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

• DOI: 10.1371/journal.pone.0161509
• Publication Date: 2016-08-23T17:40:23Z
• Authors: Jianrong Wu; Huajun Liu; Ge Zhang; Ling Gu; Yanle Zhang; Ju Gao; Yuquan Wei; Zhigui Ma
• Keywords: Pyridones; Science; Antineoplastic Agents; Apoptosis; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Proto-Oncogene Proteins c-myc; 03 medical and health sciences; 0302 clinical medicine; Cell Line, Tumor; Humans; Glucocorticoids; beta Catenin; Cell Proliferation; Q; R; Drug Synergism; Cell Cycle Checkpoints; Ciclopirox; 3. Good health; Drug Resistance, Neoplasm; Ferritins; Medicine; Research Article; Signal Transduction

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.