Anti-hepatoma immunotherapy of Pholiota adiposa polysaccharide-coated selenium nanoparticles by reversing M2-like tumor-associated macrophage polarization.

Targeting macrophages to regulate the tumor microenvironment is a promising strategy for treating cancer. This study developed a stable nano drug (PAP-SeNPs) using Se nanoparticles (SeNPs) and the Pholiota adiposa polysaccharide component (PAP-1a) and reported their physical stability, M2-like macrophages targeting efficacy and anti-hepatoma immunotherapy potential, as well as their molecular mechanisms. Furthermore, the zero-valent and well-dispersed spherical PAP-SeNPs were also successfully synthesized with an average size of 55.84 nm and a negative ζ-potential of -51.45 mV. Moreover, it was observed that the prepared PAP-SeNPs were stable for 28 days at 4 °C. Intravital imaging highlighted that PAP-SeNPs had the dual effect of targeting desirable immune organs and tumors. In vitro analyses showed that the PAP-SeNPs polarized M2-like macrophages towards the M1 phenotype to induce hepatoma cell death, triggered by the time-dependent lysosomal endocytosis in macrophages. Mechanistically, PAP-SeNPs significantly activated the Tlr4/Myd88/NF-κB axis to transform tumor-promoting macrophages into tumor-inhibiting macrophages and successfully initiated antitumor immunotherapy. Furthermore, PAP-SeNPs also enhanced CD3+CD4+ T cells and CD3+CD8+ T cells, thereby further stimulating anti-hepatoma immune responses. These results suggest that the developed PAP-SeNPs is a promising immunostimulant that can assist hepatoma therapy.

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.

ROS generation attenuates the anti-cancer effect of CPX on cervical cancer cells by inducing autophagy and inhibiting glycophagy.

Cervical cancer is one of the most common gynecological malignancies with poor prognosis due to constant chemoresistance and repeated relapse. Ciclopirox olamine (CPX), a synthetic antifungal agent, has recently been identified to be a promising anti-cancer candidate. However, the detailed mechanisms related to its anti-cancer effects remain unclear and need to be further elucidated. In this study, we found that CPX could induce proliferation inhibition in cervical cancer cells by targeting PARK7. Further results demonstrated that CPX could induce cytoprotective autophagy by downregulating the expression of PARK7 to activate PRKAA1 or by PARK7-independent accumulation of ROS to inhibit mTOR signaling. Meanwhile, CPX treatment increased the glycogen clustering and glycophagy in cervical cancer cells. The presence of N-acetyl-l-cysteine (NAC), a ROS scavenger, led to further clustering of glycogen in cells by reducing autophagy and enhancing glycophagy, which promoted CPX-induced inhibition of cervical cancer cell proliferation. Together, our study provides new insights into the molecular mechanisms of CPX in the anti-cancer therapy and opens new avenues for the glycophagy in cancer therapeutics.