{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,25]],"date-time":"2026-10-25T05:11:49Z","timestamp":1792905109230,"version":"4.5.0"},"reference-count":48,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,11,30]],"date-time":"2023-11-30T00:00:00Z","timestamp":1701302400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Mol. Biosci."],"abstract":"<jats:p>The tumour-associated carbonic anhydrases (CA) IX and XII are upregulated by cancer cells to combat cellular and metabolic stress imparted by hypoxia and acidosis in solid tumours. Owing to its tumour-specific expression and function, CAIX is an attractive therapeutic target and this has driven intense efforts to develop pharmacologic agents to target its activity, including small molecule inhibitors. Many studies in multiple solid tumour models have demonstrated that targeting CAIX activity with the selective CAIX\/XII inhibitor, SLC-0111, results in anti-tumour efficacy, particularly when used in combination with chemotherapy or immune checkpoint blockade, and has now advanced to the clinic. However, it has been observed that sustainability and durability of CAIX inhibition, even in combination with chemotherapy agents, is limited by the occurrence of adaptive resistance, resulting in tumour recurrence. Importantly, the data from these models demonstrates that CAIX inhibition may sensitize tumour cells to cytotoxic drugs and evidence now points to ferroptosis, an iron-dependent form of regulated cell death (RCD) that results from accumulation of toxic levels of phospholipid peroxidation as a major mechanism involved in CAIX-mediated sensitization to cancer therapy. In this mini-review, we discuss recent advances demonstrating the mechanistic role CAIX plays in sensitizing cancer cells to ferroptosis.<\/jats:p>","DOI":"10.3389\/fmolb.2023.1327310","type":"journal-article","created":{"date-parts":[[2023,11,30]],"date-time":"2023-11-30T07:19:00Z","timestamp":1701328740000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":15,"title":["Co-vulnerabilities of inhibiting carbonic anhydrase IX in ferroptosis-mediated tumor cell death"],"prefix":"10.3389","volume":"10","author":[{"given":"Paul C.","family":"McDonald","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shoukat","family":"Dedhar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,11,30]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"639","DOI":"10.1038\/nature24637","article-title":"NFS1 undergoes positive selection in lung tumours and protects cells from ferroptosis","volume":"551","author":"Alvarez","year":"2017","journal-title":"Nature"},{"key":"B2","doi-asserted-by":"publisher","first-page":"216338","DOI":"10.1016\/j.canlet.2023.216338","article-title":"The CAIX inhibitor SLC-0111 exerts anti-cancer activity on gastric cancer cell lines and resensitizes resistant cells to 5-Fluorouracil, taxane-derived, and platinum-based drugs","author":"Andreucci","year":"2023","journal-title":"Cancer Lett."},{"key":"B3","doi-asserted-by":"publisher","first-page":"e92928","DOI":"10.1172\/jci.insight.92928","article-title":"Addition of carbonic anhydrase 9 inhibitor SLC-0111 to temozolomide treatment delays glioblastoma growth in vivo","volume":"2","author":"Boyd","year":"2017","journal-title":"JCI Insight"},{"key":"B4","doi-asserted-by":"publisher","first-page":"6328","DOI":"10.1021\/acs.jmedchem.8b00770","article-title":"Discovery of 4-Hydroxy-3-(3-(phenylureido)benzenesulfonamides as SLC-0111 analogues for the treatment of hypoxic tumors overexpressing carbonic anhydrase IX","volume":"61","author":"Bozdag","year":"2018","journal-title":"J. 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