Treatment Of Liver Cancer Research Articles

Dietary vitamin B3 supplementation induces the antitumor immunity against liver cancer via biased GPR109A signaling in myeloid cell

The impact of dietary nutrients on tumor immunity remains an area of ongoing investigation, particularly regarding the specific role of vitamins and their mechanism. Here, we demonstrate that vitamin B3 (VB3) induces antitumor immunity against liver cancer through biased GPR109A axis in myeloid cell. Nutritional epidemiology studies suggest that higher VB3 intake reduces liver cancer risk. VB3 supplementation demonstrates antitumor efficacy in multiple mouse models through alleviating the immunosuppressive tumor microenvironment (TME) mediated by tumor-infiltrating myeloid cell, thereby augmenting effectiveness of immunotherapy or targeted therapy in a CD8+ Tcell-dependent manner. Mechanically, the TME induces aberrant GPR109A/nuclear factor κB (NF-κB) activation in myeloid cell to shape the immunosuppressive TME. In contrast, VB3 activates β-Arrestin-mediated GPR109A degradation and NF-κB inhibition to suppress the immunosuppressive polarization of myeloid cell, thereby activating the cytotoxic function of CD8+ Tcell. Overall, these results expand the understanding of how vitamins regulate the TME, suggesting that dietary VB3 supplementation is an adjunctive treatment for liver cancer.

A pH-Responsive Drug-Delivery System Based on Apatinib-Loaded Metal-Organic Frameworks for Ferroptosis-Targeted Synergistic Anti-Tumor Therapy.

The efficacy of systemic therapy for hepatocellular carcinoma (HCC) is limited mainly by the complex tumor defense mechanism and the severe toxic side-effects of drugs. The efficacy of apatinib (Apa), a key liver cancer treatment, is unsatisfactory due to inadequate targeting and is accompanied by notable side-effects. Leveraging nanomaterials to enhance its targeting represents a crucial strategy for improving the effectiveness of liver cancer therapy. A metal polyphenol network-coated apatinib-loaded metal-organic framework-based multifunctional drug-delivery system (MIL-100@Apa@MPN) was prepared by using metal-organic frameworks (MOFs) as carriers. The nanoparticles (NPs) were subsequently characterized using techniques such as X-ray diffraction (XRD), transmission electron microscopy (TEM), zeta potential measurements, and particle size analysis. In vitro experiments were conducted to observe the drug release kinetics and cytotoxic effects of MIL-100@Apa@MPN on HepG2 cells. The in vivo anti-tumor efficacy of MIL-100@Apa@MPN was evaluated using the H22 tumor-bearing mouse model. The formulated MIL-100@Apa@MPN demonstrates remarkable thermal stability and possesses a uniform structure, with measured drug-loading (DL) and encapsulation efficiency (EE) rates of 28.33% and 85.01%, respectively. In vitro studies demonstrated that HepG2 cells efficiently uptake coumarin-6-loaded NPs, and a significant increase in cumulative drug release was observed under lower pH conditions (pH 5.0), leading to the release of approximately 73.72% of Apa. In HepG2 cells, MIL-100@Apa@MPN exhibited more significant antiproliferative activity compared to free Apa. In vivo, MIL-100@Apa@MPN significantly inhibited tumor growth, attenuated side-effects, and enhanced therapeutic effects in H22 tumor-bearing mice compared to other groups. We have successfully constructed a MOF delivery system with excellent safety, sustained-release capability, pH-targeting, and improved anti-tumor efficacy, highlighting its potential as a therapeutic approach for the treatment of HCC.

Oroxylin A, a broad‑spectrum anticancer agent, relieves monocrotaline‑induced pulmonary arterial hypertension by inhibiting the Warburg effect in rats.

Pulmonary arterial hypertension (PAH) is a chronic and fatal disease characterized by pulmonary vascular remodeling, similar to the 'Warburg effect' observed in cancer, which is caused by reprogramming of glucose metabolism. Oroxylin A (OA), an active compound derived from Scutellaria baicalensis, which can inhibit glycolytic enzymes [hexokinase 2 (HK2), Lactate dehydrogenase (LDH), and pyruvate dehydrogenase kinase 1 (PDK1) by downregulating aerobic glycolysis to achieve the treatment of liver cancer. To the best of our knowledge, however, the impact of OA on PAH has not been addressed. Consequently, the present study aimed to evaluate the potential protective role and mechanism of OA against PAH induced by monocrotaline (MCT; 55 mg/kg). The mean pulmonary artery pressure (mPAP) was measured using the central venous catheter method; HE and Masson staining were used to observe pulmonary artery remodeling. Non‑targeted metabolomics was used to analyze the metabolic pathways and pathway metabolites in MCT‑PAH rats. Western Blot analysis was employed to assess the levels of glucose transporter 1 (Glut1), HK2), pyruvate kinase (PK), isocitrate dehydrogenase 2 (IDH2), pyruvate dehydrogenase kinase 1(PDK1), and lactate dehydrogenase (LDH) protein expression in both lung tissue samples from MCT‑PAH rats. The results demonstrated that intragastric administration of OA (40 and 80 mg/kg) significantly decreased mPAP from 43.61±1.88 mmHg in PAH model rats to 26.51±1.53 mmHg and relieve pulmonary artery remodeling. Untargeted metabolomic analysis and multivariate analysis indicated abnormal glucose metabolic pattern in PAH model rats, consistent with the Warburg effect. OA administration decreased this effect on the abnormal glucose metabolism. The protein levels of key enzymes involved in glucose metabolism were evaluated by western blotting, which demonstrated that OA could improve aerobic glycolysis and inhibit PAH by decreasing the protein levels of Glut1, HK2, LDH, PDK1 and increasing the protein levels of PK and IDH2. In conclusion, OA decreased MCT‑induced PAH in rats by reducing the Warburg effect.

The Fisetin on Anti-senescence of Hepatocellular Carcinoma Cell

Liver cancer, as a global health issue, is of critical importance in termsal of treatment and prognosis. Quercetin, a flavonoid compound widely found in fruits, vegetables, and beverages, has become a research focus in recent years for its antioxidant, anti-inflammatory, anti-viral, and anti-tumor properties. Studies, especially on the inhibition of hepatocellular growth, the blocking of metastasis, and the regulation of cellular senescence mechanisms, have suggested that quercetin has potential therapeutic value. This article primarily reviews the progress of quercetin in the anti-senescence research of liver cancer cells. Studies have shown that quercetin can affect the proliferation, survival, and apoptosis of liver cancer cells through different molecular mechanisms. Firstly, quercetin can directly inhibit the growth of liver cancer cells by inducing cell cycle arrest at the G0/G1 or G2/M phases, and by upregulating pro-apoptotic proteins such as the caspase family and downregulating anti-apoptotic proteins like the Bcl-2 family, thereby promoting apoptosis of liver cancer cells. Secondly, quercetin can inhibit the invasion and metastasis of liver cancer cells, which may be related to its regulation of matrix metalloproteinase expression, significant in preventing distant metastases of liver cancer. Furthermore, quercetin can influence the biological behaviors of liver cancer cells by regulating related signaling pathways, such as PI3K/Akt, MAPKs, and NF-κB. In addition, quercetin exhibits a unique mechanism in regulating the senescence of liver cancer cells by promoting senescence through the activation of the p53/p21 and p16/Rb pathways. Finally, addressing the issue of quercetin's bioavailability, research has found that combining it with other drugs or improving the administration methods could enhance its therapeutic effect. In summary, as a multi-target natural compound, quercetin shows extensive potential in the treatment of liver cancer. However, its application in clinical therapy still requires further in vitro, in vivo experiments, and clinical studies to validate its effectiveness and safety.

Feasibility and safety study of ultrasound-guided percutaneous microwave ablation for sub-cardiac liver cancers without artificial ascites assistance.

To investigate the efficacy and safety of ultrasound (US)-guided microwave ablation (MWA) without artificial ascites (AA) inpatients with sub-cardiac (SC) liver cancers. This retrospective study included patients with the left lobe and caudate lobe of the liver cancer who underwent US-guided MWA in our institute from January 2020 to December 2022. According to whether the target lesion was located ≤5 mm from the pericardium, patients were divided into the SC group and the non-sub-cardiac (NSC) group. In the SC group, AA was not employed during the ablation procedure. The results of technical success, technical efficiency, local tumour progression (LTP), and major complications were recorded. A total of 79 patients with 87 lesions were enrolled. There were 38 patients with 38 lesions in the SC group and 41 patients with 49 lesions in the NSC group. The median follow-up of all patients was 15 (range, 3-44) months. There was no significant difference in technical success rates (100% vs 100%), technique efficiency rates (100% vs 95.7%), LTP rates (2.63% vs 0%,), and major complication rates (2.63% vs 7.32%) between the SC group and the NSC group (P > .05). No cardiac-related complications occurred. US-guided MWA without AA for SC liver cancers was safe and effective. The clinical prognosis of thermal ablation without AA in the treatment of SC liver cancers is still unclear. The finding of this study provided evidence supporting the efficacy and safety of US-guided MWA without AA for treating this tricky location.

Independent risk factor of drug eruption in immune checkpoint inhibitors treated liver cancer patients: high systemic immune-inflammation index

Purpose The clinical application of immune checkpoint inhibitors (ICIs) has significantly improved the prognosis of liver cancer patients. However, drug eruption associated with ICI monotherapy or combination therapy not only impacts the quality of life and treatment progress of liver cancer patients but also poses a potential threat to their lives. The study aims to investigate the risk factors of drug eruption in liver cancer patients undergoing ICIs in real-world settings. Methods We retrospectively collected data from liver cancer patients who underwent ICI therapies at the Third Affiliated Hospital of Sun Yat-sen University between 2021 and 2022. A propensity score matching (PSM) method was employed to match 31 liver cancer patients with ICI-related drug eruption (drug eruption group) to 228 liver cancer patients without immune-related adverse reactions (control group) in a 1:2 ratio, creating two groups of patients with comparable baseline characteristics. Subsequently, logistic regression analysis was then conducted to analyze the clinical risk factors associated with drug eruption caused by ICIs. Results Before PSM, there were statistically significant differences between the drug eruption group (31 cases) and the control group (228 cases) in two variables: Child-Pugh liver function classification and presence of vascular invasion (both p < 0.05). However, after PSM, no statistically significant differences were found in the clinical variables between the drug eruption group (28 cases) and the control group (52 cases). Univariate analysis revealed significantly higher levels of aspartate amino­transferase, alanine aminotransferase, glutamyl transpeptidase, and systemic immune-inflammation index (SII) and a significantly lower rate of liver cancer resection surgery before immunotherapy in liver cancer patients with drug eruption compared to the control group (p < 0.05). Multivariate analysis indicated that an elevated SII level before immunotherapy was significantly associated with the occurrence of drug eruption in liver cancer patients treated with ICIs (p < 0.05). The predictive performance of SII before immunotherapy in liver cancer patients for ICI-related drug eruption yielded an area under the receiver operator characteristic curve of 0.852, with a critical value of 749.189. Sensitivity and specificity were determined as 85.7% and 75%, respectively (p < 0.05). Conclusions Elevated systemic immune-inflammation index is identified as a risk factor for drug eruption occurrence in liver cancer patients treated with ICI therapies.

Current status and new advancements in molecular imaging of liver cancer

Early-stage diagnosis of liver cancer is challenging, with an overall poor prognosis. The tumor microenvironment of primary liver cancer is complex, exhibiting significant heterogeneity both interpersonally and intratumorally. Therefore, it is of paramount importance to dynamically analyze biological markers in the tumor microenvironment of primary liver cancer in vivo. In recent years, significant progress has been made in the imaging diagnosis and treatment of liver cancer with the development of molecular imaging. Molecular imaging techniques utilize specific nano-imaging probes to evaluate pathological changes of liver cancer at the molecular and cellular levels in real-time. These techniques enable precise imaging to reveal key molecular biomarkers involved in the occurrence and progression of liver cancer, exploring their associations with cancer progression and outcomes. This article focuses on molecular imaging, emphasizing the current research status and latest advancements in the field of liver cancer diagnosis and therapy using techniques such as CT, MRI, optical imaging, PET imaging, and multimodal imaging. It also identifies important future directions and significant challenges for further development.

Tryptanthrin targets GSTP1 to induce senescence and increases the susceptibility to apoptosis by senolytics in liver cancer cells

Targeting senescence has emerged as a promising strategy for liver cancer treatment. However, the lack of a safe agent capable of inducing complete senescence and being combined with senolytics poses a limitation. Here, we screened a natural product library and identified tryptanthrin (TRYP) as a potent inducer of cellular senescence in liver cancer cells both in vitro and in vivo. Mechanistically, Glutathione S-transferase P1 (GSTP1), a key regulator for redox homeostasis, was identified as a target protein for TRYP-induced senescence. TRYP directly bound to GSTP1 and inhibited its enzymatic activity, mediating reactive oxygen species (ROS) accumulation, followed by DNA damage response (DDR), consequently contributing to initiating primary senescence. Furthermore, TRYP triggered DNA damage-dependent activation of NF-κB pathway, which evoked senescence-associated secretory phenotype (SASP), thereby leading to senescence reinforcement. Importantly, TRYP exposed the vulnerability of tumor cells and sensitized senescent cells to apoptosis induced by senolytic agent ABT263, a Bcl2 inhibitor. Taken together, our findings reveal that TRYP induces cellular senescence via GSTP1/ROS/DDR/NF-κB/SASP axis, providing a novel potential application in synergizing with senolytic therapy in liver cancer.

Nano-Formulations of Natural Antioxidants for the Treatment of Liver Cancer.

Oxidative stress is a key factor in the pathological processes that trigger various chronic liver diseases, and significantly contributes to the development of hepatocarcinogenesis. Natural antioxidants reduce oxidative stress by neutralizing free radicals and play a crucial role in the treatment of free-radical-induced liver diseases. However, their efficacy is often limited by poor bioavailability and metabolic stability. To address these limitations, recent advances have focused on developing nano-drug delivery systems that protect them from degradation and enhance their therapeutic potential. Among the several critical benefits, they showed to be able to improve bioavailability and targeted delivery, thereby reducing off-target effects by specifically directing the antioxidant to the liver tumor site. Moreover, these nanosystems led to sustained release, prolonging the therapeutic effect over time. Some of them also exhibited synergistic effects when combined with other therapeutic agents, allowing for improved overall efficacy. This review aims to discuss recent scientific advances in nano-formulations containing natural antioxidant molecules, highlighting their potential as promising therapeutic approaches for the treatment of liver cancer. The novelty of this review lies in its comprehensive focus on the latest developments in nano-formulations of natural antioxidants for the treatment of liver cancer.

Clinical predictive factors of the efficacy of immune checkpoint inhibitors and kinase inhibitors in advanced hepatocellular cancer.

Hepatocellular carcinoma (HCC) is a highly aggressive tumor associated with significant morbidity and mortality rates. Combination therapy with immune checkpoint inhibitors (ICIs) and kinase inhibitors has emerged as a promising strategy for liver cancer treatment in recent years. However, the clinical factors predicting the outcomes of combination therapy in patients with advanced liver cancer remain uncertain. Therefore, this study investigated the relationships between clinical predictors and the efficacy of ICI plus kinase inhibitor therapy to personalize treatment plans. We retrospectively enrolled 98 patients who received combination treatment with ICIs and kinase inhibitors for advanced HCC. Based on blood lipid levels and other clinical factors prior to treatment, we investigated potential biomarkers that could predict treatment responses in this patient population. Mean progression-free survival (PFS) and overall survival (OS) in this cohort were 10.1 and 17.2months, respectively. Via multivariate analysis, the absence of extrahepatic metastasis, the absence of portal vein thrombosis (PVT), neutrophil-to-lymphocyte ratio (NLR) < 3.225, platelet-to-lymphocyte ratio (PLR) < 140.75, and prognostic nutritional index (PNI) ≥ 37.25 were identified as independent predictors of improved PFS. Factors associated with better OS included PLR < 140.75 and total cholesterol (TC) < 3.46mmol/L. Univariate analysis identified significant associations of Eastern Cooperative Oncology Group performance status (ECOG PS), hepatitis B virus (HBV) DNA levels, Child-Pugh classification, alpha-fetoprotein (AFP), TC, and the receipt of regorafenib with PFS. Additionally, ECOG PS, Child-Pugh classification, AFP, PVT, NLR, PNI, and the receipt of regorafenib were significantly associated with OS. PLR and TC were potential clinical predictive factors for survival outcomes in patients with advanced HCC who received ICI/kinase inhibitor combination therapy. It is important to know the clinical characteristics of patients prior to treatment initiation to optimize outcomes.

Laparoscopic ablation for liver malignancies: initial experience at a Scandinavian high volume HPB center

BackgroundAblation is an effective, parenchymal-sparing treatment for primary liver cancer and liver metastases. The purpose of this study was to report our initial experience with laparoscopic microwave ablation regarding postoperative complications, rate of conversions to open procedure, and technical efficacy.MethodsThis was a quality improvement project carried out at a tertiary care center in Denmark. Patients ≥ 18 years old with liver malignancies, not available for percutaneous ablation, and treated with ultrasound-guided laparoscopic ablation were included.ResultsFrom March 2023 to December 2023, 39 patients were referred for laparoscopic ablation after a multidisciplinary team conference. Of these, two procedures were converted to open procedures due to adhesion and tumor progression. Three patients rejected the sharing of medical information, two procedures were canceled and in one case the strategy was changed perioperatively. Therefore, 32 procedures in 31 patients were available for analysis. Complete ablation was evaluated after 1 month and was achieved in 100% of the procedures. None of the patients died, and no complications were reported in 21 cases (65.6%). Most patients with complications had a grade 1 complication based on the Clavien–Dindo classification, which among others included abdominal and shoulder pain, atrial fibrillation, and subcutaneous hematoma. Two patients had a complication grade 2 (wound infection and decompensated cirrhosis) and one had a grade 4b (sepsis due to pneumonia and urinary tract infection). The median Comprehensive Complication Index was 12.2 (interquartile range 8.7–24.2). Furthermore, univariable logistic regression showed that ≥ 2 tumors treated were associated with a higher risk of complications (odds ratio 6.37, 95% confidence interval [1.20;33.85], p-value = 0.0297).ConclusionUltrasound-guided laparoscopic microwave ablation of liver malignancies is feasible and safe with little risk for complications, a high technical efficacy, and a low rate of conversions to open procedures.

Research on tumors segmentation based on image enhancement method

One of the most effective ways to treat liver cancer is to perform precise liver resection surgery, the key step of which includes precise digital image segmentation of the liver and its tumor. However, traditional liver parenchymal segmentation techniques often face several challenges in performing liver segmentation: lack of precision, slow processing speed, and computational burden. These shortcomings limit the efficiency of surgical planning and execution. In this work, the model initially describes in detail a new image enhancement algorithm that enhances the key features of an image by adaptively adjusting the contrast and brightness of the image. Then, a deep learning-based segmentation network was introduced, which was specially trained on the enhanced images to optimize the detection accuracy of tumor regions. In addition, multi-scale analysis techniques have been incorporated into the study, allowing the model to analyze images at different resolutions to capture more nuanced tumor features. In the presentation of the experimental results, the study used the 3Dircadb dataset to test the effectiveness of the proposed method. The experimental results show that compared with the traditional image segmentation method, the new method using image enhancement technology has significantly improved the accuracy and recall rate of tumor identification.

109Pd/109mAg in-vivo generator in the form of nanoparticles for combined β- - Auger electron therapy of hepatocellular carcinoma

BackgroundConvenient therapeutic protocols for hepatocellular carcinoma (HCC) are often ineffective due to late diagnosis and high tumor heterogeneity, leading to poor long-term outcomes. However, recently performed studies suggest that using nanostructures in liver cancer treatment may improve therapeutic effects. Inorganic nanoparticles represent a unique material that tend to accumulate in the liver when introduced in-vivo. Typically, this is a major drawback that prevents the therapeutic use of nanoparticles in medicine. However, in HCC tumours, this may be advantageous because nanoparticles may accumulate in the target organ, where the leaky vasculature of HCC causes their accumulation in tumour cells via the EPR effect. On the other hand, recent studies have shown that combining low- and high-LET radiation emitted from the same radionuclide, such as 161Tb, can increase the effectiveness of radionuclide therapy. Therefore, to improve the efficacy of radionuclide therapy for hepatocellular carcinoma, we suggest utilizing radioactive palladium nanoparticles in the form of 109Pd/109mAg in-vivo generator that simultaneously emits β− particles and Auger electrons.ResultsPalladium nanoparticles with a size of 5 nm were synthesized using 109Pd produced through neutron irradiation of natural palladium or enriched 108Pd. Unlike the 109Pd-cyclam complex, where the daughter radionuclide diffuses away from the molecules, 109mAg remains within the nanoparticles after the decay of 109Pd. In vitro cell studies using radioactive 109Pd nanoparticles revealed that the nanoparticles accumulated inside cells, reaching around 50% total uptake. The 109Pd-PEG nanoparticles exhibited high cytotoxicity, even at low levels of radioactivity (6.25 MBq/mL), resulting in almost complete cell death at 25 MBq/mL. This cytotoxic effect was significantly greater than that of PdNPs labeled with β− (131I) and Auger electron emitters (125I). The metabolic viability of HCC cells was found to be correlated with cell DNA DSBs. Also, successful radioconjugate anticancer activity was observed in three-dimensional tumor spheroids, resulting in a significant treatment response.ConclusionThe results indicate that nanoparticles labeled with 109Pd can be effectively used for combined β− - Auger electron-targeted radionuclide therapy of HCC. Due to the decay of both components (β− and Auger electrons), the 109Pd/109mAg in-vivo generator presents a unique potential in this field.

Fabrication of ibuprofen/naringenin-coloaded into zein/sodium caseinate nanoparticles: evaluation of antiproliferative activity and apoptosis induction in liver cancer cells

Nowadays, liver cancer is one of the most disturbing types of cancer that can affect either sex. Nanoparticles (NPs) of zein/sodium caseinate incorporating ibuprofen (IBU) and naringenin (NAR) have improved bioavailability and a high encapsulation efficiency (EE%). These nanoparticles are uniformly spherical. In vitro, cytotoxicity analysis on HepG2 cell lines, which are used to study human liver cancer, shows that encapsulated drugs (86.49% ± 1.90, and 78.52% ± 1.98 for NAR and IBU, respectively) have significantly lower IC50 values than individual drugs or their combined free form. In addition, the combination indices of 0.623 and 0.155 for IBU and NAR, respectively, show that the two have joint beneficial effects. The scratch wound healing assay results also show that the free drugs and the engineered NPs have a more significant anti-migratory effect than the untreated cells. The designed nanoparticles also reduce angiogenesis and proliferation while inducing apoptosis, according to in vitro results. In conclusion, a new approach to treating liver cancer may lie in the nanoencapsulation of numerous drugs within nanoparticles.

Structure of POU2AF1 recombinant protein and it affects the progression and treatment of liver cancer based on WGCNA and molecular docking analysis

Hepatocellular carcinoma, also referred to as HCC, is the most frequent form of primary liver cancer. It is anticipated that the discovery of the molecular pathways related with HCC would open up new possibilities for the treatment of HCC.WGCNA (Weighted gene co-expression network analysis) and molecular docking analysis were used to study the structural characteristics of POU2AF1 recombinant protein and its interaction with related proteins. Normal samples were placed in one group, and tumor samples were placed in another group inside the GEO database. We continued our investigation of the DEGs by performing an enrichment analysis using GO and KEGG. The GSCA platform is utilized in the process of doing an analysis of the connection between gene expression and medication sensitivity. In the end, the core target and the active molecule were both given the green light for a molecular docking investigation. POU2AF1 is being considered as a possible therapeutic target for HCC, and the results of our work have presented novel concepts for the treatment of HCC.

Gut Microbiota, Deranged Immunity, and Hepatocellular Carcinoma.

Liver cancer, particularly hepatocellular carcinoma (HCC), is a significant gastrointestinal disease with a mortality rate as high as nearly 80% within five years. The disease's pathophysiology involves deranged immune responses and bile acid metabolism, with the gut microbiota (GM) playing a crucial role. Recent research highlights the potential of GM in influencing HCC treatment outcomes, especially regarding immune checkpoint inhibitors (ICIs). However, few patients currently benefit from ICIs due to a lack of effective response biomarkers. This review aimed to explore the literature on HCC treatment issues, focusing on immune response, bile acid metabolism, and GM dysbiosis. This review included studies from PubMed, Medline, and major gastroenterology and hepatology meetings, using keywords like gut microbiota, immune system, liver cancer, and checkpoint inhibitors. GM dysbiosis significantly impacts immune response and bile acid metabolism, making it a promising biomarker for ICI response. Modulating GM can enhance ICI treatment efficacy, although more research is needed to confirm its direct therapeutic benefits for HCC. GM dysbiosis is integral to liver cancer pathogenesis and treatment response. Its modulation offers promising therapeutic avenues for improving HCC prognosis and response to immunotherapy.

Calculus bovis inhibits M2 tumor-associated macrophage polarization via Wnt/β-catenin pathway modulation to suppress liver cancer.

Calculus bovis (CB), used in traditional Chinese medicine, exhibits anti-tumor effects in various cancer models. It also constitutes an integral component of a compound formulation known as Pien Tze Huang, which is indicated for the treatment of liver cancer. However, its impact on the liver cancer tumor microenvironment, particularly on tumor-associated macrophages (TAMs), is not well understood. To elucidate the anti-liver cancer effect of CB by inhibiting M2-TAM polarization via Wnt/β-catenin pathway modulation. This study identified the active components of CB using UPLC-Q-TOF-MS, evaluated its anti-neoplastic effects in a nude mouse model, and elucidated the underlying mechanisms via network pharmacology, transcriptomics, and molecular docking. In vitro assays were used to investigate the effects of CB-containing serum on HepG2 cells and M2-TAMs, and Wnt pathway modulation was validated by real-time reverse transcriptase-polymerase chain reaction and Western blot analysis. This study identified 22 active components in CB, 11 of which were detected in the bloodstream. Preclinical investigations have demonstrated the ability of CB to effectively inhibit liver tumor growth. An integrated approach employing network pharmacology, transcriptomics, and molecular docking implicated the Wnt signaling pathway as a target of the antineoplastic activity of CB by suppressing M2-TAM polarization. In vitro and in vivo experiments further confirmed that CB significantly hinders M2-TAM polarization and suppresses Wnt/β-catenin pathway activation. The inhibitory effect of CB on M2-TAMs was reversed when treated with the Wnt agonist SKL2001, confirming its pathway specificity. This study demonstrated that CB mediates inhibition of M2-TAM polarization through the Wnt/β-catenin pathway, contributing to the suppression of liver cancer growth.

The current status and future of targeted-immune combination for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common cancers and the third leading cause of death worldwide. surgery, transarterial chemoembolization (TACE), systemic therapy, local ablation therapy, radiotherapy, and targeted drug therapy with agents such as sorafenib. However, the tumor microenvironment of liver cancer has a strong immunosuppressive effect. Therefore, new treatments for liver cancer are still necessary. Immune checkpoint molecules, such as programmed death-1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T lymphocyte antigen-4 (CTLA-4), along with high levels of immunosuppressive cytokines, induce T cell inhibition and are key mechanisms of immune escape in HCC. Recently, immunotherapy based on immune checkpoint inhibitors (ICIs) as monotherapy or in combination with tyrosine kinase inhibitors, anti-angiogenesis drugs, chemotherapy agents, and topical therapies has offered great promise in the treatment of liver cancer. In this review, we discuss the latest advances in ICIs combined with targeted drugs (targeted-immune combination) and other targeted-immune combination regimens for the treatment of patients with advanced HCC (aHCC) or unresectable HCC (uHCC), and provide an outlook on future prospects. The literature reviewed spans the last five years and includes studies identified using keywords such as "hepatocellular carcinoma," "immune checkpoint inhibitors," "targeted therapy," "combination therapy," and "immunotherapy".

Chrysophanol Induces Cell Death and Inhibits Invasiveness through Alteration of Calcium Levels in HepG2 Human Liver Cancer Cells.

To investigate the effect of chrysophanol, a phytochemical derived from Radix et Rhizoma Rhei on HepG2 liver cancer cells. HepG2 cell line was treated with different concentrations chrysophanol (0-100 μmol/L) for 24 h. The cell counting kit 8 assay was employed to assess cell viability. Intracellular calcium levels were examined using Fluo-4 AM and Mag-fluo-4 AM staining, followed by flow cytometry analysis. Mitochondrial membrane potential was measured with JC-1 assay kit. Additionally, the expressions of key proteins such as p-JNK, Bax, cytochrome c (Cyt C), cleaved caspase-3 (cCaspase-3), and caspase-8 were analyzed by Western blot. The inhibitory effects of chrysophanol on the invasion of cells were determined using a Transwell assay. Analysis of invasiveness was conducted by wound healing assay. Chrysophanol significantly reduced the proliferation of HepG2 liver cancer cells by affecting intracellular calcium distribution, diminishing mitochondrial membrane potential, and enhancing the expressions of p-JNK, Bax, Cyt C, cCaspase-3, and caspase-8 in the groups treated with 75 or 100 μmol/L chrysophanol compared to the control group (P<0.05). Additionally, 75 and 100 μmol/L chrysophanol exhibited inhibitory effects on cell migration and wound healing. Chrysophanol demonstrates potential against HepG2 liver cancer cells, suggesting its potential use as a therapeutic agent for liver cancer treatment.

Development of cantharidin/baicalin co-delivery system based on mitochondrial targeting strategy for enhanced hepatocellular carcinoma therapy

Cantharidin (CTD) as a treatment for primary liver cancer are well known, and although structural alteration and nano-delivery are efficient in diminishing toxicity, its urinary and digestive toxicity has hindered its clinical application. Based on the synergistic effect of CTD and baicalin (BA) on proliferation inhibition of liver tumor cells, the highly expressed folic acid (FA) receptor of liver cancer cell membrane and the high negative membrane potential of tumor cell mitochondria, we synthesized CHEMS-FRFK and prepared a dual-ligand modified co-delivery liposomes (FA/FRFK-CTD/BA-Lips). Liposomes were spherical particles with uniform particle size, high encapsulation rate, good stability and no hemolysis. The results confirmed that FA/FRFK-CTD/BA-Lips had good targeting to mitochondria of tumor cells, and its target effect on mitochondria of HepG2 was better than that of Huh-7 cells. Compared with CTD, the cytotoxicity of liposomes on HepG2 is 7.0 times higher, while the cytotoxic effect on normal liver cells Thle-2 is 2.1 times lower. It may be related to increasing clathrin-mediated endocytosis, inhibiting tumor cell migration, arresting cell cycle in G1/G0 phase, and promoting mitochondria-mediated endogenous Bcl-2/Caspase 3 apoptosis pathway. Meanwhile, FA/FRFK-CTD/BA-Lips could alter the pharmacokinetic behavior of CTD and BA by increasing concentrations in vivo, slowing release and excretion, good anti-tumor with no obvious toxicity, and successfully delivered CTD/BA to liver tissue, tumor cells and mitochondria. Therefore, FA/FRFK-CTD/BA-Lips, as a delivery system targeting the mitochondria of liver cancer cells, has promising development potential, and could provide a new strategy for solving the problem of CTD toxicity and the treatment of hepatocellular carcinoma.