{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T08:16:33Z","timestamp":1768292193500,"version":"3.49.0"},"reference-count":26,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2019,10,29]],"date-time":"2019-10-29T00:00:00Z","timestamp":1572307200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"SBI Pharmaceuticals Co., Ltd. (Tokyo, Japan).","award":["There is no number."],"award-info":[{"award-number":["There is no number."]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Artemisinin and its derivatives, including artesunate (ART) and artemether (ARM), exert anticancer effects in the micromolar range in drug and radiation-resistant cell lines. Artemisinin has been reported to sensitize cervical cancer cells to radiotherapy. In the present study, we determined whether ART and ARM could enhance the cytotoxicity of 5-aminolevulinic acid (5-ALA)-based photodynamic therapy (PDT) against the mammary tumor cells of mice. The corrected PpIX fluorescence intensities in the control, 5-ALA, 5-ALA + ART, and 5-ALA + ARM groups were 3.385 \u00b1 3.730, 165.7 \u00b1 33.45, 139.0 \u00b1 52.77, and 165.4 \u00b1 51.10 a.u., respectively. At light doses of 3 and 5 J\/cm2, the viability of 5-ALA-PDT-treated cells significantly decreased with ART (p &lt; 0.01 and p &lt; 0.01) and ARM treatment (p &lt; 0.01 and p &lt; 0.01). Besides, the number of annexin V-FITC and ethidium homodimer III-positive cells was greater in the 5-ALA-PDT with ARM group than that in the other groups. N-acetylcysteine could not significantly inhibit the percentages of apoptotic cells or inviable cells induced by 5-ALA-PDT with ARM. These reactive oxygen species-independent mechanisms might enhance cytotoxicity in 5-ALA-PDT with ARM-treated tumor cells, suggesting that the use of 5-ALA-PDT with ARM could be a new strategy to enhance PDT cytotoxicity against tumor cells. However, as these results are only based on in vitro studies, further in vivo investigations are required.<\/jats:p>","DOI":"10.3390\/molecules24213891","type":"journal-article","created":{"date-parts":[[2019,10,31]],"date-time":"2019-10-31T05:18:26Z","timestamp":1572499106000},"page":"3891","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Antimalarial Drugs Enhance the Cytotoxicity of 5-Aminolevulinic Acid-Based Photodynamic Therapy against the Mammary Tumor Cells of Mice In Vitro"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2689-9435","authenticated-orcid":false,"given":"Tomohiro","family":"Osaki","sequence":"first","affiliation":[{"name":"Joint Department of Veterinary Medicine, Faculty of Agriculture, Tottori University, Tottori 680-8553, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kiwamu","family":"Takahashi","sequence":"additional","affiliation":[{"name":"SBI Pharmaceuticals Co., Ltd., Tokyo 106-6020, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masahiro","family":"Ishizuka","sequence":"additional","affiliation":[{"name":"SBI Pharmaceuticals Co., Ltd., Tokyo 106-6020, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tohru","family":"Tanaka","sequence":"additional","affiliation":[{"name":"SBI Pharmaceuticals Co., Ltd., Tokyo 106-6020, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoshiharu","family":"Okamoto","sequence":"additional","affiliation":[{"name":"Joint Department of Veterinary Medicine, Faculty of Agriculture, Tottori University, Tottori 680-8553, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,10,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"69","DOI":"10.3322\/caac.20107","article-title":"Global cancer statistics","volume":"61","author":"Jemal","year":"2011","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.pdpdt.2010.02.001","article-title":"Oncologic photodynamic therapy photosensitizers: A clinical review","volume":"7","author":"Allison","year":"2010","journal-title":"Photodiagn. Photodyn. Ther."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"4140","DOI":"10.3390\/molecules16054140","article-title":"Aminolevulinic Acid (ALA) as a Prodrug in Photodynamic Therapy of Cancer","volume":"16","author":"Wachowska","year":"2011","journal-title":"Molecules"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1016\/j.jss.2013.02.002","article-title":"Aminolevulinic acid (ALA): Photodynamic detection and potential therapeutic applications","volume":"181","author":"Nokes","year":"2013","journal-title":"J. Surg. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1002\/lsm.10246","article-title":"Effect of 5-aminolevulinic acid-mediated photodynamic therapy on MCF-7 and MCF-7\/ADR cells","volume":"34","author":"Tsai","year":"2004","journal-title":"Lasers Surg. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/0166-6851(91)90062-B","article-title":"Artemisinin (qinghaosu): The role of intracellular hemin in its mechanism of antimalarial action","volume":"49","author":"Meshnick","year":"1991","journal-title":"Mol. Biochem Parasitol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1016\/S1471-4922(00)01838-9","article-title":"Possible modes of action of the artemisinin-type compounds","volume":"17","author":"Olliaro","year":"2001","journal-title":"Trends Parasitol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/j.pharmthera.2013.12.001","article-title":"Artemisinins: Pharmacological actions beyond anti-malarial","volume":"142","author":"Ho","year":"2014","journal-title":"Pharmacol. Ther."},{"key":"ref_9","first-page":"247597","article-title":"Antitumor activity of artemisinin and its derivatives: From a well-known antimalarial agent to a potential anticancer drug","volume":"2012","author":"Wei","year":"2012","journal-title":"J. Biomed. Biotechnol"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Wang, J., Huang, L., Li, J., Fan, Q., Long, Y., Li, Y., and Zhou, B. (2010). Artemisinin directly targets malarial mitochondria through its specific mitochondrial activation. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0009582"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.ijpharm.2007.09.003","article-title":"Anticancer properties of artemisinin derivatives and their targeted delivery by transferrin conjugation","volume":"354","author":"Nakase","year":"2008","journal-title":"Int. J. Pharm."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1124\/mol.64.2.382","article-title":"Molecular modes of action of artesunate in tumor cell lines","volume":"64","author":"Efferth","year":"2003","journal-title":"Mol. Pharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Efferth, T., Giaisi, M., Merling, A., Krammer, P.H., and Li-Weber, M. (2007). Artesunate induces ROS-mediated apoptosis in doxorubicin-resistant T leukemia cells. PLoS ONE, 2.","DOI":"10.1371\/journal.pone.0000693"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1475","DOI":"10.3892\/ol.2013.1545","article-title":"Reversal of multidrug resistance by the anti-malaria drug artesunate in the esophageal cancer Eca109\/ABCG2 cell line","volume":"6","author":"Liu","year":"2013","journal-title":"Oncol. Lett."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1108","DOI":"10.1128\/AAC.37.5.1108","article-title":"Iron-dependent free radical generation from the antimalarial agent artemisinin (qinghaosu)","volume":"37","author":"Meshnick","year":"1993","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1016\/S0035-9203(99)90376-0","article-title":"A randomized safety and tolerability trial of artesunate plus sulfadoxine-pyrimethamine versus sulfadoxine-pyrimethamine alone for the treatment of uncomplicated malaria in Gambian children","volume":"93","author":"Doherty","year":"1999","journal-title":"Trans. R Soc. Trop. Med. Hyg."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1186\/1748-717X-9-84","article-title":"Artemisinin derivative artesunate induces radiosensitivity in cervical cancer cells in vitro and in vivo","volume":"9","author":"Luo","year":"2014","journal-title":"Radiat. Oncol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1527","DOI":"10.1159\/000358716","article-title":"Dihydroartemisinin accentuates the anti-tumor effects of photodynamic therapy via inactivation of NF-\u03baB in Eca109 and Ec9706 esophageal cancer cells","volume":"33","author":"Li","year":"2014","journal-title":"Cell Physiol. Biochem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.yexmp.2019.01.006","article-title":"The anti-malarial drug artesunate causes cell cycle arrest and apoptosis of triple-negative MDA-MB-468 and HER2-enriched SK-BR-3 breast cancer cells","volume":"107","author":"Greenshields","year":"2019","journal-title":"Exp. Mol. Pathol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Osaki, T., Uto, Y., Ishizuka, M., Tanaka, T., Yamanaka, N., Kurahashi, T., Azuma, K., Murahata, Y., Tsuka, T., and Itoh, N. (2017). Artesunate Enhances the Cytotoxicity of 5-Aminolevulinic Acid-Based Sonodynamic Therapy against Mouse Mammary Tumor Cells In Vitro. Molecules, 22.","DOI":"10.3390\/molecules22040533"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"5519","DOI":"10.1158\/1078-0432.CCR-08-0197","article-title":"Experimental therapy of hepatoma with artemisinin and its derivatives: In vitro and in vivo activity, chemosensitization, and mechanisms of action","volume":"14","author":"Hou","year":"2008","journal-title":"Clin. Cancer Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1705","DOI":"10.3390\/molecules15031705","article-title":"The molecular mechanism of action of artemisinin\u2014The debate continues","volume":"15","author":"Barton","year":"2010","journal-title":"Molecules"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Li, Z., Li, Q., Wu, J., Wang, M., and Yu, J. (2016). Artemisinin and Its Derivatives as a Repurposing Anticancer Agent: What Else Do We Need to Do?. Molecules, 21.","DOI":"10.3390\/molecules21101331"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1074\/jbc.M110.144188","article-title":"The role of heme and the mitochondrion in the chemical and molecular mechanisms of mammalian cell death induced by the artemisinin antimalarials","volume":"286","author":"Mercer","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1021\/acscentsci.7b00156","article-title":"Mechanistic Investigation of the Specific Anticancer Property of Artemisinin and Its Combination with Aminolevulinic Acid for Enhanced Anticolorectal Cancer Activity","volume":"3","author":"Wang","year":"2017","journal-title":"ACS Cent. Sci."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Ba, Q., Zhou, N., Duan, J., Chen, T., Hao, M., Yang, X., Li, J., Yin, J., Chu, R., and Wang, H. (2012). Dihydroartemisinin exerts its anticancer activity through depleting cellular iron via transferrin receptor-1. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0042703"}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/24\/21\/3891\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:30:13Z","timestamp":1760189413000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/24\/21\/3891"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,10,29]]},"references-count":26,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2019,11]]}},"alternative-id":["molecules24213891"],"URL":"https:\/\/doi.org\/10.3390\/molecules24213891","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,10,29]]}}}