{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T11:35:37Z","timestamp":1784892937406,"version":"3.55.0"},"reference-count":54,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2022,11,1]],"date-time":"2022-11-01T00:00:00Z","timestamp":1667260800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Deanship of Scientific Research, Vice Presidency for Graduate Studies and Scientific Research, King Faisal University, Saudi Arabia","award":["1462"],"award-info":[{"award-number":["1462"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Turmeric spice contains curcuminoids, which are polyphenolic compounds found in the Curcuma longa plant\u2019s rhizome. This class of molecules includes curcumin, demethoxycurcumin, and bisdemethoxycurcumin. Using prostate cancer cell lines PC3, LNCaP, DU145, and C42B, we show that curcuminoids inhibit cell proliferation (measured by MTT assay) and induce apoptosis-like cell death (measured by DNA\/histone ELISA). A copper chelator (neocuproine) and reactive oxygen species scavengers (thiourea for hydroxyl radical, superoxide dismutase for superoxide anion, and catalase for hydrogen peroxide) significantly inhibit this reaction, thus demonstrating that intracellular copper reacts with curcuminoids in cancer cells to cause DNA damage via ROS generation. We further show that copper-supplemented media sensitize normal breast epithelial cells (MCF-10A) to curcumin-mediated growth inhibition, as determined by decreased cell proliferation. Copper supplementation results in increased expression of copper transporters CTR1 and ATP7A in MCF-10A cells, which is attenuated by the addition of curcumin in the medium. We propose that the copper-mediated, ROS-induced mechanism of selective cell death of cancer cells may in part explain the anticancer effects of curcuminoids.<\/jats:p>","DOI":"10.3390\/molecules27217410","type":"journal-article","created":{"date-parts":[[2022,11,1]],"date-time":"2022-11-01T06:01:28Z","timestamp":1667282488000},"page":"7410","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":38,"title":["Curcumin and Its Derivatives Induce Apoptosis in Human Cancer Cells by Mobilizing and Redox Cycling Genomic Copper Ions"],"prefix":"10.3390","volume":"27","author":[{"given":"Mohammed Ahmed Ismail","family":"Alhasawi","sequence":"first","affiliation":[{"name":"Department of Medical Education, College of Medicine, King Faisal University, Al-Ahsa 31982, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1748-2160","authenticated-orcid":false,"given":"Mohammad","family":"Aatif","sequence":"additional","affiliation":[{"name":"Department of Public Health, College of Applied Medical Sciences, King Faisal University, Al-Ahsa 31982, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3328-3559","authenticated-orcid":false,"given":"Ghazala","family":"Muteeb","sequence":"additional","affiliation":[{"name":"Department of Nursing, College of Applied Medical Sciences, King Faisal University, Al-Ahsa 31982, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5190-0103","authenticated-orcid":false,"given":"Mir Waqas","family":"Alam","sequence":"additional","affiliation":[{"name":"Department of Physics, College of Science, King Faisal University, Al-Ahsa 31982, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5193-0759","authenticated-orcid":false,"given":"Mohamed El","family":"Oirdi","sequence":"additional","affiliation":[{"name":"Department of Basic Sciences, Preparatory Year Deanship, King Faisal University, Al-Ahsa 31982, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1519-9644","authenticated-orcid":false,"given":"Mohd","family":"Farhan","sequence":"additional","affiliation":[{"name":"Department of Basic Sciences, Preparatory Year Deanship, King Faisal University, Al-Ahsa 31982, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/j.jtcme.2016.05.005","article-title":"Biological activities of curcuminoids, other biomolecules from turmeric and their derivatives\u2014A review","volume":"7","author":"Amalraj","year":"2017","journal-title":"J. Tradit. Complement. Med."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Hafez Ghoran, S., Calcaterra, A., Abbasi, M., Taktaz, F., Nieselt, K., and Babaei, E. (2022). Curcumin-based nanoformulations: A promising adjuvant towards cancer treatment. Molecules, 27.","DOI":"10.3390\/molecules27165236"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"4503","DOI":"10.2147\/DDDT.S327378","article-title":"Anti-inflammatory effects of curcumin in the inflammatory diseases: Status, limitations and countermeasures","volume":"15","author":"Peng","year":"2021","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1016\/j.jtcme.2016.08.002","article-title":"Curcumin: An age-old anti-inflammatory and anti-neoplastic agent","volume":"7","author":"Fadus","year":"2017","journal-title":"J. Tradit. Complement. Med."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Tomeh, M.A., Hadianamrei, R., and Zhao, X. (2019). A review of curcumin and its derivatives as anticancer agents. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20051033"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Mansouri, K., Rasoulpoor, S., Daneshkhah, A., Abolfathi, S., Salari, N., Mohammadi, M., Rasoulpoor, S., and Shabani, S. (2020). Clinical effects of curcumin in enhancing cancer therapy: A systematic review. BMC Cancer, 20.","DOI":"10.1186\/s12885-020-07256-8"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Jakubczyk, K., Druzga, A., Katarzyna, J., and Skonieczna-Zydecka, K. (2020). Antioxidant potential of curcumin-a meta-analysis of randomized clinical trials. Antioxidants, 9.","DOI":"10.3390\/antiox9111092"},{"key":"ref_8","first-page":"e13584","article-title":"Antioxidant properties of novel curcumin analogues: A combined experimental and computational study","volume":"45","author":"Angelova","year":"2021","journal-title":"J. Food Biochem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.cbi.2008.05.003","article-title":"Antioxidant and radical scavenging properties of curcumin","volume":"174","author":"Ak","year":"2008","journal-title":"Chem.-Biol. Interact."},{"key":"ref_10","first-page":"73","article-title":"Toxicity studies on turmeric (curcuma longa): Acute toxicity studies in rats, guineapigs & monkeys","volume":"18","author":"Shankar","year":"1980","journal-title":"Indian J. Exp. Biol."},{"key":"ref_11","first-page":"273","article-title":"Effect of oral curcumin administration on serum peroxides and cholesterol levels in human volunteers","volume":"36","author":"Soni","year":"1992","journal-title":"Indian J. Physiol. Pharmacol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/0304-3835(95)03903-A","article-title":"Effects of curcumin on the formation of benzo[a]pyrene derived DNA adducts in vitro","volume":"96","author":"Deshpande","year":"1995","journal-title":"Cancer Lett."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Kim, K.S., Kim, N.Y., Son, J.Y., Park, J.H., Lee, S.H., Kim, H.R., Kim, B., Kim, Y.G., Jeong, H.G., and Lee, B.M. (2019). Curcumin ameliorates benzo[a]pyrene-induced DNA damages in stomach tissues of sprague-dawley rats. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20225533"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Barzegar, A., and Moosavi-Movahedi, A.A. (2011). Intracellular ros protection efficiency and free radical-scavenging activity of curcumin. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0026012"},{"key":"ref_15","first-page":"563","article-title":"Cytotoxicity, ros-generation activity and radical-scavenging activity of curcumin and related compounds","volume":"24","author":"Fujisawa","year":"2004","journal-title":"Anticancer Res."},{"key":"ref_16","first-page":"2818","article-title":"Curcumin induces apoptosis in breast cancer cells and inhibits tumor growth in vitro and in vivo","volume":"7","author":"Lv","year":"2014","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1002\/mnfr.201300417","article-title":"Plant polyphenol induced cell death in human cancer cells involves mobilization of intracellular copper ions and reactive oxygen species generation: A mechanism for cancer chemopreventive action","volume":"58","author":"Khan","year":"2014","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Farhan, M., Rizvi, A., Ahmad, A., Aatif, M., Alam, M.W., and Hadi, S.M. (2022). Structure of Some Green Tea Catechins and the Availability of Intracellular Copper Influence Their Ability to Cause Selective Oxidative DNA Damage in Malignant Cells. Biomedicines, 10.","DOI":"10.3390\/biomedicines10030664"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"998346","DOI":"10.3389\/fonc.2022.998346","article-title":"Pomegranate juice anthocyanidins induce cell death in human cancer cells by mobilizing intracellular copper ions and producing reactive oxygen species","volume":"12","author":"Farhan","year":"2022","journal-title":"Front. Oncol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/0891-5849(95)00004-H","article-title":"Photoinduction of strand scission in DNA by uric acid and cu(ii)","volume":"19","author":"Shamsi","year":"1995","journal-title":"Free Radic. Biol. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"26754","DOI":"10.3390\/ijms161125992","article-title":"Mobilization of copper ions by flavonoids in human peripheral lymphocytes leads to oxidative DNA breakage: A structure activity study","volume":"16","author":"Arif","year":"2015","journal-title":"Int. J. Mol. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.abb.2015.06.019","article-title":"Mobilization of copper ions in human peripheral lymphocytes by catechins leading to oxidative DNA breakage: A structure activity study","volume":"580","author":"Farhan","year":"2015","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/0165-1161(94)90032-9","article-title":"DNA breakage by tannic acid and Cu(II): Generation of active oxygen species and biological activity of the reaction","volume":"313","author":"Bhat","year":"1994","journal-title":"Mutat. Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/S0304-3835(97)00442-4","article-title":"Strand scission in DNA induced by curcumin in the presence of Cu(II)","volume":"124","author":"Ahsan","year":"1998","journal-title":"Cancer Lett."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"20175","DOI":"10.1016\/S0021-9258(18)54906-1","article-title":"Covalent modification of guanine bases in double-stranded DNA. The 1.2-a z-DNA structure of d(cgcgcg) in the presence of cucl2","volume":"266","author":"Kagawa","year":"1991","journal-title":"J. Biol. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"20185","DOI":"10.1016\/S0021-9258(18)54907-3","article-title":"Base-specific binding of copper(ii) to z-DNA. The 1.3-a single crystal structure of d(m5cguam5cg) in the presence of cucl2","volume":"266","author":"Geierstanger","year":"1991","journal-title":"J. Biol. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"738","DOI":"10.1016\/j.ejim.2012.07.009","article-title":"Copper levels in patients with hematological malignancies","volume":"23","author":"Kaiafa","year":"2012","journal-title":"Eur. J. Intern. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.ctrv.2008.07.004","article-title":"Elevated copper and oxidative stress in cancer cells as a target for cancer treatment","volume":"35","author":"Gupte","year":"2009","journal-title":"Cancer Treat. Rev."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.abb.2017.11.001","article-title":"Physiological serum copper concentrations found in malignancies cause unfolding induced aggregation of human serum albumin in vitro","volume":"636","author":"Rizvi","year":"2017","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1002\/ijc.2910510315","article-title":"Hydrolyzable tannins: Potent inhibitors of hydroperoxide production and tumor promotion in mouse skin treated with 12-O-tetradecanoylphorbol-13-acetate in vivo","volume":"51","author":"Gali","year":"1992","journal-title":"Int J Cancer."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1080\/152165400300001471","article-title":"Putative mechanism for anticancer and apoptosis-inducing properties of plant-derived polyphenolic compounds","volume":"50","author":"Hadi","year":"2000","journal-title":"IUBMB Life"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"898","DOI":"10.1006\/bbrc.1994.2544","article-title":"Antioxidant, gallic acid induces apoptosis in HL 60 r cells","volume":"204","author":"Inoue","year":"1994","journal-title":"Biochem Biophys Res Commun."},{"key":"ref_33","first-page":"641","article-title":"Effects of 6-gingerol, an antioxidant from ginger, on inducing apoptosis in human leukemic hl-60 cells","volume":"17","author":"Wang","year":"2003","journal-title":"In Vivo"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1016\/j.semcancer.2007.04.002","article-title":"Oxidative breakage of cellular DNA by plant polyphenols: A putative mechanism for anticancer properties","volume":"17","author":"Hadi","year":"2007","journal-title":"Semin. Cancer Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/0278-6915(93)90077-C","article-title":"Assessment of genotoxic effects by lindane","volume":"31","author":"Guigas","year":"1993","journal-title":"Food Chem. Toxicol. Int. J. Publ. Br. Ind. Biol. Res. Assoc."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1376","DOI":"10.1002\/mnfr.200800547","article-title":"Cellular DNA breakage by soy isoflavone genistein and its methylated structural analogue biochanin A","volume":"53","author":"Ullah","year":"2009","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1016\/j.ejps.2012.04.014","article-title":"Apogossypolone, derivative of gossypol, mobilizes endogenous copper in human peripheral lymphocytes leading to oxidative DNA breakage","volume":"47","author":"Zubair","year":"2012","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1016\/j.jtemb.2014.04.004","article-title":"Effects of different sources of copper on ctr1, atp7a, atp7b, mt and dmt1 protein and gene expression in caco-2 cells","volume":"28","author":"Gao","year":"2014","journal-title":"J. Trace Elem. Med. Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1186\/1756-8722-6-77","article-title":"Inhibition of hedgehog signaling sensitizes nsclc cells to standard therapies through modulation of emt-regulating mirnas","volume":"6","author":"Ahmad","year":"2013","journal-title":"J. Hematol. Oncol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1002\/(SICI)1098-2280(2000)35:3<206::AID-EM8>3.0.CO;2-J","article-title":"Single cell gel\/comet assay: Guidelines for in vitro and in vivo genetic toxicology testing","volume":"35","author":"Tice","year":"2000","journal-title":"Environ. Mol. Mutagen."},{"key":"ref_41","unstructured":"Bryan, S.E. (1979). Metal Ions in Biological Systems, Marcel Dekker."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Farhan, M., Khan, H.Y., Oves, M., Al-Harrasi, A., Rehmani, N., Arif, H., Hadi, S.M., and Ahmad, A. (2016). Cancer therapy by catechins involves redox cycling of copper ions and generation of reactive oxygen species. Toxins, 8.","DOI":"10.3390\/toxins8020037"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"997","DOI":"10.1007\/s10495-016-1261-2","article-title":"Calcitriol-copper interaction leads to non enzymatic, reactive oxygen species mediated DNA breakage and modulation of cellular redox scavengers in hepatocellular carcinoma","volume":"21","author":"Rizvi","year":"2016","journal-title":"Apoptosis"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1038\/s41568-021-00417-2","article-title":"Connecting copper and cancer: From transition metal signalling to metalloplasia","volume":"22","author":"Ge","year":"2022","journal-title":"Nat. Rev. Cancer"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"6836","DOI":"10.1073\/pnas.1817473116","article-title":"Atp7a delivers copper to the lysyl oxidase family of enzymes and promotes tumorigenesis and metastasis","volume":"116","author":"Shanbhag","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1093\/mutage\/9.3.193","article-title":"Mode of binding of quercetin to DNA","volume":"9","author":"Ahmed","year":"1994","journal-title":"Mutagenesis"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/S0304-3835(01)00544-4","article-title":"Oxidative DNA damage by capsaicin and dihydrocapsaicin in the presence of cu(ii)","volume":"169","author":"Singh","year":"2001","journal-title":"Cancer Lett."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/S0304-3835(00)00351-7","article-title":"DNA breakage by resveratrol and cu(ii): Reaction mechanism and bacteriophage inactivation","volume":"154","author":"Ahmad","year":"2000","journal-title":"Cancer Lett."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1016\/j.tiv.2003.12.012","article-title":"Prooxidant property of green tea polyphenols epicatechin and epigallocatechin-3-gallate: Implications for anticancer properties","volume":"18","author":"Azam","year":"2004","journal-title":"Toxicol. In Vitro"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/S0009-2797(99)00096-4","article-title":"Pro-oxidant, anti-oxidant and cleavage activities on DNA of curcumin and its derivatives demethoxycurcumin and bisdemethoxycurcumin","volume":"121","author":"Ahsan","year":"1999","journal-title":"Chem.-Biol. Interact."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1459","DOI":"10.1039\/C5MT00149H","article-title":"Targeting copper in cancer therapy: \u2018Copper that cancer\u2019","volume":"7","author":"Denoyer","year":"2015","journal-title":"Metallomics"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"8861","DOI":"10.1007\/s13277-015-3649-y","article-title":"Targeting increased copper levels in diethylnitrosamine induced hepatocellular carcinoma cells in rats by epigallocatechin-3-gallate","volume":"36","author":"Farhan","year":"2015","journal-title":"Tumour Biol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"8155","DOI":"10.1073\/pnas.1806797115","article-title":"Ancient drug curcumin impedes 26s proteasome activity by direct inhibition of dual-specificity tyrosine-regulated kinase 2","volume":"115","author":"Banerjee","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"929853","DOI":"10.3389\/fphar.2022.929853","article-title":"Understanding the prooxidant action of plant polyphenols in the cellular microenvironment of malignant cells: Role of copper and therapeutic implications","volume":"13","author":"Farhan","year":"2022","journal-title":"Front. Pharmacol."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/21\/7410\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:07:10Z","timestamp":1760144830000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/21\/7410"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,1]]},"references-count":54,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2022,11]]}},"alternative-id":["molecules27217410"],"URL":"https:\/\/doi.org\/10.3390\/molecules27217410","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,1]]}}}