{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T01:10:51Z","timestamp":1773882651470,"version":"3.50.1"},"reference-count":62,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2022,7,13]],"date-time":"2022-07-13T00:00:00Z","timestamp":1657670400000},"content-version":"vor","delay-in-days":193,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004735","name":"Natural Science Foundation of Hunan Province","doi-asserted-by":"publisher","award":["2021JJ10077"],"award-info":[{"award-number":["2021JJ10077"]}],"id":[{"id":"10.13039\/501100004735","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81974000"],"award-info":[{"award-number":["81974000"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Oxidative Medicine and Cellular Longevity"],"published-print":{"date-parts":[[2022,1]]},"abstract":"<jats:p><jats:italic>Objective<\/jats:italic>. The prognosis of children with refractory acute myeloid leukemia (AML) is poor. Complete remission (CR) is not always achieved with current salvage chemotherapy regimens before transplantation, and some patients have no chance of transplantation. Here, we aimed to describe a new regimen of conventional chemotherapy drugs (homoharringtonine, cladribine , and aclarubicin (HCA)) for refractory AML and its mechanism in vitro. <jats:italic>Methods<\/jats:italic>. We retrospectively collected the clinical data of 5 children with primary refractory AML using HCA as reinduction chemotherapy, and CR rates, adverse reactions, and disease\u2010free survival (DFS) were analyzed. The effects of homoharringtonine, cladribine, and aclarubicin alone or in combination on the proliferation of HL60 and THP1 cells were analyzed by CCK\u20108 assay. Furthermore, CCK\u20108 was used to determine the effects of HCA, alone or in combination with apoptosis inhibitors, necroptosis inhibitors, ferroptosis inhibitors, or autophagy inhibitors, on the proliferation of HL60 and THP1 cells and to screen for possible HCA\u2010mediated death pathways in AML cells. The pathway of HCA\u2010mediated AML cell death was further verified by Hoechst\/PI staining, flow cytometry, and Western blotting. <jats:italic>Results<\/jats:italic>. After 2 cycles of conventional chemotherapy, none of the 5 children with AML achieved CR and were then treated with the HCA regimen for two cycles, 4 of 5 achieved CR, and another child achieved CR with incomplete hematological recovery (CRi). After CR, 3 children underwent hematopoietic stem cell transplantation (HSCT), and only 2 of them received consolidation therapy. As of the last follow\u2010up, all 5 patients had been in DFS for a range of 23 to 28 months. The inhibition rate of homoharringtonine, cladribine, and aclarubicin in combination on HL60 and THP1 cells was significantly greater than that of a single drug or a combination of two drugs. We found that inhibitors of apoptosis and necroptosis were able to inhibit HCA\u2010mediated cell death but not ferroptosis or autophagy inhibitors. Compared with the control group, the number of apoptotic cells in the HCA group was significantly increased and could be reduced by an apoptosis inhibitor. Western blot results showed that PARP, caspase\u20103, and caspase\u20108 proteins were activated and cleaved in the HCA group, the expression of Bax was upregulated and that of Bcl\u20102 was downregulated. The expression of apoptosis\u2010related proteins could be reversed by apoptosis inhibition. Compared with the control group, the expression levels of the necroptosis\u2010related proteins RIP1, RIP3, and MLKL were downregulated in the HCA group but were not phosphorylated. The necroptosis inhibitor increased the expression of RIP1 but caused no significant changes in RIP3 and MLKL, and none were phosphorylated. <jats:italic>Conclusions<\/jats:italic>. HCA, as a new regimen of conventional drugs, was a safe and efficacious reinduction salvage strategy in children with refractory AML before HSCT. HCA exhibits the synergistic growth inhibition of AML cells and induces cell death mainly through apoptosis.<\/jats:p>","DOI":"10.1155\/2022\/8212286","type":"journal-article","created":{"date-parts":[[2022,7,13]],"date-time":"2022-07-13T22:35:10Z","timestamp":1657751710000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Homoharringtonine combined with cladribine and aclarubicin (HCA) in acute myeloid leukemia: A new regimen of conventional drugs and its mechanism"],"prefix":"10.1155","volume":"2022","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1194-5275","authenticated-orcid":false,"given":"Fenglin","family":"Wang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1338-0044","authenticated-orcid":false,"given":"Min","family":"Xie","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0182-2909","authenticated-orcid":false,"given":"Pan","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3946-6305","authenticated-orcid":false,"given":"Dan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3746-1209","authenticated-orcid":false,"given":"Minghua","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2022,7,13]]},"reference":[{"key":"e_1_2_11_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41375-018-0071-7"},{"key":"e_1_2_11_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2009.30"},{"key":"e_1_2_11_3_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12519-019-00321-8"},{"key":"e_1_2_11_4_2","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.24712"},{"key":"e_1_2_11_5_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V84.4.1237.1237"},{"key":"e_1_2_11_6_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11684-018-0658-4"},{"key":"e_1_2_11_7_2","doi-asserted-by":"publisher","DOI":"10.1002\/mpo.1177"},{"key":"e_1_2_11_8_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12185-011-0837-4"},{"key":"e_1_2_11_9_2","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2018.191841"},{"key":"e_1_2_11_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.leukres.2019.106217"},{"key":"e_1_2_11_11_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2016-08-733196"},{"key":"e_1_2_11_12_2","doi-asserted-by":"publisher","DOI":"10.3760\/cma.j.issn.0253-2727.2017.12.004"},{"key":"e_1_2_11_13_2","doi-asserted-by":"publisher","DOI":"10.5114\/wo.2014.40436"},{"key":"e_1_2_11_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41409-019-0461-0"},{"key":"e_1_2_11_15_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2008.16.4442"},{"key":"e_1_2_11_16_2","doi-asserted-by":"publisher","DOI":"10.1080\/10428194.2019.1616185"},{"key":"e_1_2_11_17_2","doi-asserted-by":"publisher","DOI":"10.1007\/s40272-013-0048-y"},{"key":"e_1_2_11_18_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2012.43.7384"},{"key":"e_1_2_11_19_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2141.1998.00836.x"},{"key":"e_1_2_11_20_2","doi-asserted-by":"publisher","DOI":"10.1111\/ped.13378"},{"key":"e_1_2_11_21_2","doi-asserted-by":"publisher","DOI":"10.1177\/1078155218817816"},{"key":"e_1_2_11_22_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00277-018-3562-8"},{"key":"e_1_2_11_23_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12094-017-1798-8"},{"key":"e_1_2_11_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.leukres.2003.08.010"},{"key":"e_1_2_11_25_2","doi-asserted-by":"publisher","DOI":"10.1080\/10428194.2016.1235274"},{"key":"e_1_2_11_26_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00277-018-3304-y"},{"key":"e_1_2_11_27_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2141.2011.08976.x"},{"key":"e_1_2_11_28_2","first-page":"233","article-title":"Clinical studies of aclacinomycin A (ACM)","volume":"41","author":"Majima H.","year":"1987","journal-title":"Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie"},{"key":"e_1_2_11_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.toxlet.2017.06.006"},{"key":"e_1_2_11_30_2","doi-asserted-by":"publisher","DOI":"10.21873\/anticanres.13490"},{"key":"e_1_2_11_31_2","doi-asserted-by":"publisher","DOI":"10.3760\/cma.j.issn.0253-2727.2018.09.006"},{"key":"e_1_2_11_32_2","doi-asserted-by":"publisher","DOI":"10.19746\/j.cnki.issn.1009-2137.2019.02.030"},{"key":"e_1_2_11_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.leukres.2015.09.014"},{"key":"e_1_2_11_34_2","doi-asserted-by":"publisher","DOI":"10.3760\/cma.j.issn.0253-2727.2017.07.011"},{"key":"e_1_2_11_35_2","doi-asserted-by":"publisher","DOI":"10.1080\/10428194.2017.1390229"},{"key":"e_1_2_11_36_2","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.16956"},{"key":"e_1_2_11_37_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1818539116"},{"key":"e_1_2_11_38_2","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2018.208835"},{"key":"e_1_2_11_39_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0164238"},{"key":"e_1_2_11_40_2","doi-asserted-by":"publisher","DOI":"10.3760\/cma.j.issn.0253-2727.2016.02.003"},{"key":"e_1_2_11_41_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00277-013-1758-5"},{"key":"e_1_2_11_42_2","doi-asserted-by":"publisher","DOI":"10.3109\/10428194.2013.772295"},{"key":"e_1_2_11_43_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00432-010-0947-z"},{"key":"e_1_2_11_44_2","doi-asserted-by":"publisher","DOI":"10.7534\/j.issn.1009-2137.2015.02.014"},{"key":"e_1_2_11_45_2","first-page":"19891","article-title":"Sorafenib in combination with low-dose-homoharringtonine as a salvage therapy in primary refractory FLT3-ITD-positive AML: a case report and review of literature","volume":"8","author":"Xu G.","year":"2015","journal-title":"International Journal of Clinical and Experimental Medicine"},{"key":"e_1_2_11_46_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12094-020-02383-x"},{"key":"e_1_2_11_47_2","first-page":"1245","article-title":"Phase I trial of homoharringtonine in children with refractory leukemia","volume":"71","author":"Tan C. T.","year":"1987","journal-title":"Cancer Treatment Reports"},{"key":"e_1_2_11_48_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2015-01-623447"},{"key":"e_1_2_11_49_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2141.2003.04702.x"},{"key":"e_1_2_11_50_2","doi-asserted-by":"publisher","DOI":"10.1042\/bj3590537"},{"key":"e_1_2_11_51_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.leu.2401570"},{"key":"e_1_2_11_52_2","first-page":"485","article-title":"Cytotoxicity of homoharringtonine on leukemic stem-like cells in AML cell line KG-1","volume":"41","author":"Shen J. P.","year":"2012","journal-title":"Zhejiang Da Xue Xue Bao. Yi Xue Ban"},{"key":"e_1_2_11_53_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.clml.2014.09.011"},{"key":"e_1_2_11_54_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3999"},{"key":"e_1_2_11_55_2","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2012.7"},{"key":"e_1_2_11_56_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2016.06.002"},{"key":"e_1_2_11_57_2","doi-asserted-by":"publisher","DOI":"10.4149\/neo_2015_071"},{"key":"e_1_2_11_58_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.critrevonc.2011.08.004"},{"key":"e_1_2_11_59_2","doi-asserted-by":"publisher","DOI":"10.12688\/f1000research.17023.1"},{"key":"e_1_2_11_60_2","doi-asserted-by":"publisher","DOI":"10.1038\/cdd.2017.65"},{"key":"e_1_2_11_61_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2008.03.036"},{"key":"e_1_2_11_62_2","doi-asserted-by":"publisher","DOI":"10.1038\/cdd.2013.94"}],"container-title":["Oxidative Medicine and Cellular Longevity"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/downloads.hindawi.com\/journals\/omcl\/2022\/8212286.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/downloads.hindawi.com\/journals\/omcl\/2022\/8212286.xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1155\/2022\/8212286","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,3]],"date-time":"2025-06-03T00:21:35Z","timestamp":1748910095000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1155\/2022\/8212286"}},"subtitle":[],"editor":[{"given":"Xiao-Wen","family":"Zhai","sequence":"additional","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2022,1]]},"references-count":62,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2022,1]]}},"alternative-id":["10.1155\/2022\/8212286"],"URL":"https:\/\/doi.org\/10.1155\/2022\/8212286","archive":["Portico"],"relation":{},"ISSN":["1942-0900","1942-0994"],"issn-type":[{"value":"1942-0900","type":"print"},{"value":"1942-0994","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1]]},"assertion":[{"value":"2022-05-18","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-06-06","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-07-13","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"8212286"}}