Molecular mechanisms by which ciclopirox inhibits proliferation and induces apoptosis of tumor cells

Ciclopirox olamine (CPX), a synthetic fungicide clinically used to treat mycoses of the skin and nails, has been demonstated as a novel anticancer agent. Recently we have identified that CPX inhibits tumor growth by inhibiting proliferation and inducing apoptosis of tumor cells. This study was set out to determine the underlying mechanisms. Human rhabdomyosarcoma (Rh30) and breast carcinoma (MDA‐MB‐231) cells were used in this study. We found that CPX slowed down cell cycle progression, accumulating cells at G1 phase, in a concentration‐dependent manner. Concurrently, CPX downregulated cellular abundance of several key cell cycle regulators, such as Cdc25A, cyclin D1 and c‐Myc in the cells. As Cdc25A plays a decisive role in promoting cell cycle progression, and is frequently overexpressed in tumor cells, we further examined how CPX downregulates Cdc25A. It appears that CPX did not alter the mRNA and protein synthesis level, but promoted the protein degradation of Cdc25A. In addition, we found that CPX induced reactive oxygen species (ROS) and caused DNA damage. CPX increased phosphorylation of CHK1, as well as histone H2AX. Furthermore, CPX activated JNK cascade. The results suggest that CPX may inhibit cell cycle progression and cell proliferation by downregulating Cdc25A, cyclin D1 and c‐Myc, and induces apoptosis in tumor cells by activating stress kinases (CHK1 and JNK).