{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T09:20:24Z","timestamp":1791883224043,"version":"4.3.4"},"reference-count":48,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2021,6,5]],"date-time":"2021-06-05T00:00:00Z","timestamp":1622851200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004410","name":"T\u00fcrkiye Bilimsel ve Teknolojik Ara\u015ftirma Kurumu","doi-asserted-by":"publisher","award":["115Z681"],"award-info":[{"award-number":["115Z681"]}],"id":[{"id":"10.13039\/501100004410","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Carbonic anhydrase IX (CAIX) is a hypoxia-related protein that plays a role in proliferation in solid tumours. However, how CAIX increases proliferation and metastasis in solid tumours is unclear. The objective of this study was to investigate how a synthetic CAIX inhibitor triggers apoptosis in the HeLa cell line. The intracellular effects of CAIX inhibition were determined with AO\/EB, AnnexinV-PI, and \u03b3-H2AX staining; measurements of intracellular pH (pHi), reactive oxygen species (ROS), and mitochondrial membrane potential (MMP); and analyses of cell cycle, apoptotic, and autophagic modulator gene expression (Bax, Bcl-2, caspase-3, caspase-8, caspase-9, caspase-12, Beclin, and LC3), caspase protein level (pro-caspase 3 and cleaved caspase-3, -8, -9), cleaved PARP activation, and CAIX protein level. Sulphonamide CAIX inhibitor E showed the lowest IC50 and the highest selectivity index in CAIX-positive HeLa cells. CAIX inhibition changed the morphology of HeLa cells and increased the ratio of apoptotic cells, dramatically disturbing the homeostasis of intracellular pHi, MMP and ROS levels. All these phenomena consequent to CA IX inhibition triggered apoptosis and autophagy in HeLa cells. Taken together, these results further endorse the previous findings that CAIX inhibitors represent an important therapeutic strategy, which is worth pursuing in different cancer types, considering that presently only one sulphonamide inhibitor, SLC-0111, has arrived in Phase Ib\/II clinical trials as an antitumour\/antimetastatic drug.<\/jats:p>","DOI":"10.3390\/ijms22116098","type":"journal-article","created":{"date-parts":[[2021,6,6]],"date-time":"2021-06-06T23:59:55Z","timestamp":1623023995000},"page":"6098","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":45,"title":["Inhibition of Carbonic Anhydrase IX Promotes Apoptosis through Intracellular pH Level Alterations in Cervical Cancer Cells"],"prefix":"10.3390","volume":"22","author":[{"given":"Ebru","family":"Temiz","sequence":"first","affiliation":[{"name":"Program of Medical Promotion and Marketing, Health Services Vocational School, Harran University, Sanliurfa 63300, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ismail","family":"Koyuncu","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry, Faculty of Medicine, Harran University, Sanliurfa 63290, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3012-7582","authenticated-orcid":false,"given":"Mustafa","family":"Durgun","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Faculty of Arts and Sciences, Harran University, Sanliurfa 63290, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Murat","family":"Caglayan","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry, Diskapi Yildirim Beyazit Training and Research Hospital, Ankara 06110, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7200-1537","authenticated-orcid":false,"given":"Ataman","family":"Gonel","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry, Faculty of Medicine, Harran University, Sanliurfa 63290, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4351-1719","authenticated-orcid":false,"given":"Eray Metin","family":"G\u00fcler","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry, Faculty of Hamidiye Medicine, University of Health Sciences Turkey, Istanbul 34668, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdurrahim","family":"Kocyigit","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry, Faculty of Medicine, Bezmialem Vakif University, Istanbul 34093, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4262-0323","authenticated-orcid":false,"given":"Claudiu T.","family":"Supuran","sequence":"additional","affiliation":[{"name":"NEUROFARBA Department, Section of Pharmaceutical and Nutriceutical Sciences, Universit\u00e0 degli Studi di Firenze, Sesto Fiorentino, 50019 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,6,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1007\/s10555-019-09799-0","article-title":"The role of carbonic anhydrase IX in cancer development: Links to hypoxia, acidosis, and beyond","volume":"38","author":"Pastorekova","year":"2019","journal-title":"Cancer Metastasis Rev."},{"key":"ref_2","unstructured":"Hoyert, D.L. 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