Abstract
Ciclopirox olamine (CPX), a fungicide, has been demonstrated as a potential anticancer agent. However, the underlying anticancer mechanism is not well understood. Here, we found that CPX induced autophagy in human rhabdomyosarcoma (Rh30 and RD) cells. It appeared that CPX-induced autophagy was attributed to induction of reactive oxygen species (ROS), as N-acetyl-L-cysteine (NAC), a ROS scavenger and antioxidant, prevented this process. Furthermore, we observed that CPX induced activation of mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK) and p38 MAPK, which was also blocked by NAC. However, only inhibition of JNK (with SP600125) or expression of dominant negative c-Jun partially prevented CPX-induced autophagy, indicating that ROS-mediated activation of JNK signaling pathway contributed to CPX-induced autophagy. Of interest, inhibition of autophagy by chloroquine (CQ) enhanced CPX-induced cell death, indicating that CPX-induced autophagy plays a pro-survival role in human rhabdomyosarcoma cells. Our finding suggests that the combination with autophagy inhibitors may be a novel strategy in potentiating the anticancer activity of CPX for treatment of rhabdomyosarcoma.
Highlights
Ciclopirox olamine (CPX), a synthetic hydroxypyridone derivative, is currently used for the treatment of superficial fungal infections and available in a variety of formulations, including cream, lotion, gel, nail lacquer and shampoos [1]
CPX reduces cell viability and alters morphology in rhabdomyosarcoma cells To investigate the cytotoxicity of CPX in rhabdomyosarcoma cells, RD and Rh30 cells were treated with various concentrations of CPX for 72 h, followed by MTS assay
To determine whether CPX causes cell death by inducing apoptosis, cells were analyzed by flow cytometry following Annexin V-FITC and propidium iodide (PI) staining
Summary
Ciclopirox olamine (CPX) ( called Batrafen, Loprox, Penlac and Stieprox), a synthetic hydroxypyridone derivative, is currently used for the treatment of superficial fungal infections and available in a variety of formulations, including cream, lotion, gel, nail lacquer and shampoos [1]. Recent studies have shown that CPX induces cell death in different cancer cells, such as primary human acute myeloid leukemia cells, human breast cancer MDA-MB231 cells and human rhabdomyosarcoma Rh30 cells [3, 4]. The mechanism by which CPX induces cancer cell death is only at the beginning to be investigated. Eberhard et al reported that CPX displays preclinical anticancer activity against hematologic malignancies and induces cell death through its ability to chelate intracellular iron and inhibit the iron-dependent enzyme ribonucleotide reductase [4]. We showed that CPX inhibits tumor growth in human breast cancer MDA-MB231 xenografts and induces cell death through caspase-dependent and caspaseindependent mechanisms in Rh30 cells [3]
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