{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T21:44:25Z","timestamp":1782510265571,"version":"3.54.5"},"reference-count":51,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2021,8,20]],"date-time":"2021-08-20T00:00:00Z","timestamp":1629417600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Human Resources, Hungary","award":["EFOP 3.6.1.-16-2016-00004"],"award-info":[{"award-number":["EFOP 3.6.1.-16-2016-00004"]}]},{"name":"Excellence Programme of the Ministry of Human Capacities in Hungary","award":["2020-4.1.1.-TKP2020"],"award-info":[{"award-number":["2020-4.1.1.-TKP2020"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Mitochondria have emerged as a prospective target to overcome drug resistance that limits triple-negative breast cancer therapy. A novel mitochondria-targeted compound, HO-5114, demonstrated higher cytotoxicity against human breast cancer lines than its component-derivative, Mito-CP. In this study, we examined HO-5114\u2032s anti-neoplastic properties and its effects on mitochondrial functions in MCF7 and MDA-MB-231 human breast cancer cell lines. At a 10 \u00b5M concentration and within 24 h, the drug markedly reduced viability and elevated apoptosis in both cell lines. After seven days of exposure, even at a 75 nM concentration, HO-5114 significantly reduced invasive growth and colony formation. A 4 h treatment with 2.5 \u00b5M HO-5114 caused a massive loss of mitochondrial membrane potential, a decrease in basal and maximal respiration, and mitochondrial and glycolytic ATP production. However, reactive oxygen species production was only moderately elevated by HO-5114, indicating that oxidative stress did not significantly contribute to the drug\u2019s anti-neoplastic effect. These data indicate that HO-5114 may have potential for use in the therapy of triple-negative breast cancer; however, the in vivo toxicity and anti-neoplastic effectiveness of the drug must be determined to confirm its potential.<\/jats:p>","DOI":"10.3390\/ijms22169016","type":"journal-article","created":{"date-parts":[[2021,8,22]],"date-time":"2021-08-22T21:47:52Z","timestamp":1629668872000},"page":"9016","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Cytostatic Effect of a Novel Mitochondria-Targeted Pyrroline Nitroxide in Human Breast Cancer Lines"],"prefix":"10.3390","volume":"22","author":[{"given":"Kitti","family":"Andreidesz","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Medical Chemistry, University of Pecs Medical School, 7624 Pecs, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aliz","family":"Szabo","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Medical Chemistry, University of Pecs Medical School, 7624 Pecs, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8904-3976","authenticated-orcid":false,"given":"Dominika","family":"Kovacs","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Medical Chemistry, University of Pecs Medical School, 7624 Pecs, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6743-0441","authenticated-orcid":false,"given":"Balazs","family":"Koszegi","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Medical Chemistry, University of Pecs Medical School, 7624 Pecs, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viola","family":"Bagone Vantus","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Medical Chemistry, University of Pecs Medical School, 7624 Pecs, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0622-442X","authenticated-orcid":false,"given":"Eszter","family":"Vamos","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Medical Chemistry, University of Pecs Medical School, 7624 Pecs, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mostafa","family":"Isbera","sequence":"additional","affiliation":[{"name":"Institute of Organic and Medicinal Chemistry, Faculty of Pharmacy, University of Pecs, 7624 Pecs, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamas","family":"Kalai","sequence":"additional","affiliation":[{"name":"Institute of Organic and Medicinal Chemistry, Faculty of Pharmacy, University of Pecs, 7624 Pecs, Hungary"},{"name":"Szentagothai Research Centre, University of Pecs, 7624 Pecs, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0582-7755","authenticated-orcid":false,"given":"Zita","family":"Bognar","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Medical Chemistry, University of Pecs Medical School, 7624 Pecs, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krisztina","family":"Kovacs","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Medical Chemistry, University of Pecs Medical School, 7624 Pecs, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1906-4333","authenticated-orcid":false,"given":"Ferenc","family":"Gallyas","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Medical Chemistry, University of Pecs Medical School, 7624 Pecs, Hungary"},{"name":"Szentagothai Research Centre, University of Pecs, 7624 Pecs, Hungary"},{"name":"HAS-UP Nuclear-Mitochondrial Interactions Research Group, 1245 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,8,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Dong, L., Gopalan, V., Holland, O., and Neuzil, J. (2020). Mitocans Revisited: Mitochondrial Targeting as Efficient Anti-Cancer Therapy. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21217941"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"8788","DOI":"10.1073\/pnas.1003428107","article-title":"Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity","volume":"107","author":"Weinberg","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1186\/s40880-019-0412-6","article-title":"Targeting mitochondria as an anticancer strategy","volume":"39","author":"Dong","year":"2019","journal-title":"Cancer Commun."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"922","DOI":"10.3389\/fphar.2018.00922","article-title":"Mitochondrial-Targeting Anticancer Agent Conjugates and Nanocarrier Systems for Cancer Treatment","volume":"9","author":"Battogtokh","year":"2018","journal-title":"Front. Pharmacol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1016\/S0167-7799(97)01068-8","article-title":"Selective targeting of bioactive compounds to mitochondria","volume":"15","author":"Murphy","year":"1997","journal-title":"Trends Biotechnol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"5407","DOI":"10.1073\/pnas.0931245100","article-title":"Delivery of bioactive molecules to mitochondria in vivo","volume":"100","author":"Smith","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"10043","DOI":"10.1021\/acs.chemrev.7b00042","article-title":"Mitochondria-Targeted Triphenylphosphonium-Based Compounds: Syntheses, Mechanisms of Action, and Therapeutic and Diagnostic Applications","volume":"117","author":"Zielonka","year":"2017","journal-title":"Chem. Rev."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.1016\/j.bbagen.2010.06.001","article-title":"Rapid uptake of lipophilic triphenylphosphonium cations by mitochondria in vivo following intravenous injection: Implications for mitochondria-specific therapies and probes","volume":"1800","author":"Porteous","year":"2010","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1038\/nature11706","article-title":"How cancer metabolism is tuned for proliferation and vulnerable to disruption","volume":"491","author":"Schulze","year":"2012","journal-title":"Nature"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"13748","DOI":"10.1038\/s41598-019-50141-z","article-title":"Role of mitochondria in rescuing glycolytically inhibited subpopulation of triple negative but not hormone-responsive breast cancer cells","volume":"9","author":"Reda","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_11","first-page":"93","article-title":"Triple-negative breast cancer: Treatment challenges and solutions","volume":"8","author":"Collignon","year":"2016","journal-title":"Breast Cancer"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1016\/j.freeradbiomed.2005.04.016","article-title":"Mitochondria superoxide dismutase mimetic inhibits peroxide-induced oxidative damage and apoptosis: Role of mitochondrial superoxide","volume":"39","author":"Dhanasekaran","year":"2005","journal-title":"Free Radic. Biol. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2634","DOI":"10.1158\/0008-5472.CAN-11-3928","article-title":"Mitochondria-targeted drugs synergize with 2-deoxyglucose to trigger breast cancer cell death","volume":"72","author":"Cheng","year":"2012","journal-title":"Cancer Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"14891","DOI":"10.1074\/jbc.RA117.001469","article-title":"Mitochondria-targeted drugs stimulate mitophagy and abrogate colon cancer cell proliferation","volume":"293","author":"Boyle","year":"2018","journal-title":"J. Biol. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Isbera, M., Bogn\u00e1r, B., Gallyas, F., B\u00e9nyei, A., Jek\u0151, J., and K\u00e1lai, T. (2021). Syntheses and Study of a Pyrroline Nitroxide Condensed Phospholene Oxide and a Pyrroline Nitroxide Attached Diphenylphosphine. Molecules, 26.","DOI":"10.3390\/molecules26144366"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1112","DOI":"10.1038\/nprot.2006.179","article-title":"Sulforhodamine B colorimetric assay for cytotoxicity screening","volume":"1","author":"Vichai","year":"2006","journal-title":"Nat. Protoc."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Ghoneum, A., Abdulfattah, A.Y., Warren, B.O., Shu, J., and Said, N. (2020). Redox Homeostasis and Metabolism in Cancer: A Complex Mechanism and Potential Targeted Therapeutics. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21093100"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e00126","DOI":"10.1042\/BSR20140031","article-title":"Using real-time impedance-based assays to monitor the effects of fibroblast-derived media on the adhesion, proliferation, migration and invasion of colon cancer cells","volume":"34","author":"Dowling","year":"2014","journal-title":"Biosci. Rep."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"120","DOI":"10.5306\/wjco.v8.i2.120","article-title":"Targeted therapies in breast cancer: New challenges to fight against resistance","volume":"8","author":"Masoud","year":"2017","journal-title":"World J. Clin. Oncol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1016\/j.bbabio.2017.01.012","article-title":"Mitochondria and cancer chemoresistance","volume":"1858","author":"Guerra","year":"2017","journal-title":"Biochim. Biophys. Acta Bioenerg."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1016\/j.trecan.2017.10.006","article-title":"Mitochondria, Bioenergetics and Apoptosis in Cancer","volume":"3","author":"Burke","year":"2017","journal-title":"Trends Cancer"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2977","DOI":"10.1016\/j.bbamcr.2016.09.012","article-title":"Activation of apoptosis signalling pathways by reactive oxygen species","volume":"1863","year":"2016","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"4862","DOI":"10.1038\/s41467-019-12412-1","article-title":"Fate-mapping post-hypoxic tumor cells reveals a ROS-resistant phenotype that promotes metastasis","volume":"10","author":"Godet","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1016\/j.trecan.2016.10.016","article-title":"Hypoxia-Inducible Factors: Master Regulators of Cancer Progression","volume":"2","author":"Schito","year":"2016","journal-title":"Trends Cancer"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"480","DOI":"10.3389\/fonc.2019.00480","article-title":"Breast Cancer Subtypes Present a Differential Production of Reactive Oxygen Species (ROS) and Susceptibility to Antioxidant Treatment","volume":"9","author":"Pelayo","year":"2019","journal-title":"Front. Oncol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Kwon, Y. (2021). Possible Beneficial Effects of N-Acetylcysteine for Treatment of Triple-Negative Breast 555 Cancer. Antioxidants, 10.","DOI":"10.3390\/antiox10020169"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Martinez-Reyes, I., and Chandel, N.S. (2021). Cancer metabolism: Looking forward. Nat. Rev. Cancer.","DOI":"10.1038\/s41568-021-00378-6"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1146\/annurev.biochem.76.052705.163409","article-title":"Translocation of proteins into mitochondria","volume":"76","author":"Neupert","year":"2007","journal-title":"Annu. Rev. Biochem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.ab.2017.07.009","article-title":"Mitochondrial membrane potential","volume":"552","author":"Zorova","year":"2018","journal-title":"Anal. Biochem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/S0014-5793(97)01159-9","article-title":"High protonic potential actuates a mechanism of production of reactive oxygen species in mitochondria","volume":"416","author":"Korshunov","year":"1997","journal-title":"FEBS Lett."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1016\/j.bbabio.2017.01.004","article-title":"Mitochondrial dysfunction and mitochondrial dynamics\u2014The cancer connection","volume":"1858","author":"Srinivasan","year":"2017","journal-title":"Biochim. Biophys. Acta Bioenerg."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1309","DOI":"10.1126\/science.281.5381.1309","article-title":"Mitochondria and apoptosis","volume":"281","author":"Green","year":"1998","journal-title":"Science"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"a008706","DOI":"10.1101\/cshperspect.a008706","article-title":"Mitochondrial regulation of cell death","volume":"5","author":"Tait","year":"2013","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2000","DOI":"10.1111\/bph.12416","article-title":"Parthanatos: Mitochondrial-linked mechanisms and therapeutic opportunities","volume":"171","author":"Fatokun","year":"2014","journal-title":"Br. J. Pharmacol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1007\/s12975-013-0283-0","article-title":"Mitochondrial dysfunction induced by nuclear poly(ADP-ribose) polymerase-1: A treatable cause of cell death in stroke","volume":"5","author":"Baxter","year":"2014","journal-title":"Transl. Stroke Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1759091418818261","DOI":"10.1177\/1759091418818261","article-title":"Mitochondrial Substrate-Level Phosphorylation as Energy Source for Glioblastoma: Review and Hypothesis","volume":"10","author":"Chinopoulos","year":"2018","journal-title":"ASN Neuro"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"113218","DOI":"10.1016\/j.expneurol.2020.113218","article-title":"Acute sources of mitochondrial NAD(+) during respiratory chain dysfunction","volume":"327","author":"Chinopoulos","year":"2020","journal-title":"Exp. Neurol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1038\/nchembio.1712","article-title":"Targeting mitochondria metabolism for cancer therapy","volume":"11","author":"Weinberg","year":"2015","journal-title":"Nat. Chem. Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1016\/j.bbrc.2008.11.059","article-title":"Mitochondrial DNA is a direct target of anti-cancer anthracycline drugs","volume":"378","author":"Ashley","year":"2009","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"4319","DOI":"10.1038\/s41467-020-18084-6","article-title":"Defining the ATPome reveals cross-optimization of metabolic pathways","volume":"11","author":"Bennett","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1126\/science.124.3215.269","article-title":"On respiratory impairment in cancer cells","volume":"124","author":"Warburg","year":"1956","journal-title":"Science"},{"key":"ref_42","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_43","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1016\/j.ccr.2008.05.005","article-title":"Tumor cell metabolism: Cancer\u2019s Achilles\u2019 heel","volume":"13","author":"Kroemer","year":"2008","journal-title":"Cancer Cell"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"LeBleu, V.S., O\u2019Connell, J.T., Gonzalez Herrera, K.N., Wikman, H., Pantel, K., Haigis, M.C., de Carvalho, F.M., Damascena, A., Domingos Chinen, L.T., and Rocha, R.M. (2014). PGC-1alpha mediates mitochondrial biogenesis and oxidative phosphorylation in cancer cells to promote metastasis. Nat. Cell Biol., 16.","DOI":"10.1038\/ncb3039"},{"key":"ref_45","first-page":"316","article-title":"Role of mitochondrial function in the invasiveness of human colon cancer cells","volume":"39","author":"Lin","year":"2018","journal-title":"Oncol. Rep."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"101076","DOI":"10.1016\/j.redox.2018.101076","article-title":"Metabolic reprogramming of oncogene-addicted cancer cells to OXPHOS as a mechanism of drug resistance","volume":"25","author":"Hirpara","year":"2019","journal-title":"Redox. Biol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1834","DOI":"10.1172\/JCI82661","article-title":"Targeting mitochondrial biogenesis to overcome drug resistance to MAPK inhibitors","volume":"126","author":"Zhang","year":"2016","journal-title":"J. Clin. Investig."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2482","DOI":"10.1158\/1078-0432.CCR-17-3070","article-title":"Oxidative Phosphorylation as an Emerging Target in Cancer Therapy","volume":"24","author":"Ashton","year":"2018","journal-title":"Clin. Cancer Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1016\/j.bbabio.2017.01.005","article-title":"Mitochondrial uncoupling in cancer cells: Liabilities and opportunities","volume":"1858","author":"Baffy","year":"2017","journal-title":"Biochim. Biophys. Acta Bioenerg."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"960","DOI":"10.1073\/pnas.1317400111","article-title":"UCP2 transports C4 metabolites out of mitochondria, regulating glucose and glutamine oxidation","volume":"111","author":"Vozza","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.semcancer.2019.08.003","article-title":"Epithelial-to-mesenchymal transition and invadopodia markers in breast cancer: Lumican a key regulator","volume":"62","author":"Karamanou","year":"2020","journal-title":"Semin. Cancer Biol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/16\/9016\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:48:29Z","timestamp":1760165309000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/16\/9016"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,20]]},"references-count":51,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2021,8]]}},"alternative-id":["ijms22169016"],"URL":"https:\/\/doi.org\/10.3390\/ijms22169016","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,20]]}}}