The antitumor activity of the fungicide ciclopirox

Abstract

Ciclopirox olamine (CPX) is a synthetic antifungal agent clinically used to treat mycoses of the skin and nails. Here, we show that CPX inhibited tumor growth in human breast cancer MDA-MB-231 xenografts. To unveil the underlying mechanism, we further studied the antitumor activity of CPX in cell culture. The results indicate that CPX inhibited cell proliferation and induced apoptosis in human rhabdomyosarcoma (Rh30), breast carcinoma (MDA-MB231) and colon adenocarcinoma (HT-29) cells in a concentration-dependent manner. By cell cycle analysis, CPX induced accumulation of cells in G 1 /G 0 phase of the cell cycle. Concurrently, CPX downregulated cellular protein expression of cyclins (A, B1, D1 and E) and cyclin-dependent kinases (CDK2 and CDK4) and upregulated expression of the CDK inhibitor p21Cip1 , leading to hypophosphorylation of retinoblastoma protein. CPX also downregulated protein expression of Bcl-xL and survivin and enhanced cleavages of Bcl-2. Z-VAD-FMK, a pan-caspase inhibitor, partially prevented CPX-induced cell death, suggesting that CPX-induced apoptosis of cancer cells is mediated at least in part through caspase-dependent mechanism. The results indicate that CPX is a potential antitumor agent.Ciclopirox olamine (CPX) (also called Batrafen, Loprox, Penlac and Stieprox), the ethanolamine salt of 6-cyclohexyl-1-hydroxy-4-methyl-2(1H)-pyridone, is a synthetic antifungal agent used to treat mycoses of the skin and nails for more than 20 years. 1-3Studies have shown that CPX has a very broad spectrum of action against dermatophytes, yeast, filamentous fungi and bacteria. 4,5 The mechanisms of these actions of CPX seem diverse, involving disruption of membrane function in fungi or targeting different metabolic (respiratory) and energy-producing processes in bacteria.1,2 In the yeast Saccharomyces cerevisiae, CPX may also exert its effect by disrupting DNA repair, cell division signals and structures (mitotic spindles) as well as some elements of intracellular transport.6 Apart from its antimycotic and antibacterial activities, CPX arrests the cell cycle at G 1 phase in mammalian cells 7,8 and G 2 /M phase in the yeast S. cerevisiae. 9 CPX also prevents the death of tropic factor-deprived PC12 cells and postmitotic sympathetic neurons by blocking the cell cycle progression 7 or the death of cerebellar granule neurons in low K þ -containing medium, 10 but it induces an active cell death in S. cerevisiae. 9In addition, CPX is a well-known iron chelator, inhibiting the iron-containing enzymes, such as catalase and peroxidase.11 Most recent studies have revealed that the chelation of intracellular iron and the inhibition of the iron-dependent enzyme ribonucleotide reductase were associated with CPXinduced cell death.12 It appeared that CPX induced cell death in primary human acute myeloid leukemia (AML) cells and inhibited engraftment of primary AML cells in NOD/SCID mouse models without gross organ toxicity or loss of body weight.12 Previous safety and toxicity studies of CPX also demonstrated that a 4-w...

Translational Downregulation of HSP90 Expression by Iron Chelators in Neuroblastoma Cells

“…Of note, IG 50 values of about 1-10 mM detected in CPX-treated NB cells are pharmacologically achievable (Weir et al, 2011;Minden et al, 2014). The CPX-mediated effect on viability of NB cells resulted from a combination of cell cycle deregulation and induction of apoptosis, corroborating previously published data on other tumor cell types (Zhou et al, 2010).…”

“…Interestingly, CPX exerted inhibition of DOHH in HUVEC and HeLa cells in a concentration-dependent manner with IC 50 values of 5 and 6.25 mM, respectively (Clement et al, 2002;Mémin et al, 2014), coincident with the dose threshold region of CPX effects observed in CHP134 cells. In addition to DOHH, the G 1 arrest induced by CPX could be mediated by multiple mechanisms involving cyclin D1, CDK2, RB1, and CDK inhibitor p21 CIP1/WAF1 (Zhou et al, 2010). However, the link between these proteins and upstream irondependent events remains unclear.…”

“…The fourth molecule was an off-patent synthetic antimicrobial agent, ciclopirox olamine (CPX). Although originally developed for the topical treatment of cutaneous fungal infections, CPX has recently been reported to display preclinical efficacy as an effective antitumor agent in the treatment of various cancers (Clement et al, 2002;Eberhard et al, 2009;Zhou et al, 2010;Song et al, 2011; This work was supported by a grant from the Italian Neuroblastoma Foundation. dx.doi.org/10.1124Foundation.…”

Translation Regulation as a Therapeutic Target in Cancer

“…N1-guanyl-1,7-diaminoheptane (GC7) and ciclopirox olamine (CPX) are potent inhibitors of deoxyhypusine synthase, which catalyzes eIF5A hypusination. GC7 and CPX have shown antiproliferative effects in various cell lines (137,138) and antitumor activity in vivo in breast cancer, melanoma, leukemia, and myeloma models (139)(140)(141).…”

Immunomodulatory effects of antimicrobial agents. Part II: antiparasitic and antifungal agents

“…It inhibits tumor growth in human breast cancer MDA-MB-231 xenografts, it inhibits cell proliferation and induces apoptosis in human rhabdomyosarcoma (Rh30), breast carcinoma (MDA-MB231) and colon adenocarcinoma (HT-29) cells and inhibits Wnt/betacatenin signaling in myeloma. Ciclopirox-induced apoptosis of cancer cells is mediated, at least in part, through a caspasedependent mechanism [100]. Griseofulvin has similar chemical features as compared with ciclopirox olamine.…”