{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,25]],"date-time":"2026-10-25T05:11:51Z","timestamp":1792905111503,"version":"4.5.0"},"reference-count":104,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2021,12,14]],"date-time":"2021-12-14T00:00:00Z","timestamp":1639440000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006769","name":"Russian Science Foundation","doi-asserted-by":"publisher","award":["21-73-20264"],"award-info":[{"award-number":["21-73-20264"]}],"id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Combination therapy is becoming imperative for the treatment of many cancers, as it provides a higher chance of avoiding drug resistance and tumor recurrence. Among the resistance-conferring factors, the tumor microenvironment plays a major role, and therefore, represents a viable target for adjuvant therapeutic agents. Thus, hypoxia and extracellular acidosis are known to select for the most aggressive and resilient phenotypes and build poorly responsive regions of the tumor mass. Carbonic anhydrase (CA, EC 4.2.1.1) IX isoform is a surficial zinc metalloenzyme that is proven to play a central role in regulating intra and extracellular pH, as well as modulating invasion and metastasis processes. With its strong association and distribution in various tumor tissues and well-known druggability, this protein holds great promise as a target to pharmacologically interfere with the tumor microenvironment by using drug combination regimens. In the present review, we summarized recent publications revealing the potential of CA IX inhibitors to intensify cancer chemotherapy and overcome drug resistance in preclinical settings.<\/jats:p>","DOI":"10.3390\/ijms222413405","type":"journal-article","created":{"date-parts":[[2021,12,14]],"date-time":"2021-12-14T09:34:25Z","timestamp":1639474465000},"page":"13405","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":75,"title":["Carbonic Anhydrase IX Inhibitors as Candidates for Combination Therapy of Solid Tumors"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6421-1208","authenticated-orcid":false,"given":"Stanislav","family":"Kalinin","sequence":"first","affiliation":[{"name":"Institute of Chemistry, Saint Petersburg State University, 199034 Saint Petersburg, Russia"},{"name":"School of Pharmacy, University of Eastern Finland, 70211 Kuopio, Finland"},{"name":"Medicinal Chemistry Center, Togliatti State University, 445020 Togliatti, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Malkova","sequence":"additional","affiliation":[{"name":"Institute of Chemistry, Saint Petersburg State University, 199034 Saint Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatiana","family":"Sharonova","sequence":"additional","affiliation":[{"name":"Institute of Chemistry, Saint Petersburg State University, 199034 Saint Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3717-0471","authenticated-orcid":false,"given":"Vladimir","family":"Sharoyko","sequence":"additional","affiliation":[{"name":"Institute of Chemistry, Saint Petersburg State University, 199034 Saint Petersburg, Russia"},{"name":"Medicinal Chemistry Center, Togliatti State University, 445020 Togliatti, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6408-8329","authenticated-orcid":false,"given":"Alexander","family":"Bunev","sequence":"additional","affiliation":[{"name":"Medicinal Chemistry Center, Togliatti State University, 445020 Togliatti, Russia"}],"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, Universita degli Studi di Firenze, 50019 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0200-4772","authenticated-orcid":false,"given":"Mikhail","family":"Krasavin","sequence":"additional","affiliation":[{"name":"Institute of Chemistry, Saint Petersburg State University, 199034 Saint Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1038\/s41586-019-1730-1","article-title":"A view on drug resistance in cancer","volume":"575","author":"Vasan","year":"2019","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"339","DOI":"10.15171\/apb.2017.041","article-title":"The different mechanisms of cancer drug resistance: A brief review","volume":"7","author":"Mansoori","year":"2017","journal-title":"Adv. Pharm. Bull."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Roma-Rodrigues, C., Mendes, R., Baptista, P.V., and Fernandes, A.R. (2019). Targeting tumor microenvironment for cancer therapy. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20040840"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2032","DOI":"10.1021\/mp200292c","article-title":"Drug resistance and cellular adaptation to tumor acidic pH microenvironment","volume":"8","author":"Wojtkowiak","year":"2011","journal-title":"Mol. Pharm."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1007\/s10555-019-09792-7","article-title":"Causes, consequences, and therapy of tumors acidosis","volume":"38","author":"Pillai","year":"2019","journal-title":"Cancer Metastasis Rev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1007\/s10555-019-09787-4","article-title":"Acidosis and cancer: From mechanism to neutralization","volume":"38","author":"Estrella","year":"2019","journal-title":"Cancer Metastasis Rev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3935","DOI":"10.1073\/pnas.79.13.3935","article-title":"Growth factor activation of an amiloride-sensitive Na+\/H+ exchange system in quiescent fibroblasts: Coupling to ribosomal protein S6 phosphorylation","volume":"79","author":"Chambard","year":"1982","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Frost, S., and McKenna, R. (2014). Carbonic Anhydrase IX: Regulation and Role in Cancer. Carbonic Anhydrase: Mechanism, Regulation, Links to Disease, and Industrial Applications, Springer. Chapter 11.","DOI":"10.1007\/978-94-007-7359-2"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"20299","DOI":"10.1074\/jbc.M109.006478","article-title":"The role of carbonic anhydrase 9 in regulating extracellular and intracellular pH in three-dimensional tumor cell growths","volume":"284","author":"Swietach","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1158\/0008-5472.CAN-08-2470","article-title":"Hypoxia-inducible carbonic anhydrase IX and XII promote tumor cell growth by counteracting acidosis through the regulation of the intracellular pH","volume":"69","author":"Chiche","year":"2009","journal-title":"Cancer Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2485","DOI":"10.1002\/med.21713","article-title":"Progress in the development of human carbonic anhydrase inhibitors and their pharmacological applications: Where are we today?","volume":"40","author":"Mishra","year":"2020","journal-title":"Med. Res. Rev."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Singh, S., Lomelino, C.L., Mboge, M.Y., Frost, S.C., and McKenna, R. (2018). Cancer drug development of carbonic anhydrase inhibitors beyond the active site. Molecules, 23.","DOI":"10.3390\/molecules23051045"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1016\/S0960-894X(03)00091-X","article-title":"Carbonic anhydrase inhibitors: Inhibition of the tumor-associated isozyme IX with aromatic and heterocyclic sulfonamides","volume":"13","author":"Vullo","year":"2003","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3828","DOI":"10.1016\/j.bmcl.2005.06.055","article-title":"Carbonic anhydrase inhibitors: Inhibition of the transmembrane isozyme XIV with sulfonamides","volume":"15","author":"Nishimori","year":"2005","journal-title":"Bioorganic Med. Chem. Lett."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2569","DOI":"10.1016\/j.bmc.2017.03.027","article-title":"Synthesis and carbonic anhydrase inhibition of a series of SLC-0111 analogs","volume":"25","author":"Carta","year":"2017","journal-title":"Bioorganic Med. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1016\/j.bmcl.2004.11.058","article-title":"Carbonic anhydrase inhibitors: Synthesis and inhibition of cytosolic\/tumor-associated carbonic anhydrase isozymes I, II, and IX with bis-sulfamates","volume":"15","author":"Winum","year":"2005","journal-title":"Bioorganic Med. Chem. Lett."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1080\/14756366.2016.1177525","article-title":"Lansoprazole and carbonic anhydrase IX inhibitors sinergize against human melanoma cells","volume":"31","author":"Federici","year":"2016","journal-title":"J. Enzym. Inhib. Med. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"11402","DOI":"10.3390\/ijms140611402","article-title":"Application of monoclonal antibody G250 recognizing carbonic anhydrase IX in renal cell carcinoma","volume":"14","author":"Boerman","year":"2013","journal-title":"Int. J. Mol. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"4322","DOI":"10.7150\/thno.21848","article-title":"Past, present, and future: Development of theranostic agents targeting carbonic anhydrase IX","volume":"7","author":"Lau","year":"2017","journal-title":"Theranostics"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"369","DOI":"10.3892\/ol.2021.12630","article-title":"Altered glycolysis results in drug-resistant in clinical tumor therapy","volume":"21","author":"Peng","year":"2021","journal-title":"Oncol. Lett."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1016\/j.radonc.2013.06.018","article-title":"Targeting carbonic anhydrase IX by nitroimidazole based sulfamides enhances the therapeutic effect of tumor irradiation: A new concept of dual targeting drugs","volume":"108","author":"Dubois","year":"2013","journal-title":"Radiother. Oncol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1016\/j.radonc.2011.05.045","article-title":"Specific inhibition of carbonic anhydrase IX activity enhances the in vivo therapeutic effect of tumor irradiation","volume":"99","author":"Dubois","year":"2011","journal-title":"Radiother. Oncol."},{"key":"ref_23","unstructured":"(2021, October 16). Inhibition of CArbonic Anhydrase in Combination with Platinum and Etoposide-based Radiochemotherapy in Patients with Localized Small Cell Lung Cancer\u2014Full Text View\u2014ClinicalTrials.gov, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT03467360."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1186\/1479-5876-8-57","article-title":"Proton dynamics in cancer","volume":"8","author":"Huber","year":"2010","journal-title":"J. Transl. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1038\/nrd3554","article-title":"Interfering with pH regulation in tumours as a therapeutic strategy","volume":"10","author":"Neri","year":"2011","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1016\/j.apsb.2015.05.007","article-title":"HIF-1\u03b1 pathway: Role, regulation and intervention for cancer therapy","volume":"5","author":"Masoud","year":"2015","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1016\/j.febslet.2004.10.043","article-title":"Hypoxia activates the capacity of tumor-associated carbonic anhydrase IX to acidify extracellular pH","volume":"577","author":"Casini","year":"2004","journal-title":"FEBS Lett."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1080\/1475636031000138732","article-title":"Carbonic anhydrase inhibitors. Inhibition of cytosolic isozymes I and II and transmembrane, cancer-associated isozyme IX with anions","volume":"18","author":"Vullo","year":"2003","journal-title":"J. Enzym. Inhib. Med. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Mboge, M.Y., Mahon, B.P., McKenna, R., and Frost, S.C. (2018). Carbonic anhydrases: Role in pH control and cancer. Metabolites, 8.","DOI":"10.3390\/metabo8010019"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1906","DOI":"10.1080\/14756366.2020.1825409","article-title":"An overview of carbohydrate-based carbonic anhydrase inhibitors","volume":"35","author":"Cuffaro","year":"2020","journal-title":"J. Enzym. Inhib. Med. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1207","DOI":"10.1016\/S0006-2952(03)00467-2","article-title":"Tumor acidity, ion trapping and chemotherapeutics: I. Acid pH affects the distribution of chemotherapeutic agents in vitro","volume":"66","author":"Mahoney","year":"2003","journal-title":"Biochem. Pharmacol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1038\/s41416-019-0642-z","article-title":"Carbonic anhydrase IX and acid transport in cancer","volume":"122","author":"Becker","year":"2020","journal-title":"Br. J. Cancer"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"360","DOI":"10.3109\/14756366.2012.736979","article-title":"Inhibition of carbonic anhydrase activity modifies the toxicity of doxorubicin and melphalan in tumour cells in vitro","volume":"28","author":"Gieling","year":"2012","journal-title":"J. Enzym. Inhib. Med. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Mokhtari, R.B., Kumar, S., Islam, S.S., Yazdanpanah, M., Adeli, K., Cutz, E., and Yeger, H. (2013). Combination of carbonic anhydrase inhibitor, acetazolamide, and sulforaphane, reduces the viability and growth of bronchial carcinoid cell lines. BMC Cancer, 13.","DOI":"10.1186\/1471-2407-13-378"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"5438179","DOI":"10.1155\/2018\/5438179","article-title":"Anticancer activity of sulforaphane: The epigenetic mechanisms and the Nrf2 signaling pathway","volume":"2018","author":"Su","year":"2018","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"33982","DOI":"10.18632\/oncotarget.26125","article-title":"Sulforaphane inhibits growth and blocks Wnt\/\u03b2-catenin signaling of colorectal cancer cells","volume":"9","author":"Bernkopf","year":"2018","journal-title":"Oncotarget"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Rai, R., Essel, K.G., Benbrook, D.M., Garland, J., Zhao, Y.D., and Chandra, V. (2020). Preclinical efficacy and involvement of AKT, mTOR, and ERK kinases in the mechanism of sulforaphane against endometrial cancer. Cancers, 12.","DOI":"10.3390\/cancers12051273"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1186\/s13148-015-0132-y","article-title":"Nrf2 status affects tumor growth, HDAC3 gene promoter associations, and the response to sulforaphane in the colon","volume":"7","author":"Rajendran","year":"2015","journal-title":"Clin. Epigenetics"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1186\/s13045-016-0311-0","article-title":"Modification of platinum sensitivity by KEAP1\/NRF2 signals in non-small cell lung cancer","volume":"9","author":"Tian","year":"2016","journal-title":"J. Hematol. Oncol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1158\/1535-7163.MCT-09-0589","article-title":"Loss of kelch-like ECH-associated protein 1 function in prostate cancer cells causes chemoresistance and radioresistance and promotes tumor growth","volume":"9","author":"Zhang","year":"2010","journal-title":"Mol. Cancer Ther."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"5487","DOI":"10.1158\/0008-5472.CAN-07-6171","article-title":"Serotonin receptors, novel targets of sulforaphane identified by proteomic analysis in Caco-2 cells","volume":"68","author":"Mastrangelo","year":"2008","journal-title":"Cancer Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1007\/s12272-020-01225-2","article-title":"Sulforaphane as an anticancer molecule: Mechanisms of action, synergistic effects, enhancement of drug safety, and delivery systems","volume":"43","author":"Kamal","year":"2020","journal-title":"Arch. Pharm. Res."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Mokhtari, R.B., Baluch, N., Morgatskaya, E., Kumar, S., Sparaneo, A., Muscarella, L.A., Zhao, S., Cheng, H.L., Das, B., and Yeger, H. (2019). Human bronchial carcinoid tumor initiating cells are targeted by the combination of acetazolamide and sulforaphane. BMC Cancer, 19.","DOI":"10.1186\/s12885-019-6018-1"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1007\/s11523-015-0386-5","article-title":"Simultaneous Targeting of Bladder Tumor Growth, Survival, and Epithelial-to-Mesenchymal Transition with a Novel Therapeutic Combination of Acetazolamide (AZ) and Sulforaphane (SFN)","volume":"11","author":"Islam","year":"2016","journal-title":"Target. Oncol."},{"key":"ref_45","first-page":"9299","article-title":"Combined treatment with acetazolamide and cisplatin enhances chemosensitivity in laryngeal carcinoma Hep-2 cells","volume":"15","author":"Gao","year":"2018","journal-title":"Oncol. Lett."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.det.2016.07.001","article-title":"Mosaic Disorders of the PI3K\/PTEN\/AKT\/TSC\/mTORC1 Signaling Pathway","volume":"35","author":"Nathan","year":"2017","journal-title":"Dermatol. Clin."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2052","DOI":"10.1056\/NEJMra1704560","article-title":"Phosphatidylinositol 3-Kinase, Growth Disorders, and Cancer","volume":"379","author":"Goncalves","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"571","DOI":"10.2174\/187152010793498663","article-title":"Updates of mTOR Inhibitors","volume":"10","author":"Zhou","year":"2012","journal-title":"Anticancer. Agents Med. Chem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1007\/s11523-011-0167-8","article-title":"Mechanisms of mTOR inhibitor resistance in cancer therapy","volume":"6","author":"Carew","year":"2011","journal-title":"Target. Oncol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"36666","DOI":"10.18632\/oncotarget.9134","article-title":"Targeting carbonic anhydrase IX improves the anti-cancer efficacy of mTOR inhibitors","volume":"7","author":"Faes","year":"2016","journal-title":"Oncotarget"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"9023","DOI":"10.1007\/s13277-016-4785-8","article-title":"Inhibition of carbonic anhydrase potentiates bevacizumab treatment in cholangiocarcinoma","volume":"37","author":"Vaeteewoottacharn","year":"2016","journal-title":"Tumor Biol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1038\/sj.bjc.6604129","article-title":"Clinicopathological and prognostic significance of EGFR, VEGF, and HER2 expression in cholangiocarcinoma","volume":"98","author":"Yoshikawa","year":"2008","journal-title":"Br. J. Cancer"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1439","DOI":"10.5754\/hge11156","article-title":"Hypoxia inducible factor expression in intrahepatic cholangiocarcinoma","volume":"58","author":"Morine","year":"2011","journal-title":"Hepatogastroenterology."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.taap.2016.12.017","article-title":"Carbonic anhydrase inhibition boosts the antitumor effects of Imatinib mesylate via potentiating the antiangiogenic and antimetastatic machineries","volume":"316","author":"Darwish","year":"2017","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1186\/s43042-019-0035-0","article-title":"Exploring receptor tyrosine kinases-inhibitors in Cancer treatments","volume":"20","author":"Metibemu","year":"2019","journal-title":"Egypt. J. Med. Hum. Genet."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Singh, A.K., Bishayee, A., and Pandey, A.K. (2018). Targeting Histone Deacetylases with Natural and Synthetic Agents: An Emerging Anticancer Strategy. Nutrients, 10.","DOI":"10.3390\/nu10060731"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1102","DOI":"10.1002\/bies.201600070","article-title":"Histone deacetylase inhibitors for cancer therapy: An evolutionarily ancient resistance response may explain their limited success","volume":"38","author":"Halsall","year":"2016","journal-title":"BioEssays"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"92","DOI":"10.3389\/fonc.2018.00092","article-title":"Combination therapy with histone deacetylase inhibitors (HDACi) for the treatment of cancer: Achieving the full therapeutic potential of HDACi","volume":"8","author":"Suraweera","year":"2018","journal-title":"Front. Oncol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"436","DOI":"10.2174\/138161209787315774","article-title":"Targeting Histone Deacetylases in Neuroblastoma","volume":"15","author":"Witt","year":"2009","journal-title":"Curr. Pharm. Des."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Bayat Mokhtari, R., Baluch, N., Ka Hon Tsui, M., Kumar, S., Homayouni, T.S., Aitken, K., Das, B., Baruchel, S., and Yeger, H. (2017). Acetazolamide potentiates the anti-tumor potential of HDACi, MS-275, in neuroblastoma. BMC Cancer, 17.","DOI":"10.1186\/s12885-017-3126-7"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"e838","DOI":"10.1016\/S2352-3026(20)30222-2","article-title":"A perspective on improving the R-CHOP regimen: From Mega-CHOP to ROBUST R-CHOP, the PHOENIX is yet to rise","volume":"7","author":"Lue","year":"2020","journal-title":"Lancet Haematol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1097\/00001622-200009000-00005","article-title":"Treatment of non-Hodgkin lymphoma","volume":"12","author":"Hauke","year":"2000","journal-title":"Curr. Opin. Oncol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"2286","DOI":"10.1182\/bloodadvances.2020001816","article-title":"High metabolic heterogeneity on baseline 18FDG-PET\/CT scan as a poor prognostic factor for newly diagnosed diffuse large B-cell lymphoma","volume":"4","author":"Senjo","year":"2020","journal-title":"Blood Adv."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Klener, P. (2020). Drug Resistance in Non-Hodgkin Lymphomas. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21062081"},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"M\u00e9hes, G., Matolay, O., Beke, L., Czenke, M., P\u00f3rsz\u00e1sz, R., Mik\u00f3, E., Bai, P., Ber\u00e9nyi, E., and Trencs\u00e9nyi, G. (2020). Carbonic anhydrase inhibitor acetazolamide enhances chop treatment response and stimulates effector t-cell infiltration in a20\/balbc murine b-cell lymphoma. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21145001"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1186\/s12967-016-1073-8","article-title":"A novel non-Hodgkin lymphoma murine model closer to the standard clinical scenario","volume":"14","author":"Bascuas","year":"2016","journal-title":"J. Transl. Med."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1167\/iovs.08-2435","article-title":"The vasodilating effect of acetazolamide and dorzolamide involves mechanisms other than carbonic anhydrase inhibition","volume":"50","author":"Torring","year":"2009","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Joshi, K., Ghosalkar, J.D., Sonawane, V.R., Raut, S.R., and Malhotra, G. (April, January 29). Abstract 2013: A carbonic anhydrase inhibitor methazolamide potentiates efficacy of gemcitabine by modulating anti-proliferative activity and cancer stem cell markers in pancreatic carcinoma. Proceedings of the AACR Annual Meeting 2019, Atlanta, GA, USA.","DOI":"10.1158\/1538-7445.SABCS18-2013"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1080\/14756366.2018.1532419","article-title":"The carbonic anhydrase IX inhibitor SLC-0111 sensitises cancer cells to conventional chemotherapy","volume":"34","author":"Andreucci","year":"2019","journal-title":"J. Enzym. Inhib. Med. Chem."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"16022","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":"ref_71","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1053\/j.gastro.2019.05.004","article-title":"Regulation of pH by Carbonic Anhydrase 9 Mediates Survival of Pancreatic Cancer Cells with Activated KRAS in Response to Hypoxia","volume":"157","author":"McDonald","year":"2019","journal-title":"Gastroenterology"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"16022","DOI":"10.1038\/nrdp.2016.22","article-title":"Pancreatic cancer","volume":"2","author":"Kleeff","year":"2016","journal-title":"Nat. Rev. Dis. Prim."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1158\/2159-8290.CD-15-0822","article-title":"Hif1a deletion reveals pro-neoplastic function of B cells in pancreatic neoplasia","volume":"6","author":"Lee","year":"2016","journal-title":"Cancer Discov."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Van Kuijk, S.J.A., Gieling, R.G., Niemans, R., Lieuwes, N.G., Biemans, R., Telfer, B.A., Haenen, G.R.M.M., Yaromina, A., Lambin, P., and Dubois, L.J. (2016). The sulfamate small molecule CAIX inhibitor S4 modulates doxorubicin efficacy. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0161040"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"4681","DOI":"10.1016\/j.bmcl.2012.05.083","article-title":"Ureido-substituted sulfamates show potent carbonic anhydrase IX inhibitory and antiproliferative activities against breast cancer cell lines","volume":"22","author":"Winum","year":"2012","journal-title":"Bioorganic Med. Chem. Lett."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"24856","DOI":"10.18632\/oncotarget.4498","article-title":"Evaluation of carbonic anhydrase IX as a therapeutic target for inhibition of breast cancer invasion and metastasis using a series of in vitro breast cancer models","volume":"6","author":"Ward","year":"2015","journal-title":"Oncotarget"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"5591","DOI":"10.1021\/jm300529u","article-title":"Antimetastatic effect of sulfamate carbonic anhydrase IX inhibitors in breast carcinoma xenografts","volume":"55","author":"Gieling","year":"2012","journal-title":"J. Med. Chem."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1002\/ijc.31042","article-title":"Novel carbonic anhydrase IX-targeted therapy enhances the anti-tumour effects of cisplatin in small cell lung cancer","volume":"142","author":"Bryant","year":"2017","journal-title":"Int. J. Cancer"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"109326","DOI":"10.1016\/j.cbi.2020.109326","article-title":"Combined 3-O-acetylbetulin treatment and carbonic anhydrase IX inhibition results in additive effects on human breast cancer cells","volume":"333","author":"Petrenko","year":"2021","journal-title":"Chem. Biol. Interact."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.2217\/fon.14.60","article-title":"Targeting DNA repair pathways for cancer treatment: What\u2019s new?","volume":"10","author":"Kelley","year":"2014","journal-title":"Futur. Oncol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1089\/ars.2008.2194","article-title":"The many functions of APE1\/Ref-1: Not only a DNA repair enzyme","volume":"11","author":"Tell","year":"2009","journal-title":"Antioxid. Redox Signal."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1698","DOI":"10.1158\/1535-7163.MCT-11-0107","article-title":"Impact of APE1\/ref-1 redox inhibition on pancreatic tumor growth","volume":"10","author":"Fishel","year":"2011","journal-title":"Mol. Cancer Ther."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"2722","DOI":"10.1158\/1535-7163.MCT-16-0253","article-title":"Regulation of HIF1 \u03b1 under Hypoxia by APE1\/Ref-1 Impacts CA9 Expression: Dual-Targeting in Patient-Derived 3D Pancreatic Cancer Models","volume":"15","author":"Logsdon","year":"2016","journal-title":"Mol. Cancer Ther."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"13759","DOI":"10.1038\/s41598-018-32034-9","article-title":"Blocking HIF signaling via novel inhibitors of CA9 and APE1\/Ref-1 dramatically affects pancreatic cancer cell survival","volume":"8","author":"Logsdon","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Hedlund, E.M.E., McDonald, P.C., Nemirovsky, O., Awrey, S., Jensen, L.D.E., and Dedhar, S. (2019). Harnessing induced essentiality: Targeting carbonic anhydrase IX and angiogenesis reduces lung metastasis of triple negative breast cancer xenografts. Cancers, 11.","DOI":"10.3390\/cancers11071002"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1038\/s41467-020-17670-y","article-title":"A decade of immune-checkpoint inhibitors in cancer therapy","volume":"11","author":"Robert","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"86","DOI":"10.3389\/fonc.2018.00086","article-title":"Anti-PD-1 and anti-CTLA-4 therapies in cancer: Mechanisms of action, efficacy, and limitations","volume":"8","author":"Seidel","year":"2018","journal-title":"Front. Oncol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1064","DOI":"10.1158\/2326-6066.CIR-18-0657","article-title":"Targeting hypoxia-induced carbonic anhydrase IX enhances immune-checkpoint blockade locally and systemically","volume":"7","author":"Chafe","year":"2019","journal-title":"Cancer Immunol. Res."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1247","DOI":"10.1634\/theoncologist.12-10-1247","article-title":"FDA Approval Summary: Vorinostat for Treatment of Advanced Primary Cutaneous T-Cell Lymphoma","volume":"12","author":"Mann","year":"2007","journal-title":"Oncologist"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1080\/14756366.2019.1706090","article-title":"A potentiated cooperation of carbonic anhydrase IX and histone deacetylase inhibitors against cancer","volume":"35","author":"Ruzzolini","year":"2020","journal-title":"J. Enzym. Inhib. Med. Chem."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1702","DOI":"10.1093\/jnci\/djh305","article-title":"Effect of proton pump inhibitor pretreatment on resistance of solid tumors to cytotoxic drugs","volume":"96","author":"Luciani","year":"2004","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"2474","DOI":"10.1002\/jcb.24122","article-title":"Reversal effects of pantoprazole on multidrug resistance in human gastric adenocarcinoma cells by down-regulating the V-ATPases\/mTOR\/HIF-1\u03b1\/P-gp and MRP1 signaling pathway in vitro and in vivo","volume":"113","author":"Chen","year":"2012","journal-title":"J. Cell. Biochem."},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Uchiyama, A.A.T., Silva, P.A.I.A., Lopes, M.S.M., Yen, C.T., Ricardo, E.D., Mut\u00e3o, T., Pimenta, J.R., Machado, L.M., Shimba, D.S., and Peixoto, R.D. (2021). Proton pump inhibitors and oncologic treatment efficacy: A practical review of the literature for oncologists. Curr. Oncol., 28.","DOI":"10.3390\/curroncol28010076"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1186\/s12967-015-0735-2","article-title":"Evidence-based support for the use of proton pump inhibitors in cancer therapy","volume":"13","author":"Fais","year":"2015","journal-title":"J. Transl. Med."},{"key":"ref_95","doi-asserted-by":"crossref","unstructured":"Iessi, E., Logozzi, M., Mizzoni, D., Di Raimo, R., Supuran, C.T., and Fais, S. (2018). Rethinking the combination of proton exchanger inhibitors in cancer therapy. Metabolites, 8.","DOI":"10.3390\/metabo8010002"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1097\/COC.0000000000000691","article-title":"A Phase 1 Study of SLC-0111, a Novel Inhibitor of Carbonic Anhydrase IX, in Patients with Advanced Solid Tumors","volume":"43","author":"McDonald","year":"2020","journal-title":"Am. J. Clin. Oncol. Cancer Clin. Trials"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1053\/j.seminoncol.2018.12.003","article-title":"Systemic treatment of pancreatic cancer revisited","volume":"46","author":"Ducreux","year":"2019","journal-title":"Semin. Oncol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1111\/j.1582-4934.2009.00994.x","article-title":"Tumour hypoxia induces a metabolic shift causing acidosis: A common feature in cancer","volume":"14","author":"Chiche","year":"2010","journal-title":"J. Cell. Mol. Med."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1016\/j.canlet.2008.07.034","article-title":"A CD147-targeting siRNA inhibits the proliferation, invasiveness, and VEGF production of human malignant melanoma cells by down-regulating glycolysis","volume":"273","author":"Su","year":"2009","journal-title":"Cancer Lett."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"L941","DOI":"10.1152\/ajplung.00528.2005","article-title":"HIF-1 regulates hypoxic induction of NHE1 expression and alkalinization of intracellular pH in pulmonary arterial myocytes","volume":"291","author":"Shimoda","year":"2006","journal-title":"Am. J. Physiology-Lung Cell. Mol. Physiol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"2570","DOI":"10.1128\/MCB.00166-09","article-title":"Hypoxia-Induced Autophagy Is Mediated through Hypoxia-Inducible Factor Induction of BNIP3 and BNIP3L via Their BH3 Domains","volume":"29","author":"Bellot","year":"2009","journal-title":"Mol. Cell. Biol."},{"key":"ref_102","doi-asserted-by":"crossref","unstructured":"Chen, J.L.Y., Lucas, J.E., Schroeder, T., Mori, S., Wu, J., Nevins, J., Dewhirst, M., West, M., and Chi, J.T. (2008). The genomic analysis of lactic acidosis and acidosis response in human cancers. PLoS Genet., 4.","DOI":"10.1371\/journal.pgen.1000293"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"eabj0364","DOI":"10.1126\/sciadv.abj0364","article-title":"Genome-wide synthetic lethal screen unveils novel CAIX-NFS1\/xCT axis as a targetable vulnerability in hypoxic solid tumors","volume":"7","author":"Chafe","year":"2021","journal-title":"Sci. Adv."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"963","DOI":"10.1080\/13543784.2018.1548608","article-title":"Carbonic anhydrase inhibitors: An update on experimental agents for the treatment and imaging of hypoxic tumors","volume":"27","author":"Supuran","year":"2021","journal-title":"Expert. Opin. Investig. Drugs"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/24\/13405\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:47:17Z","timestamp":1760168837000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/24\/13405"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,14]]},"references-count":104,"journal-issue":{"issue":"24","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["ijms222413405"],"URL":"https:\/\/doi.org\/10.3390\/ijms222413405","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,14]]}}}