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.

Ciclopirox activates PERK-dependent endoplasmic reticulum stress to drive cell death in colorectal cancer

“…CPX was found to inhibit rhabdomyosarcoma by inhibiting mTORC1 signaling through the activation of the AMPK pathway 10 . CPX also has an antileukemic and -neuroblastic effect by inhibiting β-Catenin and c-Myc signaling 11,12 . In addition, CPX could induce autophagy by reactive oxygen species (ROS)mediated JNK activation 13 .…”

Ciclopirox Olamine Induces Ferritinophagy and Ameliorates Disease Progression in Polycystic Kidney Disease

“…Next, we examined potential mechanisms by which CPX-O could reduce cystogenesis. CPX-O is an iron chelator, and ferritin degradation has been shown as a mechanism of CPX-O 22…”

“…Ferritin degradation via autophagy has been a proposed mechanism of action of CPX-O 11,22 . Autophagy is a process that results in the formation of autophagosomes in which double membraned vesicular structures sequester cytoplasmic components and fuse with lysosomes to form autolysosomes.…”

“…The preclinical studies have shown that systemic administration of CPX in hematologic malignancies resulted in antitumor effects 19 . The proposed mechanisms of CPX include chelation of polyvalent metal cations, such Fe3+ by which it can inhibit iron dependent enzymes, such as ribonucleotide reductase and components of hypoxia, Wnt, and Notch signaling 10,20,21 . CPX is also involved in ferritin degradation 22 and protection against ferroptosis [23][24][25] .…”

“…The proposed mechanisms of CPX include chelation of polyvalent metal cations, such Fe3+ by which it can inhibit iron dependent enzymes, such as ribonucleotide reductase and components of hypoxia, Wnt, and Notch signaling 10,20,21 . CPX is also involved in ferritin degradation 22 and protection against ferroptosis [23][24][25] . Ferritin is a hetero-polymeric molecule composed of 24 heavy and light subunits which can store excess iron in cells of up to 4500 iron atoms 26 .…”