Ciclopirox Olamine Induces Proliferation Inhibition and Protective Autophagy in Hepatocellular Carcinoma

Hepatocellular carcinoma is one of the most common fatal malignancies worldwide. Thus far, the hepatocellular carcinoma prognosis has been bleak due to deficiencies in the identification and diagnosis of early hepatocellular carcinoma. Ciclopirox olamine (CPX) is a synthetic antifungal agent and has been considered as an anti-cancer candidate drug recently, though the detailed mechanisms related to its anti-cancer effect in hepatocellular carcinoma have not yet been revealed. Here, we found that CPX could inhibit proliferation in HCC cells but not in intrahepatic cholangiocarcinoma cells by arresting the cell cycle. Moreover, the anti-cancer effects of CPX in HCC cells were also attributed to CPX-triggered ROS accumulation and DJ-1 downregulation. Additionally, CPX could promote complete autophagic flux, which alleviated the anti-cancer effect of CPX in HCC cells, whereas the ROS scavenger (NAC) would attenuate CPX-induced protective autophagy. Interestingly, CPX could also induce glycogen clustering in HCC cells. Altogether, this study provides a new insight into the detailed molecular mechanisms of CPX as an anti-cancer therapy and a strategy for treating hepatocellular carcinoma.

Automated summary

Hepatocellular carcinoma is a prevalent and deadly cancer, but early identification and diagnosis remain challenging. The synthetic antifungal agent, Ciclopirox olamine (CPX), has shown potential as an anti-cancer drug for hepatocellular carcinoma, although its specific mechanisms of action have not been fully elucidated. This study demonstrates that CPX inhibits HCC cell proliferation by arresting the cell cycle, while also triggering ROS accumulation and downregulating DJ-1. CPX also induces complete autophagic flux, although this can mitigate its anti-cancer effects, and it induces glycogen clustering in HCC cells. Overall, this research provides new insights into the molecular mechanisms of CPX as an anti-cancer therapy for hepatocellular carcinoma.