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Cancer is a major threat to human health, with high mortality and a low cure rate, continuously challenging public health worldwide. Extensive clinical application of traditional Chinese medicine (TCM) for patients with poor outcomes of radiotherapy and chemotherapy provides a new direction in anticancer therapy. Anticancer mechanisms of the active ingredients in TCM have also been extensively studied in the medical field. As a type of TCM against cancer, Rhizoma Paridis (Chinese name: Chonglou) has important antitumor effects in clinical application. The main active ingredients of Rhizoma Paridis (e.g., total saponins, polyphyllin I, polyphyllin II, polyphyllin VI, and polyphyllin VII) have shown strong antitumor activities in various cancers, such as breast cancer, lung cancer, colorectal cancer, hepatocellular carcinoma (HCC), and gastric cancer. Rhizoma Paridis also has low concentrations of certain other active ingredients with antitumor effects, such as saponins polyphyllin E, polyphyllin H, Paris polyphylla -22, gracillin, and formosanin-C. Many researchers have studied the anticancer mechanism of Rhizoma Paridis and its active ingredients. This review article describes research progress regarding the molecular mechanism and antitumor effects of the active ingredients in Rhizoma Paridis, suggesting that various active ingredients in Rhizoma Paridis may be potentially therapeutic against cancer.

Background: Polyphyllin VII (PP7), a steroidal saponin from Paris polyphylla, has been found to exert strong anticancer activity. Little is known about the anti-inflammatory property of PP7. In this study, the anti-inflammatory activity and its underlying mechanisms of PP7 were evaluated in lipopolysaccharide (LPS)-stimulated RAW264.7 cells and in multiple animal models. Methods: The content of nitric oxide (NO) was determined by spectrophotometry. The levels of prostaglandin E2 (PGE2) and cytokines were measured by enzyme-linked immunosorbent assay (ELISA) assay. The mRNA expression of pro-inflammatory genes was determined by qPCR. The total and phosphorylated protein levels were examined by Western blotting. The in vivo anti-inflammatory activities were evaluated by using mouse and zebrafish models. Results: PP7 reduced the production of NO and PGE2 and the protein and mRNA expressions of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) and enzymes (inducible NO synthase [iNOS], cyclooxygenase-2 [COX-2], and Matrix metalloproteinase-9 [MMP-9]) in LPS-induced RAW264.7 cells by suppressing the NF-κB and MAPKs pathways. Notably, PP7 markedly inhibited xylene-induced ear edema and cotton pellet-induced granuloma formation in mice and suppressed LPS and CuSO4-induced inflammation and toxicity in zebrafish embryos. Conclusion: This study demonstrates that PP7 exerts strong anti-inflammatory activities in multiple in vitro and in vivo models and suggests that PP7 is a potential novel therapeutic agent for inflammatory diseases.

Circulating tumor cells (CTCs) are cells that detach from the primary tumor and enter the bloodstream, playing a crucial role in the metastasis of lung cancer. Unfortunately, there is currently a lack of drugs specifically designed to target CTCs and prevent tumor metastasis. In this study, we present evidence that polyphyllin VII, a potent anticancer compound, effectively inhibits the metastasis of lung cancer by inducing a process called anoikis in CTCs. We observed that polyphyllin VII had significant cytotoxicity and inhibited colony formation, migration, and invasion in both our newly established cell line CTC-TJH-01 and a commercial lung cancer cell line H1975. Furthermore, we found that polyphyllin VII induced anoikis and downregulated the TrkB and EGFR-MEK/ERK signaling pathways. Moreover, activation of TrkB protein did not reverse the inhibitory effect of polyphyllin VII on CTCs, while upregulation of EGFR protein effectively reversed it. Furthermore, our immunodeficient mouse models recapitulated that polyphyllin VII inhibited lung metastasis, which was associated with downregulation of the EGFR protein, and reduced the number of CTCs disseminated into the lungs by inducing anoikis. Together, these results suggest that polyphyllin VII may be a promising compound for the treatment of lung cancer metastasis by targeting CTCs.Circulating tumor cells (CTCs) are cells that detach from the primary tumor and enter the bloodstream, playing a crucial role in the metastasis of lung cancer. Unfortunately, there is currently a lack of drugs specifically designed to target CTCs and prevent tumor metastasis. In this study, we present evidence that polyphyllin VII, a potent anticancer compound, effectively inhibits the metastasis of lung cancer by inducing a process called anoikis in CTCs. We observed that polyphyllin VII had significant cytotoxicity and inhibited colony formation, migration, and invasion in both our newly established cell line CTC-TJH-01 and a commercial lung cancer cell line H1975. Furthermore, we found that polyphyllin VII induced anoikis and downregulated the TrkB and EGFR-MEK/ERK signaling pathways. Moreover, activation of TrkB protein did not reverse the inhibitory effect of polyphyllin VII on CTCs, while upregulation of EGFR protein effectively reversed it. Furthermore, our immunodeficient mouse models recapitulated that polyphyllin VII inhibited lung metastasis, which was associated with downregulation of the EGFR protein, and reduced the number of CTCs disseminated into the lungs by inducing anoikis. Together, these results suggest that polyphyllin VII may be a promising compound for the treatment of lung cancer metastasis by targeting CTCs.

Polyphyllin VII, a compound extracted from the rhizomes of Paris polyphylla, has strong antitumor effects on various human tumor cell lines. However, few studies have reported the possible effect of Polyphyllin VII on human osteosarcoma (OS) cell lines. The present study revealed that Polyphyllin VII promoted OS cell apoptosis and inhibited cell proliferation via upregulating the expression of LC3II, Atg5, Atg7 and the Atg12-Atg5 complex. By contrast, treatment of OS cells with Polyphyllin VII downregulated Atg12 and p62 expression. Following treatment with class III PI 3-kinase inhibitor (3-MA; an autophagy inhibitor), the Polyphyllin VII-mediated apoptotic effect was reversed. These findings indicated that the inhibition of autophagy could attenuate U2OS cell apoptosis in cells treated with high concentrations of Polyphyllin VII. The present study also demonstrated that Polyphyllin VII upregulated the intracellular hydrogen peroxide (H2O2) levels in U2OS cells. However, treatment of U2OS cells with N-acetyl-L cysteine (NAC) effectively reversed this effect. The western blot analysis results indicated that the c-Jun N-terminal kinase (JNK) signaling pathway was closely associated with Polyphyllin VII-induced apoptosis and autophagy. In conclusion, the results of the present study demonstrated that Polyphyllin VII could effectively inhibit cell viability and promote autophagy and apoptosis in U2OS cells. In addition, the mechanism underlying these effects could be associated with the intracellular H2O2 levels and the JNK signaling pathway.

Ovarian cancer is a gynecological malignancy with high mortality. Adjuvant therapy such as chemoradiotherapy inevitably leads to side effects and drug resistance. In recent years, traditional Chinese medicine has been widely studied for its safety, effectiveness, and unique pharmacological effects. Polyphyllin VII is an important component of Rhizoma paridis saponins, and has cytotoxic effects on many types of cancer cells. The aim of the present study was to evaluate the anti-tumor activity of polyphyllin VII in human ovarian cancer cells. Recent studies found that polyphyllin VII induces mitochondrial pathway apoptosis by increasing mitochondrial division, but the specific mechanism was unclear. The results of this study revealed that polyphyllin VII could effectively induce mitochondrial dysfunction, including increased mitochondrial division and reactive oxygen species (ROS) production. Notably, the mitochondrial location of dynamin-related protein 1 (DRP1) plays an important role in its function. In addition, polyphyllin VII enhanced the mitochondrial localization of DRP1 which is mediated by increased protein phosphatase 2A (PP2A) activity, and decreased AKT activity. A specific PP2A inhibitor, LB100, attenuated mitochondrial division and apoptosis in cells caused by polyphyllin VII, confirming the function of the PP2A/AKT pathway in polyphyllin VII treatment. Additionally, xenotransplantation experiments have also confirmed the anti-tumor effect of polyphyllin VII in vivo. Therefore, interference of the mitochondrial translocation of DRP1 through PP2A/AKT pathway may be an attractive and effective therapeutic approach by polyphyllin VII in ovarian cancer. This may provide new strategies for polyphyllin VII in the clinical treatment of ovarian cancer.

Ferroptosis has been shown to mediate the development of fibrosis. Polyphyllin VII (PP7), a bioactive component of Paris polyphylla, exhibits potent anti-inflammatory activity and can significantly alleviate liver fibrosis. In this study, treatment with PP7 significantly inhibited the proliferation and activation of hepatic stellate cells (HSCs), which could be suppressed by a ferroptosis inhibitor. In addition, it promoted HSC ferroptosis by suppressing glutathione (GSH) peroxidase 4 (GPX4) and enhanced the expression of CX3C chemokine ligand 1 (CX3CL1). Depletion of CX3CL1 attenuated the effects of PP7 on the activation and ferroptosis of HSCs and the expression of GPX4. Notably, CX3CL1 directly interacted with GPX4, triggering HSC ferroptosis. The transcription factor hypermethylated in cancer 1 (Hic1), which binds to the Cx3cl1 promoter, increased the expression of CX3CL1. Its absence resulted in downregulation of CX3CL1, suppressing the GPX4-dependent ferroptosis of PP7-treated HSCs and promoting their activation. HIC1 was found to directly interact with PP7 at the GLY164 site. Co-culture experiments showed that PP7-induced HSC ferroptosis attenuated macrophage recruitment by regulating inflammation-related genes. HSC-specific inhibition of HIC1 counteracted PP7-induced collagen depletion and HSC ferroptosis in vivo. These findings suggest that PP7 induces HSC ferroptosis through the HIC1/CX3CL1/GPX4 axis. [Display omitted] •PP7 effectively inactivated HSC and alleviated CCl4-induced liver fibrosis, and this is a first report.•PP7 promotes HSC inactivation via ferroptosis pathway.•HIC1 is the key medium in the ferroptosis process induced by PP7.•PP7-induced HSC ferroptosis is via HIC1/C3XCL1/GPX4 axis.

Poor response and resistance to cisplatin (DDP)-based chemotherapy frequently leads to treatment failure in advanced non-small cell lung cancer (NSCLC). The underlying molecular mechanism is extremely complex and currently remains unclear. The overexpression of cancerous inhibitor of protein phosphatase 2A (CIP2A) indicates poor prognosis and promotes the epithelial-to-mesenchymal transition (EMT) and metastasis. The EMT has been reported to promote drug resistance in numerous previous studies. CIP2A and its downstream protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway also plays a role in mediating DDP resistance. Polyphyllin I (PPI) and polyphyllin VII (PPVII) are natural components extracted from Paris polyphylla that display anti-cancer properties. In the present study, the chemosensitizing effects of PPI and PPVII were investigated in the DDP-resistant NSCLC cell line A549/DDP, as well as the underlying molecular mechanisms. The results demonstrated that PPI and PPVII could significantly inhibit cell proliferation and enhance the sensitivities of A549/DDP cells to DDP. When assessing the underlying molecular mechanism, it was revealed that PPI and PPVII enhanced DDP-induced apoptosis in A549/DDP cells via p53 upregulation and the caspase-dependent pathway. Furthermore, PPI and PPVII reversed the EMT and suppressed CIP2A and its downstream AKT/mTOR signaling cascade in A549/DDP cells. Overall, the results from the present study demonstrated that PPI and PPVII may function as chemosensitizers by enhancing apoptosis via the p53 pathway, reversing EMT and suppressing the CIP2A/AKT/mTOR signaling axis, and the combination with DDP may be a promising strategy for the development of new therapeutic agents.

Non-small cell lung cancer (NSCLC) frequently develops acquired resistance to immune checkpoint inhibitors (ICIs), necessitating innovative strategies to remodel the immunosuppressive tumor microenvironment (TME). This study engineered an inhalable pH-responsive nano-liposome co-delivering Astragaloside IV (AS-IV) and Polyphyllin VII (Pol VII) (AS-IV/Pol VII-Lipo) to overcome anti-PD-1 resistance via spatiotemporal-controlled dual-drug delivery. AS-IV/Pol VII-Lipo (1:1 mass ratio) exhibited optimal physicochemical properties: high drug loading and pH-triggered release. Nebulized inhalation achieved 3.4-fold higher lung accumulation than oral administration. Suppressed orthotopic LLC-Luc tumor growth by 54% and reduced exhausted CD8⁺ T cells while increasing cytotoxic CD8⁺Granzyme B⁺ T cells. Combination therapy further inhibited tumor metastasis and elevated survival. Transcriptomics (RNA-seq) identified suppression of IL-2/STAT5/BLIMP1 pathway and T-cell exhaustion genes. AS-IV/Pol VII-Lipo reprograms the immunosuppressive TME through three synergistic mechanisms: (1) enhanced lung-targeted drug delivery via inhalation; (2) reversal T-cell exhaustion through IL-2/STAT5/BLIMP1 pathway inhibition; (3) synergizing with αPD-1 therapy to overcome ICI resistance. This inhalable nanoplatform presents a promising clinical strategy for NSCLC patients with acquired immunotherapyresistance.

Polyphyllin VII is an active compound isolated from Paris polyphylla, which is termed Chonglou in China. The present study was designed to investigate the underlying mechanisms of the antitumor effect of Polyphyllin VII in lung cancer cells. The cytotoxic effect of Polyphyllin VII in human lung cancer A549 cells was analyzed; the results revealed an IC50 value of 0.41±0.10 µM at 24 h. The associated mechanisms were investigated by phase-contrast microscopy, fluorescence microscopy, flow cytometry and western blot analysis. Exposure of A549 cells to Polyphyllin VII resulted in apoptosis. Pyrrolidine dithiocarbamate (PDTC), an inhibitor of NF-κB, and wortmannin, an inhibitor of PI3K, both decreased the proportion of viable A549 cells in the presence of Polyphyllin VII. The ratio of apoptotic cells increased in the presence of wortmannin and PDTC. Western blot analysis revealed that PI3K, phosphorylated (p)-PI3K, Akt, p-Akt, NF-κB and p-NF-κB were downregulated following treatment with Polyphyllin VII. Increased caspase-3 activity, increased poly-(ADP-ribose) polymerase cleavage and a downregulation of inhibitor of caspase-activated DNase were observed following treatment with Polyphyllin VII, and these effects were enhanced by either wortmannin or PDTC. The present results revealed that Polyphyllin VII was able to induce apoptotic cell death in A549 human lung cancer cells via inhibition of the PI3K/Akt and NF-κB pathways.

Endometrial carcinoma (EC) often exhibits resistance to hormone therapies, such as medroxyprogesterone acetate (MPA), highlighting the need for novel strategies to enhance therapeutic efficacy. The present study aimed to investigate the effects of polyphyllin VII (PPVII) on the efficacy of MPA in EC, focusing on the regulatory role of microRNA (miR)-33a-5p. Briefly, an MPA-resistant Ishikawa cell line (Ishikawa/MPA-R), maintained with 10 µM MPA, was established and transfected with negative control (NC) and miR-33a-5p inhibitors. Following treatment with PPVII and MPA, the proliferation capacity and apoptosis levels of the Ishikawa and Ishikawa/MPA-R cells were evaluated using reverse transcription-quantitative polymerase chain reaction, MTT assay, clonogenic assay, flow cytometry, western blotting and dual-luciferase assay. Next, the expression levels of miR-33a-5p and F-box and leucine rich repeat protein 16 (FBXL16) were measured, and the regulatory relationship between miR-33a-5p and FBXL16 was analyzed. Significant reductions in cell viability were observed in all groups following treatment with increased concentrations of MPA and PPVII, with the greatest effect observed in the combined MPA + PPVII group (P<0.01). The apoptosis levels of the Ishikawa/MPA-R cells were significantly increased in all drug treatment groups, particularly in the MPA + PPVII group (P<0.05). PPVII treatment significantly increased the expression level of miR-33a-5p in Ishikawa/MPA-R cells (P<0.01). In the PPVII + miR-33a-5p inhibitor group, the Ishikawa/MPA-R cells exhibited an upregulation in the viability (P<0.01), colony formation ability (P<0.01), proportion in the G1 phase (P<0.05) and the protein expression levels of cyclin D1 (P<0.01) and cyclin-dependent kinase 4 (P<0.01), and a reduction in the miR-33a-5p expression (P<0.01), apoptosis levels (P<0.05), proportion in the S (P<0.05) and G2 phases and the levels of Bcl-2-associated X protein (P<0.001). The FBXL16 protein expression in Ishikawa/MPA-R cells was significantly higher compared with Ishikawa cells, and the mRNA and protein expression levels of FBXL16 were markedly elevated in the PPVII + miR-33a-5p inhibitor group compared with the PPVII + NC group (P<0.01). These findings suggested that PPVII upregulated the expression of miR-33a-5p, enhanced the sensitivity of EC cells to MPA and potentially exerted anticancer effects in EC through the synergistic action of the miR-33a-5p/FBXL16 axis in combination with MPA.