{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T22:44:09Z","timestamp":1791845049073,"version":"4.3.4"},"reference-count":79,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2024,9,17]],"date-time":"2024-09-17T00:00:00Z","timestamp":1726531200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>This study proposes a novel therapeutic strategy for cancer management by combining the antitumor effects of hydrogen sulfide (H2S) and inhibition of carbonic anhydrases (CAs; EC 4.2.1.1), specifically isoforms IV, IX, and XII. H2S has demonstrated cytotoxicity against various cancers at high concentrations. The inhibition of tumor-associated CAs leads to lethal intracellular alkalinization and acidification of the extracellular tumor microenvironment and restores tumor responsiveness to the immune system, chemotherapy, and radiotherapy. The study proposes H2S donor\u2013CA inhibitor (CAI) hybrids for tumor management. These compounds effectively inhibit the target CAs, release H2S consistently, and exhibit potent antitumor effects against MDA-MB-231, HCT-116, and A549 cancer cell lines. Notably, some compounds display high cytotoxicity across all investigated cell lines. Derivative 30 shows a 2-fold increase in cytotoxicity (0.93 \u00b1 0.02 \u00b5M) under chemically induced hypoxia in HCT-116 cells. These compounds also disturb the cell cycle, leading to a reduction in cell populations in G0\/G1 and S phases, with a notable increase in G2\/M and Sub-G1. This disruption is correlated with induced apoptosis, with fold increases of 37.2, 24.5, and 32.9 against HCT-116 cells and 14.2, 13.1, and 19.9 against A549 cells compared to untreated cells. These findings suggest the potential of H2S releaser\u2013CAI hybrids as effective and versatile tools in cancer treatment.<\/jats:p>","DOI":"10.3390\/ijms251810006","type":"journal-article","created":{"date-parts":[[2024,9,18]],"date-time":"2024-09-18T00:51:43Z","timestamp":1726620703000},"page":"10006","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Hydrogen Sulfide-Releasing Carbonic Anhydrase Inhibitors Effectively Suppress Cancer Cell Growth"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5520-740X","authenticated-orcid":false,"given":"Alessandro","family":"Bonardi","sequence":"first","affiliation":[{"name":"Department of NEUROFARBA, Pharmaceutical and Nutraceutical Section, University of Firenze, Via Ugo Schiff 6, Sesto Fiorentino, 50019 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3342-702X","authenticated-orcid":false,"given":"Alessio","family":"Nocentini","sequence":"additional","affiliation":[{"name":"Department of NEUROFARBA, Pharmaceutical and Nutraceutical Section, University of Firenze, Via Ugo Schiff 6, Sesto Fiorentino, 50019 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3406-833X","authenticated-orcid":false,"given":"Viviana","family":"de Luca","sequence":"additional","affiliation":[{"name":"Department of Biology, Agriculture and Food Sciences, National Research Council (CNR), Institute of Biosciences and Bioresources, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3314-2411","authenticated-orcid":false,"given":"Clemente","family":"Capasso","sequence":"additional","affiliation":[{"name":"Department of Biology, Agriculture and Food Sciences, National Research Council (CNR), Institute of Biosciences and Bioresources, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eslam B.","family":"Elkaeed","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6996-4017","authenticated-orcid":false,"given":"Wagdy M.","family":"Eldehna","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Pharos University in Alexandria, Canal El Mahmoudia St., Alexandria 21648, Egypt"},{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh 33516, Egypt"}],"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":"Department of NEUROFARBA, Pharmaceutical and Nutraceutical Section, University of Firenze, Via Ugo Schiff 6, Sesto Fiorentino, 50019 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,9,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1007\/s10555-007-9058-y","article-title":"Hypoxia and cancer","volume":"26","author":"Semenza","year":"2007","journal-title":"Cancer Metastasis Rev."},{"key":"ref_2","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_3","doi-asserted-by":"crossref","first-page":"83","DOI":"10.2147\/HP.S93413","article-title":"The role of hypoxia in cancer progression, angiogenesis, metastasis, and resistance to therapy","volume":"3","author":"Muz","year":"2015","journal-title":"Hypoxia"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Ma, Z., Xiang, X., Li, S., Xie, P., Gong, Q., Goh, B.C., and Wang, L. (2022). Targeting hypoxia-inducible factor-1 for cancer treatment: Recent advances in developing small-molecule inhibitors from natural compounds. Semin. Cancer Biol., 80.","DOI":"10.1016\/j.semcancer.2020.09.011"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"912","DOI":"10.1080\/09553002.2019.1589653","article-title":"The Warburg effect: Essential part of metabolic reprogramming and central contributor to cancer progression","volume":"95","author":"Vaupel","year":"2019","journal-title":"Int. J. Radiat. Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1745","DOI":"10.1113\/JP278810","article-title":"Revisiting the Warburg effect: Historical dogma versus current understanding","volume":"599","author":"Vaupel","year":"2021","journal-title":"J. Physiol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Liberti, M.V., and Locasale, J.W. (2016). The Warburg Effect: How Does it Benefit Cancer Cells?. Trends Biochem. Sci., 41.","DOI":"10.1016\/j.tibs.2016.01.004"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"P\u00e9rez-Tom\u00e1s, R., and P\u00e9rez-Guill\u00e9n, I. (2020). Lactate in the Tumor Microenvironment: An Essential Molecule in Cancer Progression and Treatment. Cancers, 12.","DOI":"10.3390\/cancers12113244"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1038\/nrc1478","article-title":"Why do cancers have high aerobic glycolysis?","volume":"4","author":"Gatenby","year":"2004","journal-title":"Nat. Rev. Cancer"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1038\/nrd2467","article-title":"Carbonic anhydrases: Novel therapeutic applications for inhibitors and activators","volume":"7","author":"Supuran","year":"2008","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"16233","DOI":"10.1073\/pnas.0908301106","article-title":"Crystal structure of the catalytic domain of the tumor-associated human carbonic anhydrase IX","volume":"106","author":"Alterio","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"9545","DOI":"10.1073\/pnas.161301298","article-title":"Crystal structure of the dimeric extracellular domain of human carbonic anhydrase XII, a bitopic membrane protein overexpressed in certain cancer tumor cells","volume":"98","author":"Whittington","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_13","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_14","doi-asserted-by":"crossref","unstructured":"Lee, S.H., and Griffiths, J.R. (2020). How and Why Are Cancers Acidic? Carbonic Anhydrase IX and the Homeostatic Control of Tumour Extracellular pH. Cancers, 12.","DOI":"10.3390\/cancers12061616"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Riemann, A., Schneider, B., G\u00fcndel, D., Stock, C., Gekle, M., and Thews, O. (2016). Acidosis promotes metastasis formation by enhancing tumor cell motility. Adv. Exp. Med. Biol., 876.","DOI":"10.1007\/978-1-4939-3023-4_27"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"4427","DOI":"10.1007\/s00259-022-05922-6","article-title":"Carbonic anhydrase IX stratifies patient prognosis and identifies nodal status in animal models of nasopharyngeal carcinoma using a targeted imaging strategy","volume":"49","author":"Huang","year":"2022","journal-title":"Eur. J. Nucl. Med. Mol. Imaging"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1186\/s13046-022-02345-x","article-title":"Inhibition of carbonic anhydrases IX\/XII by SLC-0111 boosts cisplatin effects in hampering head and neck squamous carcinoma cell growth and invasion","volume":"41","author":"Sarnella","year":"2022","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Rezuchova, I., Bartosova, M., Belvoncikova, P., Takacova, M., Zatovicova, M., Jelenska, L., Csaderova, L., Meciarova, I., and Pohlodek, K. (2023). Carbonic Anhydrase IX in Tumor Tissue and Plasma of Breast Cancer Patients: Reliable Biomarker of Hypoxia and Prognosis. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24054325"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1065","DOI":"10.1038\/sj.bjc.6600796","article-title":"Carbonic anhydrase XII is a marker of good prognosis in invasive breast carcinoma","volume":"88","author":"Watson","year":"2003","journal-title":"Br. J. Cancer"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1627","DOI":"10.1038\/sj.bjc.6605690","article-title":"High levels of carbonic anhydrase IX in tumour tissue and plasma are biomarkers of poor prognosis in patients with non-small cell lung cancer","volume":"102","author":"Ilie","year":"2010","journal-title":"Br. J. Cancer"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"820","DOI":"10.1016\/0016-5085(93)90900-W","article-title":"The significance of carbonic anhydrase expression in human colorectal cancer","volume":"105","author":"Mori","year":"1993","journal-title":"Gastroenterology"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1016\/j.eururo.2015.06.015","article-title":"Carbonic anhydrase IX as a diagnostic urinary marker for urothelial bladder cancer","volume":"68","author":"Lucca","year":"2015","journal-title":"Eur. Urol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Grincevi\u010dien\u0117, \u0160., Vaitkien\u0117, D., Kanopien\u0117, D., Vansevi\u010di\u016bt\u0117, R., Tykvart, J., Sukovas, A., Celie\u0161i\u016bt\u0117, J., Did\u017eiokien\u0117, E.I., \u010ci\u017eauskas, A., and Laurinavi\u010dien\u0117, A. (2022). Factors associated with elevated concentration of soluble carbonic anhydrase IX in plasma of women with cervical dysplasia. Sci. Rep., 12.","DOI":"10.1038\/s41598-022-19492-y"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Hiepp, L., Mayr, D., G\u00e4rtner, K., Schmoeckel, E., Klauschen, F., Burges, A., Mahner, S., Zeidler, R., and Czogalla, B. (2022). Carbonic anhydrase XII as biomarker and therapeutic target in ovarian carcinomas. PLoS ONE, 17.","DOI":"10.1371\/journal.pone.0271630"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Courcier, J., de la Taille, A., Nourieh, M., Leguerney, I., Lassau, N., and Ingels, A. (2020). Carbonic Anhydrase IX in Renal Cell Carcinoma, Implications for Disease Management. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21197146"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1038\/nature00767","article-title":"Structural basis for the recognition of hydroxyproline in HIF-1\u03b1 by pVHL","volume":"417","author":"Hon","year":"2002","journal-title":"Nature"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Sharma, A., Sinha, S., and Shrivastava, N. (2022). Therapeutic Targeting Hypoxia-Inducible Factor (HIF-1) in Cancer: Cutting Gordian Knot of Cancer Cell Metabolism. Front. Genet., 13.","DOI":"10.3389\/fgene.2022.849040"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1038\/nature04871","article-title":"Hypoxia signalling in cancer and approaches to enforce tumour regression","volume":"441","author":"Dayan","year":"2006","journal-title":"Nature"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1126\/science.1059796","article-title":"Targeting of HIF-\u03b1 to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation","volume":"292","author":"Jaakkola","year":"2001","journal-title":"Science"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1038\/20459","article-title":"The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis","volume":"399","author":"Maxwell","year":"1999","journal-title":"Nature"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"8247","DOI":"10.1523\/JNEUROSCI.20-22-08247.2000","article-title":"Interstitial carbonic anhydrase (CA) activity in brain is attributable to membrane-bound CA type IV","volume":"20","author":"Tong","year":"2000","journal-title":"J. Neurosci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1002\/glia.20277","article-title":"Functional demonstration of surface carbonic anhydrase IV activity on rat astrocytes","volume":"53","author":"Svichar","year":"2006","journal-title":"Glia"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1002\/glia.10187","article-title":"Surface carbonic anhydrase activity on astrocytes and neurons facilitates lactate transport","volume":"41","author":"Svichar","year":"2003","journal-title":"Glia"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Forero-Quintero, L.S., Ames, S., Schneider, H.-P., Thyssen, A., Boone, C.D., Andring, J.T., McKenna, R., Casey, J.R., Deitmer, J.W., and Becker, H.M. (2019). Membrane-anchored carbonic anhydrase IV interacts with monocarboxylate transporters via their chaperones CD147 and GP70. J. Biol. Chem., 294.","DOI":"10.1074\/jbc.RA118.005536"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2333","DOI":"10.1113\/jphysiol.2011.220152","article-title":"Lactate-flux in astrocytes is enhanced by a non-catalytic action of carbonic anhydrase II","volume":"590","author":"Stridh","year":"2012","journal-title":"J. Physiol."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Epalle, N.H., and Beitz, E. (2022). Local Attraction of Substrates and Co-Substrates Enhances Weak Acid and Base Transmembrane Transport. Biomolecules, 12.","DOI":"10.3390\/biom12121794"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Becker, H.M., and Deitmer, J.W. (2021). Proton Transport in Cancer Cells: The Role of Carbonic Anhydrases. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22063171"},{"key":"ref_38","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_39","first-page":"3","article-title":"Advances in Anti-Cancer Drug Development Targeting Carbonic Anhydrase IX and XII","volume":"5","author":"Mboge","year":"2015","journal-title":"Top. Anticancer Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1278","DOI":"10.1080\/14756366.2022.2052868","article-title":"Targeting carbonic anhydrase IX and XII isoforms with small molecule inhibitors and monoclonal antibodies","volume":"37","author":"Kciuk","year":"2022","journal-title":"J. Enzyme Inhib. Med. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"930","DOI":"10.1080\/14756366.2022.2053526","article-title":"The three-tails approach as a new strategy to improve selectivity of action of sulphonamide inhibitors against tumour-associated carbonic anhydrase IX and XII","volume":"37","author":"Bonardi","year":"2022","journal-title":"J. Enzyme Inhib. Med. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1896","DOI":"10.1021\/jm101541x","article-title":"Ureido-substituted benzenesulfonamides potently inhibit carbonic anhydrase IX and show antimetastatic activity in a model of breast cancer metastasis","volume":"54","author":"Pacchiano","year":"2011","journal-title":"J. Med. Chem."},{"key":"ref_43","unstructured":"(2024, July 25). A Study of SLC-0111 and Gemcitabine for Metastatic Pancreatic Ductal Cancer in Subjects Positive for CAIX (SLC-0111-17-01), Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT03450018."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Eloranta, K., Pihlajoki, M., Liljestr\u00f6m, E., Nousiainen, R., Soini, T., Lohi, J., Cairo, S., Wilson, D.B., Parkkila, S., and Heikinheimo, M. (2023). SLC-0111, an inhibitor of carbonic anhydrase IX, attenuates hepatoblastoma cell viability and migration. Front. Oncol., 13.","DOI":"10.3389\/fonc.2023.1118268"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Powell, C.R., Dillon, K.M., and Matson, J.B. (2018). A Review of Hydrogen Sulfide (H2S) Donors: Chemistry and Potential Therapeutic Applications. Biochem. Pharmacol., 149.","DOI":"10.1016\/j.bcp.2017.11.014"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1124\/pr.117.014050","article-title":"International Union of Basic and Clinical Pharmacology. CII: Pharmacological Modulation of H2S Levels: H2S Donors and H2S Biosynthesis Inhibitors","volume":"69","author":"Szabo","year":"2017","journal-title":"Pharmacol. Rev."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Kimura, Y., Koike, S., Shibuya, N., Lefer, D., Ogasawara, Y., and Kimura, H. (2017). 3-Mercaptopyruvate sulfurtransferase produces potential redox regulators cysteine and glutathione-persulfide (Cys-SSH and GSSH) together with signaling molecules H2S2, H2S3 and H2S. Sci. Rep., 7.","DOI":"10.1038\/s41598-017-11004-7"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"11788","DOI":"10.1039\/C4CC00968A","article-title":"Hydrogen Sulfide (H2S) Releasing Agents: Chemistry and Biological Applications","volume":"50","author":"Zhao","year":"2014","journal-title":"Chem. Commun."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Cuevasanta, E., Denicola, A., Alvarez, B., and M\u00f6ller, M.N. (2012). Solubility and Permeation of Hydrogen Sulfide in Lipid Membranes. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0034562"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1089\/ars.2014.5901","article-title":"Anti-inflammatory and cytoprotective actions of hydrogen sulfide: Translation to therapeutics","volume":"22","author":"Wallace","year":"2015","journal-title":"Antioxid. Redox Signal."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Zhang, L., Wang, Y., Li, Y., Li, L., Xu, S., Feng, X., and Liu, S. (2018). Hydrogen Sulfide (H2S)-Releasing Compounds: Therapeutic Potential in Cardiovascular Diseases. Front. Pharmacol., 9.","DOI":"10.3389\/fphar.2018.01066"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.pathophys.2018.10.005","article-title":"Hydrogen sulfide: Therapeutic or injurious in ischemic stroke?","volume":"26","author":"Gopalakrishnan","year":"2019","journal-title":"Pathophysiology"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Gambari, L., Grigolo, B., and Grassi, F. (2019). Hydrogen Sulfide in Bone Tissue Regeneration and Repair: State of the Art and New Perspectives. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20205231"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1038\/nrd.2015.1","article-title":"Gasotransmitters in cancer: From pathophysiology to experimental therapy","volume":"15","author":"Szabo","year":"2016","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1641","DOI":"10.2147\/CCID.S412588","article-title":"Exogenous Hydrogen Sulfide Induces A375 Melanoma Cell Apoptosis Through Overactivation of the Unfolded Protein Response","volume":"16","author":"Ma","year":"2023","journal-title":"Clin. Cosmet. Investig. Dermatol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.niox.2015.08.004","article-title":"Hydrogen sulfide in cancer: Friend or foe?","volume":"50","author":"Wu","year":"2015","journal-title":"Nitric Oxide"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"77819","DOI":"10.18632\/oncotarget.20836","article-title":"Lactate stimulates CA IX expression in normoxic cancer cells","volume":"8","author":"Panisova","year":"2017","journal-title":"Oncotarget"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"13143","DOI":"10.1021\/acs.jmedchem.2c00982","article-title":"Development of Hydrogen Sulfide-Releasing Carbonic Anhydrases IX- and XII-Selective Inhibitors with Enhanced Antihyperalgesic Action in a Rat Model of Arthritis","volume":"65","author":"Bonardi","year":"2022","journal-title":"J. Med. Chem."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Khalifah, R.G. (1971). The carbon dioxide hydration activity of carbonic anhydrase I. Stop-flow kinetic studies on the native human isoenzymes B and C. J. Biol. Chem., 246.","DOI":"10.1016\/S0021-9258(18)62326-9"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"111642","DOI":"10.1016\/j.ejmech.2019.111642","article-title":"From random to rational: A discovery approach to selective subnanomolar inhibitors of human carbonic anhydrase IV based on the Castagnoli-Cushman multicomponent reaction","volume":"182","author":"Kalinin","year":"2019","journal-title":"Eur. J. Med. Chem."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Li, L., Rossoni, G., Sparatore, A., Lee, L.C., Del Soldato, P., and Moore, P.K. (2007). Anti-inflammatory and gastrointestinal effects of a novel diclofenac derivative. Free Radic. Biol. Med., 42.","DOI":"10.1016\/j.freeradbiomed.2006.12.011"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"2786","DOI":"10.1021\/ol401118k","article-title":"Light-induced hydrogen sulfide release from \"caged\" gem-dithiols","volume":"15","author":"Bagdon","year":"2013","journal-title":"Org. Lett."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1180\/claymin.2011.046.3.461","article-title":"The adsorption of methylene blue on montmorillonite from acid solutions","volume":"46","author":"Klika","year":"2011","journal-title":"Clay Miner."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"9065","DOI":"10.1021\/jp9718515","article-title":"Interaction of Methylene Blue with Reduced Charge Montmorillonite","volume":"101","author":"Komadel","year":"1997","journal-title":"J. Phys. Chem. B"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.ejmech.2017.06.012","article-title":"Syntheses, toxicities and anti-inflammation of H2S-donors based on non-steroidal anti-inflammatory drugs","volume":"138","author":"Li","year":"2017","journal-title":"Eur. J. Med. Chem."},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Lee, M., Tazzari, V., Giustarini, D., Rossi, R., Sparatore, A., Del Soldato, P., McGeer, E., and McGeer, P.L. (2010). Effects of hydrogen sulfide-releasing L-DOPA derivatives on glial activation: Potential for treating Parkinson disease. J. Biol. Chem., 285.","DOI":"10.1074\/jbc.M110.115261"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1392","DOI":"10.1080\/14756366.2018.1509211","article-title":"The new H2S-releasing compound ACS94 exerts protective effects through the modulation of thiol homeostasis","volume":"33","author":"Giustarini","year":"2018","journal-title":"J. Enzyme Inhib. Med. Chem."},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Lin, H., Yu, Y., Zhu, L., Lai, N., Zhang, L., Guo, Y., Lin, X., Yang, D., Ren, N., and Zhu, Z. (2023). Implications of hydrogen sulfide in colorectal cancer: Mechanistic insights and diagnostic and therapeutic strategies. Redox Biol., 59.","DOI":"10.1016\/j.redox.2023.102601"},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Li, H., Xu, F., Gao, G., Gao, X., Wu, B., Zheng, C., Wang, P., Li, Z., Hua, H., and Li, D. (2020). Hydrogen sulfide and its donors: Novel antitumor and antimetastatic therapies for triple-negative breast cancer. Redox Biol., 34.","DOI":"10.1016\/j.redox.2020.101564"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.niox.2018.07.004","article-title":"A novel role of sONE\/NOS3\/NO signaling cascade in mediating hydrogen sulphide bilateral effects on triple negative breast cancer progression","volume":"80","author":"Youness","year":"2018","journal-title":"Nitric Oxide"},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Yang, Y.L., Zhang, K., Zhou, Z.T., Jiang, Z.L., Liu, Y., Zhang, Y.X., Liu, Z.H., Ji, X.Y., and Wu, D.D. (2022). The Role of Hydrogen Sulfide in the Development and Progression of Lung Cancer. Molecules, 27.","DOI":"10.3390\/molecules27249005"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"73","DOI":"10.7150\/ijbs.47850","article-title":"Role of hydrogen sulfide donors in cancer development and progression","volume":"17","author":"Ngowi","year":"2021","journal-title":"Int. J. Biol. Sci."},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Yang, C.T., Chen, L., Xu, S., Day, J.J., Li, X., and Xian, M. (2017). Recent Development of Hydrogen Sulfide Releasing\/Stimulating Reagents and Their Potential Applications in Cancer and Glycometabolic Disorders. Front. Pharmacol., 8.","DOI":"10.3389\/fphar.2017.00664"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"15789","DOI":"10.1074\/jbc.M110.188524","article-title":"Catalysis and pH control by membrane-associated carbonic anhydrase IX in MDA-MB-231 breast cancer cells","volume":"286","author":"Li","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1016\/j.ejcb.2010.03.004","article-title":"Carbonic anhydrase XII promotes invasion and migration ability of MDA-MB-231 breast cancer cells through the p38 MAPK signaling pathway","volume":"89","author":"Hsieh","year":"2010","journal-title":"Eur. J. Cell Biol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"3876","DOI":"10.1111\/j.1582-4934.2008.00580.x","article-title":"Cyclooxygenase-2\/carbonic anhydrase-IX up-regulation promotes invasive potential and hypoxia survival in colorectal cancer cells","volume":"13","author":"Sansone","year":"2009","journal-title":"J. Cell Mol. Med."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1200\/JCO.2003.11.132","article-title":"Carbonic anhydrase IX expression, a novel surrogate marker of tumor hypoxia, is associated with a poor prognosis in non-small-cell lung cancer","volume":"21","author":"Swinson","year":"2003","journal-title":"J. Clin. Oncol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/j.ejmech.2018.10.068","article-title":"Enhancement of the tail hydrophobic interactions within the carbonic anhydrase IX active site via structural extension: Design and synthesis of novel N-substituted isatins-SLC-0111 hybrids as carbonic anhydrase inhibitors and antitumor agents","volume":"162","author":"Eldehna","year":"2019","journal-title":"Eur. J. Med. Chem."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"112112","DOI":"10.1016\/j.ejmech.2020.112112","article-title":"Inclusion of a 5-fluorouracil moiety in nitrogenous bases derivatives as human carbonic anhydrase IX and XII inhibitors produced a targeted action against MDA-MB-231 and T47D breast cancer cells","volume":"190","author":"Petreni","year":"2020","journal-title":"Eur. J. Med. Chem."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/18\/10006\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:58:00Z","timestamp":1760111880000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/18\/10006"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,9,17]]},"references-count":79,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2024,9]]}},"alternative-id":["ijms251810006"],"URL":"https:\/\/doi.org\/10.3390\/ijms251810006","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,9,17]]}}}