XBP1s or PERK in non-cancer cells. Further genetic experiments revealed the pro-survival roles for cyclophilin A and B in mediating rencofilstat + ixazomib-induced cell death. In the Hep3B xenograft model, rencofilstat + ixazomib significantly inhibited tumor volumes\/weights without general toxicity. We conclude that rencofilstat + ixazomib amplified proteotoxic stress in hepatocellular carcinoma past a threshold pro-survival pathways could not tolerate, whereas non-cancer cells were less affected.<\/jats:p>","DOI":"10.3390\/ijms26146699","type":"journal-article","created":{"date-parts":[[2025,7,14]],"date-time":"2025-07-14T10:55:41Z","timestamp":1752490541000},"page":"6699","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["A Novel Chemotherapy Combination to Enhance Proteotoxic Cell Death in Hepatocellular Carcinoma Experimental Models Without Killing Non-Cancer Cells"],"prefix":"10.3390","volume":"26","author":[{"given":"Carlos","family":"Perez-Stable","sequence":"first","affiliation":[{"name":"Research Service, Bruce W. Carter Veterans Affairs Medical Center, Miami, FL 33125, USA"},{"name":"South Florida VA Foundation for Research and Education, Miami, FL 33125, USA"},{"name":"Geriatric Research, Education, and Clinical Center, Bruce W. Carter Veterans Affairs Medical Center, Miami, FL 33125, USA"},{"name":"Department of Medicine, Division of Gerontology & Palliative Medicine, University of Miami Miller School of Medicine, Miami, FL 33136, USA"},{"name":"Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alicia","family":"de las Pozas","sequence":"additional","affiliation":[{"name":"Research Service, Bruce W. Carter Veterans Affairs Medical Center, Miami, FL 33125, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Teresita","family":"Reiner","sequence":"additional","affiliation":[{"name":"Research Service, Bruce W. Carter Veterans Affairs Medical Center, Miami, FL 33125, USA"},{"name":"Geriatric Research, Education, and Clinical Center, Bruce W. Carter Veterans Affairs Medical Center, Miami, FL 33125, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jose","family":"Gomez","sequence":"additional","affiliation":[{"name":"Research Service, Bruce W. Carter Veterans Affairs Medical Center, Miami, FL 33125, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-1762-7324","authenticated-orcid":false,"given":"Manojavan","family":"Nagarajan","sequence":"additional","affiliation":[{"name":"Research Service, Bruce W. Carter Veterans Affairs Medical Center, Miami, FL 33125, USA"},{"name":"Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-7928-0408","authenticated-orcid":false,"given":"Robert T.","family":"Foster","sequence":"additional","affiliation":[{"name":"Hepion Pharmaceuticals, Edmonton, AB T5J 4P6, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daren R.","family":"Ure","sequence":"additional","affiliation":[{"name":"Hepion Pharmaceuticals, Edmonton, AB T5J 4P6, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7338-2041","authenticated-orcid":false,"given":"Medhi","family":"Wangpaichitr","sequence":"additional","affiliation":[{"name":"Research Service, Bruce W. Carter Veterans Affairs Medical Center, Miami, FL 33125, USA"},{"name":"South Florida VA Foundation for Research and Education, Miami, FL 33125, USA"},{"name":"Geriatric Research, Education, and Clinical Center, Bruce W. Carter Veterans Affairs Medical Center, Miami, FL 33125, USA"},{"name":"Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA"},{"name":"Department of Surgery, Division of Cardiothoracic Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1016\/j.cell.2009.02.024","article-title":"Principles of cancer therapy: Oncogene and non-oncogene addiction","volume":"136","author":"Luo","year":"2009","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Guang, M.H.Z., Kavanagh, E.L., Dunne, L.P., Dowling, P., Zhang, L., Lindsay, S., Bazou, D., Goh, C.Y., Hanley, C., and Bianchi, G. (2019). 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