Platycodin D2 enhances P21/CyclinA2-mediated senescence of HCC cells by regulating NIX-induced mitophagy.

BACKGROUND: Hepatocellular carcinoma (HCC) cells usually show strong resistance to chemotherapy, which not only reduces the efficacy of chemotherapy but also increases the side effects. Regulation of autophagy plays an important role in tumor treatment. Cell senescence is also an important anti-cancer mechanism, which has become an important target for tumor treatment. Therefore, it is of great clinical significance to find anti-HCC drugs that act through this new mechanism. Platycodin D2 (PD2) is a new saponin compound extracted from the traditional Chinese medicine Platycodon grandiflorum. PURPOSE: Our study aimed to explore the effects of PD2 on HCC and identify the underlying mechanisms. METHODS: First, the CCK8 assay was used to detect the inhibitory effect of PD2 on HCC cells. Then, different pathways of programmed cell death and cell cycle regulators were measured. In addition, we assessed the effects of PD2 on the autophagy and senescence of HCC cells by flow cytometry, immunofluorescence staining, and Western blotting. Finally, we studied the in vivo effect of PD2 on HCC cells by using a mouse tumor-bearing model. RESULTS: Studies have shown that PD2 has a good anti-tumor effect, but the specific molecular mechanism has not been clarified. In this study, we found that PD2 has no obvious toxic effect on normal hepatocytes, but it can significantly inhibit the proliferation of HCC cells, induce mitochondrial dysfunction, enhance autophagy and cell senescence, upregulate NIX and P21, and downregulate CyclinA2. Gene silencing and overexpression indicated that PD2 induced mitophagy in HCC cells through NIX, thereby activating the P21/CyclinA2 pathway and promoting cell senescence. CONCLUSIONS: These results indicate that PD2 induces HCC cell death through autophagy and aging. Our findings provide a new strategy for treating HCC.

Licochalcone A Induces Ferroptosis in Hepatocellular Carcinoma via Reactive Oxygen Species Activated by the SLC7A11/GPX4 Pathway.

Liver cancer is a common malignant tumor, and its incidence is increasing yearly. Millions of people suffer from liver cancer annually, which has a serious impact on global public health security. Licochalcone A (Lico A), an important component of the traditional Chinese herb licorice, is a natural small molecule drug with multiple pharmacological activities. In this study, we evaluated the inhibitory effects of Lico A on hepatocellular carcinoma cell lines (HepG2 and Huh-7), and explored the inhibitory mechanism of Lico A on hepatocellular carcinoma. First, we evaluated the inhibitory effects of Lico A on hepatocellular carcinoma, and showed that Lico A significantly inhibited and killed HepG2 and Huh-7 cells in vivo and in vitro. Transcriptomic analysis showed that Lico A inhibited the expression of solute carrier family 7 member 11 (SLC7A11), which induced ferroptosis. We confirmed through in vivo and in vitro experiments that Lico A promoted ferroptosis in hepatocellular carcinoma cells by downregulating SLC7A11 expression, thereby inhibiting the glutathione (GSH)-glutathione peroxidase 4 (GPX4) pathway and inducing activation of reactive oxygen species (ROS). In this study, we suggest that Lico A is a potential SLC7A11 inhibitor that induces ferroptotic death in hepatocellular carcinoma cells, thereby providing a theoretical basis for the development of natural small molecule drugs against hepatocellular carcinoma.

Neobavaisoflavone induces pyroptosis of liver cancer cells via Tom20 sensing the activated ROS signal.

BACKGROUND: Neobavaisoflavone (NBIF), a natural active ingredient isolated from Psoralea, possesses anti-inflammatory, anti-cancer, and antioxidant properties; however, the anti-tumor mechanism of NBIF has not been thoroughly investigated, and the inhibitory effect and inhibitory pathway of NBIF on liver cancer are still unknown. PURPOSE: Our study aimed to explore the effects of NBIF on hepatocellular carcinoma and its potential mechanisms. METHODS: First, we detected the inhibition of NBIF on HCC cells by the CCK8 assay and then observed the morphological changes of the cells under the microscope. Besides, we analyzed the changes in the pyroptosis level of NBIF when inhibiting the cells through flow cytometry, immunofluorescence, and a western blot assay. Finally, we used a mouse tumor-bearing model to explore the effects of NBIF in vivo on HCCLM3 cells. RESULTS: NBIF-treated HCC cells exhibited specific features of pyroptosis. Analysis of pyroptosis-related protein levels revealed that NBIF primarily induced pyroptosis in HCC cells via the caspase-3-GSDME signaling pathway. Then, we demonstrated that NBIF impacted the protein expression of Tom20 by producing ROS in HCC cells, hence promoting the recruitment of Bax to mitochondria, activating caspase-3, cutting GSDME, and triggering pyroptosis. CONCLUSIONS: By activating ROS, NBIF was able to trigger pyroptosis in HCC cells, providing an experimental basis for the future study of new treatments for liver cancer.