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
August
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
Jianrong Wu 0 1 2
Huajun Liu 0 1 2
Ge Zhang 0 1 2
Ling Gu 0 1 2
Yanle Zhang 0 1 2
Ju Gao 0 1 2
Yuquan Wei 0 2
Zhigui Ma 0 1 2
0 Natural Science Foundation of China (81071639) and the Program for Changjiang Scholars and Innovative Research Team in University (IRT0935), and also by the Applied and Basic Research Project of Sichuan Province , China (2015JY0044). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
1 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 , 2 State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University , Chengdu, 610041 , PR China
2 Editor: Kevin D Bunting, Emory University , UNITED STATES
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.
Data Availability Statement; All relevant data are within the paper
Introduction
Acute lymphoblastic leukemia (ALL) is the most common cancer diagnosed in children. With
precise risk-based stratification and optimized risk-directed therapy, it has an overall survival
rate of approximately 80%, with certain subsets experiencing a greater than 98% cure rate
Competing Interests: The authors have declared
that no competing interests exist.
[
1, 2
]. Glucocorticoids (GCs), such as prednisolone and dexamethasone (DEX), have been the
keystone in the treatment of children with ALL for over 50 years [
3, 4
]. The initial response to
GC therapy has a strong prognostic value in ALL [
5–7
]. High sensitivity of leukemic blasts to
GC determined by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT)
assay in vitro was also connected with a good prognosis [
8
]. However, clinical GC resistance
occurs in 10–30% of newly-diagnosed ALL patients and is more frequently seen in those with
T-lineage ALL (T-ALL), and it always leads to the failure of chemotherapy [
9, 10
]. T-ALL is a
highly malignant tumor representing 10–15% of pediatric and 25% of adult ALL and is
clinically regarded as a high risk disease with a relapse rate of about 30% in children [
11, 12
].
Therefore, defining the molecular mechanism and especially finding a way to overcome GC
resistance would contribute to the improvement of the outcome of T-ALL patients.
Ciclopirox olamine (CPX), an antifungal agent commonly used for the dermatologic
treatment of mycoses in clinical practice for more than 30 years [
13, 14
], has been shown recently
to have antitumor properties in multiple cancers [15], including hematological malignancies,
such as acute leukemia and multiple myeloma [
16–19
]. Yet, there is rare report on CPX’s
antileukemia effect on ALL, especially on ALL with GC resistance. In this study, we used the GC
resistant T-ALL cell lines to investigate this antileukemia effect and explore the possible
mechanisms of CPX on GC-resistant cell lines. Our findings suggest that CPX might be an attractive
new therapeutic approach for GC-resistant T-ALL patients.
Materials and Methods
Cell lines
Five T-ALL cell lines were used in the experiments. Jurkat (GC resistant) and Molt-4 (GC
resistant) were kindly provided by Dr. Stephan W. Morris (St. Jude Children’s Research Hospital,
Memphis, TN), CEM-C7 (GC sensitive) and CEM-C1 (GC resistant) were kindly provided by
Dr. E. Brad Thompson (University of Texas Medical Branch (...truncated)