title: Antileukemia Effect of Ciclopirox Olamine Is Mediated by Downregulation of Intracellular Ferritin and Inhibition β-Catenin-c-Myc Signaling Pathway in Glucocorticoid Resistant T-ALL Cell Lines.
abstract: Ciclopirox olamine (CPX) is an antifungal drug that has been reported to have antitumor effects. In this study we investigated the antileukemia effects and the possible mechanisms of CPX on glucocorticoid (GC)-resistant T-cell acute lymphoblastic leukemia (T-ALL) cell lines. The results indicated that CPX inhibited the growth of GC-resistant T-ALL cells in a time- and dose-dependent manner, and this effect was closely correlated with the downregulation of intracellular ferritin. CPX induced cell cycle arrest at G1 phase by upregulation of cyclin-dependent kinase (CDK) inhibitor of p21 and downregulation of the expressions of cyclin D, retinoblastoma protein (Rb), and phosphorylated Rb (pRb). CPX also enhanced apoptotic cell death by downregulation of anti-apoptotic proteins such as Bcl-2, Bcl-xL, and Mcl-1. More importantly, CPX demonstrated a strong synergistic antileukemia effect with GC and this effect was mediated, at least in part, by inhibition of the β-catenin-c-Myc signaling pathway. These findings suggest that CPX could be a promising antileukemia drug, and modulation of the intracellular ferritin expression might be an effective method in the treatment of ALL. Therefore, integrating CPX into the current GC-containing ALL protocols could lead to the improvement of the outcome of ALL, especially GC-resistant ALL.
authors.affiliation: Department of Pediatrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children, West China Second University Hospital, Sichuan University, Chengdu, 60041, PR China.
authors.forename: Jianrong
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Pediatrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children, West China Second University Hospital, Sichuan University, Chengdu, 60041, PR China.
authors.forename: Huajun
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Pediatrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children, West China Second University Hospital, Sichuan University, Chengdu, 60041, PR China.
authors.forename: Ge
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Department of Pediatrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children, West China Second University Hospital, Sichuan University, Chengdu, 60041, PR China.
authors.forename: Ling
authors.initials: L
authors.lastname: Gu
authors.affiliation: Department of Pediatrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children, West China Second University Hospital, Sichuan University, Chengdu, 60041, PR China.
authors.forename: Yanle
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pediatrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children, West China Second University Hospital, Sichuan University, Chengdu, 60041, PR China.
authors.forename: Ju
authors.initials: J
authors.lastname: Gao
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, PR China.
authors.forename: Yuquan
authors.initials: Y
authors.lastname: Wei
authors.affiliation: Department of Pediatrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children, West China Second University Hospital, Sichuan University, Chengdu, 60041, PR China.|State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, PR China.
authors.forename: Zhigui
authors.identifier: http://orcid.org/0000-0003-2966-361X
authors.initials: Z
authors.lastname: Ma
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D000077768:Ciclopirox; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005293:Ferritins / Q000378:metabolism*; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D011728:Pyridones / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D005938:Glucocorticoids; D016271:Proto-Oncogene Proteins c-myc; D011728:Pyridones; D051176:beta Catenin; D000077768:Ciclopirox; D005293:Ferritins