{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T12:51:06Z","timestamp":1777035066365,"version":"3.51.4"},"reference-count":54,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2023,1,23]],"date-time":"2023-01-23T00:00:00Z","timestamp":1674432000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Japan Society for the Promotion of Science (JSPS) KAKENHI","award":["20K07136"],"award-info":[{"award-number":["20K07136"]}]},{"name":"Solasia Pharma K.K.","award":["20K07136"],"award-info":[{"award-number":["20K07136"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>To explore the molecular mechanisms of action underlying the antileukemia activities of darinaparsin, an organic arsenical approved for the treatment of peripheral T\u2013cell lymphoma in Japan, cytotoxicity of darinaparsin was evaluated in leukemia cell lines NB4, U-937, MOLT-4 and HL-60. Darinaparsin was a more potent cytotoxic than sodium arsenite, and induced apoptosis\/necrosis in NB4 and HL-60 cells. In NB4 cells exhibiting the highest susceptibility to darinaparsin, apoptosis induction was accompanied by the activation of caspase-8\/-9\/-3, a substantial decrease in Bid expression, and was suppressed by Boc-D-FMK, a pancaspase inhibitor, suggesting that darinaparsin triggered a convergence of the extrinsic and intrinsic pathways of apoptosis via Bid truncation. A dramatic increase in the expression level of \u03b3H2AX, a DNA damage marker, occurred in parallel with G2\/M arrest. Activation of p53 and the inhibition of cdc25C\/cyclin B1\/cdc2 were concomitantly observed in treated cells. Downregulation of c-Myc, along with inactivation of E2F1 associated with the activation of Rb, was observed, suggesting the critical roles of p53 and c-Myc in darinaparsin-mediated G2\/M arrest. Trolox, an antioxidative reagent, suppressed the apoptosis induction but failed to correct G2\/M arrest, suggesting that oxidative stress primarily contributed to apoptosis induction. Suppression of Notch1 signaling was also confirmed. Our findings provide novel insights into molecular mechanisms underlying the cytotoxicity of darinaparsin and strong rationale for its new clinical application for patients with different types of cancer.<\/jats:p>","DOI":"10.3390\/ijms24032282","type":"journal-article","created":{"date-parts":[[2023,1,24]],"date-time":"2023-01-24T01:29:45Z","timestamp":1674523785000},"page":"2282","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Cytotoxic Effects of Darinaparsin, a Novel Organic Arsenical, against Human Leukemia Cells"],"prefix":"10.3390","volume":"24","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, Sakado 350-0295, 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, Sakado 350-0295, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jingmei","family":"Li","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacology, Graduate School of Pharmaceutical Sciences, Josai University, Sakado 350-0295, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Atsushi","family":"Kawabata","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacology, Graduate School of Pharmaceutical Sciences, Josai University, Sakado 350-0295, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3884-2989","authenticated-orcid":false,"given":"Kozo","family":"Yao","sequence":"additional","affiliation":[{"name":"Product Development Division, Solasia Pharma K.K., Tokyo 105-0011, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Norio","family":"Takagi","sequence":"additional","affiliation":[{"name":"Department of Applied Biochemistry, School of Pharmacy, Tokyo University of Pharmacy & Life Sciences, Hachioji 192-0392, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mari","family":"Okazaki","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacology, Graduate School of Pharmaceutical Sciences, Josai University, Sakado 350-0295, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Sun, H. 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