The anticancer mechanisms of cicloprirox.

摘要

The ever-growing expenditure of cancer therapy urges a fundamental solution to reduce the treatment cost. Ciclopirox olamine (CPX), an off-patent fungicide with recognized anticancer activity, is such a candidate for this purpose. However, the studies on anticancer mechanisms of CPX are quite limited till now. Therefore, this study set up to understand the anticancer mechanisms of CPX in order to providing data for future clinical application. Our long term goal is to repurpose CPX for selective cancer therapy. In this study, we found that CPX inhibited cell proliferation in a concentration-dependent manner. Besides, CPX arrested cells at G1 phase of the cell cycle, and downregulated the expression of multiple cell cycle regulators including c-Myc and cyclin D1, which are critical for G1/S transition. Prominently, CPX also reduced the protein level of Cdc25A, a key valve governing the activity of cyclin-dependent kinases (CDKs). Thus, CPX accumulated the inhibitory phosphorylation on CDK2 as expected. Moreover, CPX downregulated Cdc25A expression by promoting its turnover, and Cdc25A-S82A mutant that was immune to CPX-induced degradation conferred resistance to CPX inhibition of cell proliferation. In respect to cell death, we found that CPX could induce both apoptosis and autophagy in a concentration-dependent manner. Further studies showed that c-Jun N-terminal kinase (JNK) cascade, one of the major regulators of caspases-dependent apoptosis, was activated by CPX treatment. Our results also revealed that CPX did dissociate apoptosis signal-regulating kinase 1 (ASK1), an upstream kinase of JNK, from its inhibitor, Cdc25A, implying CPX might activate JNK cascade by targeting Cdc25A. Concerning autophagy, we disclosed that CPX disrupted interaction between mTOR and ULK1, which is critical for inhibition of autophagy. The study on the molecular mechanism of CPX-induced Cdc25A degradation demonstrated that CPX promoted Cdc25A turnover by chelating the iron, causing the DNA damage, and activating ATR-Chk1 pathway. Therefore, our study demonstrated that CPX inhibited cancer development, at least in part, by targeting Cdc25A.