{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,26]],"date-time":"2026-01-26T19:49:07Z","timestamp":1769456947214,"version":"3.49.0"},"reference-count":60,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2022,10,4]],"date-time":"2022-10-04T00:00:00Z","timestamp":1664841600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science (JSPS) KAKENHI grant to B.Y.","doi-asserted-by":"publisher","award":["20K07136"],"award-info":[{"award-number":["20K07136"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>The cytotoxicity of a trivalent arsenic derivative (arsenite, AsIII) combined with arenobufagin or gamabufotalin was evaluated in human U-87 glioblastoma cells. Synergistic cytotoxicity with upregulated intracellular arsenic levels was observed, when treated with AsIII combined with arenobufagin instead of gamabufotalin. Apoptosis and the activation of caspase-9\/-8\/-3 were induced by AsIII and further strengthened by arenobufagin. The magnitude of increase in the activities of caspase-9\/-3 was much greater than that of caspase-8, suggesting that the intrinsic pathway played a much more important role in the apoptosis. An increase in the number of necrotic cells, enhanced LDH leakage, and intensified G2\/M phase arrest were observed. A remarkable increase in the expression level of \u03b3H2AX, a DNA damage marker, was induced by AsIII+arenobufagin. Concomitantly, the activation of autophagy was observed, suggesting that autophagic cell death associated with DNA damage was partially attributed to the cytotoxicity of AsIII+arenobufagin. Suppression of Notch signaling was confirmed in the combined regimen-treated cells, suggesting that inactivation of Jagged1\/Notch signaling would probably contribute to the synergistic cytotoxic effect of AsIII+arenobufagin. Given that both AsIII and arenobufagin are capable of penetrating into the blood\u2013brain barrier, our findings may provide fundamental insight into the clinical application of the combined regimen for glioblastoma.<\/jats:p>","DOI":"10.3390\/molecules27196577","type":"journal-article","created":{"date-parts":[[2022,10,9]],"date-time":"2022-10-09T23:31:43Z","timestamp":1665358303000},"page":"6577","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Enhanced Cytotoxic Effects of Arenite in Combination with Active Bufadienolide Compounds against Human Glioblastoma Cell Line U-87"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3406-258X","authenticated-orcid":false,"given":"Bo","family":"Yuan","sequence":"first","affiliation":[{"name":"Laboratory of Pharmacology, Graduate School of Pharmaceutical Sciences, Josai University, Keyakidai, Sakado 350-0295, Saitama, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jingmei","family":"Li","sequence":"additional","affiliation":[{"name":"Laboratory of Immunobiochemistry, Graduate School of Pharmaceutical Sciences, Josai University, Keyakidai, Sakado 350-0295, Saitama, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2762-2147","authenticated-orcid":false,"given":"Shin-Ich","family":"Miyashita","sequence":"additional","affiliation":[{"name":"National Institute of Advanced Industrial Science and Technology (AIST), AIST Tsukuba Central 3, 1-1-1 Umezono, Tsukuba 305-8563, Ibaraki, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7704-4859","authenticated-orcid":false,"given":"Hidetomo","family":"Kikuchi","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacotherapy, Graduate School of Pharmaceutical Sciences, Josai University, Keyakidai, Sakado 350-0295, Saitama, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Meiyan","family":"Xuan","sequence":"additional","affiliation":[{"name":"Laboratory of Organic and Medicinal Chemistry; Graduate School of Pharmaceutical Sciences, Josai University, Keyakidai, Sakado 350-0295, Saitama, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hirokazu","family":"Matsuzaki","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacology, Graduate School of Pharmaceutical Sciences, Josai University, Keyakidai, Sakado 350-0295, Saitama, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naohiro","family":"Iwata","sequence":"additional","affiliation":[{"name":"Laboratory of Immunobiochemistry, Graduate School of Pharmaceutical Sciences, Josai University, Keyakidai, Sakado 350-0295, Saitama, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shinya","family":"Kamiuchi","sequence":"additional","affiliation":[{"name":"Laboratory of Immunobiochemistry, Graduate School of Pharmaceutical Sciences, Josai University, Keyakidai, Sakado 350-0295, Saitama, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katsuyoshi","family":"Sunaga","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacotherapy, Graduate School of Pharmaceutical Sciences, Josai University, Keyakidai, Sakado 350-0295, Saitama, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takeshi","family":"Sakamoto","sequence":"additional","affiliation":[{"name":"Laboratory of Organic and Medicinal Chemistry; Graduate School of Pharmaceutical Sciences, Josai University, Keyakidai, Sakado 350-0295, Saitama, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasuhide","family":"Hibino","sequence":"additional","affiliation":[{"name":"Laboratory of Immunobiochemistry, Graduate School of Pharmaceutical Sciences, Josai University, Keyakidai, Sakado 350-0295, Saitama, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mari","family":"Okazaki","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacology, Graduate School of Pharmaceutical Sciences, Josai University, Keyakidai, Sakado 350-0295, Saitama, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2683","DOI":"10.1101\/gad.1596707","article-title":"Malignant astrocytic glioma: Genetics, biology, and paths to treatment","volume":"21","author":"Furnari","year":"2007","journal-title":"Genes Dev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"v190","DOI":"10.1093\/annonc\/mdq187","article-title":"High-grade malignant glioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up","volume":"21","author":"Stupp","year":"2010","journal-title":"Ann. 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