Treatment Of Hepatic Carcinoma Research Articles

Self-Amplified pH/ROS Dual-Responsive Co-Delivery Nano-System with Chemo-Photodynamic Combination Therapy in Hepatic Carcinoma Treatment.

Chemo-photodynamic combination therapy has demonstrated significant potential in the treatment of cancer. Triptolide (TPL), a naturally derived anticancer agent, whencombined with the photosensitizer Chlorin e6 (Ce6), has shown to provide enhanced anti-tumor benefits. However, the development of stimuli-responsive nanovehicles for the co-delivery of TPL and Ce6 could further enhance the efficacy of this combination therapy. In this study, we synthesized a pH/ROS dual-responsive mPEG-TK-PBAE copolymer, which contains a pH-sensitive PBAE moiety and a ROS-sensitive thioketal (TK) linkage. Through a self-assembly process, TPL and Ce6 were successfully co-loaded into mPEG-TK-PBAE nanoparticles, hereafter referred to as TPL/Ce6 NPs. We evaluated the pH- and ROS-sensitive drug release and particle size changes. Furthermore, we investigated both the in vitro suppression of cellular proliferation and induction of apoptosis in HepG2 cells, as well as the in vivo anti-tumor efficacy of TPL/Ce6 NPs in H22 xenograft nude mice. The mPEG-TK-PBAE copolymer was synthesized through a one-pot Michael-addition reaction and successfully co-encapsulated both TPL and Ce6 by self-assembly. Upon exposure to acid pH values and high ROS levels, the payloads in TPL/Ce6 NPs were rapidly released. Notably, the abundant ROS generated by the released Ce6 under laser irradiation further accelerated the degradation of the nanosystem, thereby amplifying the tumor microenvironment-responsive drug release and enhancing anticancer efficacy. Consequently, TPL/Ce6 NPs significantly increased PDT-induced oxidative stress and augmented TPL-induced apoptosis in HepG2 cells, leading to synergistic anticancer effects in vitro. Moreover, administering TPL/Ce6 NPs (containing 0.3 mg/kg of TPL and 4 mg/kg of Ce6) seven times, accompanied by 650 nm laser irradiation, efficiently inhibited tumor growth in H22 tumor-bearing mice, while exhibiting lower systemic toxicity. Overall, we have developed a tumor microenvironment-responsive nanosystem for the co-delivery of TPL and Ce6, demonstrating amplified synergistic effects of chemo-photodynamic therapy (chemo-PDT) for hepatocellular carcinoma (HCC) treatment.

Revealing distinct DNA methylation patterns in hepatic carcinoma through high-throughput sequencing

Abstract Objectives To study the relationship between DNA methylation and tumour development and provide experimental evidence for the personalized diagnosis and treatment of hepatic carcinoma. Methods The DNA of hepatic carcinoma tissue (Ca group) and adjacent normal tissue (T group) were extracted using the phenol-chloroform method and then treated with bisulfite. Twenty-five genes including 45 subtypes were amplified by PCR. The PCR products were sequenced via the Illumina 450k methylation array assay. The changes of methylated DNA performance were analysed through principal component analysis (PCA). Cluster analysis was used to evaluate the classification of methylated DNA regions. Haplotype abundance variation was tested for methylation differences. Statistical analysis was performed using the chi-square (χ2) test or Fisher’s exact test. Results Sequencing discoveries indicated CG-type methylation pervading all amplicons. However, CHG-type and CHH-type methylations were confined to only four amplicons (or nine subtypes). The methylation ratios of three specific amplicons (DAB2IP, PRDM14-1, Rab31-1) out of 45 amplicon subtypes in the Ca group significantly increased (over 10 %) compared to the T group (p<0.05). Nineteen amplicons demonstrated minor distinction (methylation pattern variations between 1 and 10 %), with the remaining 23 amplicons showing only minimal disparities (under 1 %). PCA and cluster analysis unveiled a marked difference in methylation levels between cancerous and healthy tissues (p<0.05). Conclusions The changes in haplotypes and methylation sites could serve as a biomarker for the clinical diagnosis of hepatic carcinoma. Methylation patterns might play an important role in the occurrence and development of hepatic carcinoma.

Phellinus igniarius polysaccharides induced mitochondrial apoptosis of hepatic carcinoma by enhancing reactive oxygen species-mediated AKT/p53 signalling pathways

Phellinus igniarius (PI) has various kinds of biological activities, such as antitumour activities, and polysaccharides are one of its main components. In this study, polysaccharides from PI (PIP) were prepared, purified, analysed for their structure and investigated for their antitumour activity and mechanism in vitro. PIP consists of 12138 kDa of carbohydrates containing 90.5 ± 1.6% neutral carbohydrates. PIP consists of glucose, galactose, mannose, xylose, D-fructose, L-guluronic acid, glucosamine hydrochloride, rhamnose, arabinose and D-mannoturonic acid. PIP can significantly inhibit HepG2 cell proliferation, induce cell apoptosis and also inhibited migration and invasion in a concentration-dependent manner. PIP increased reactive oxygen species (ROS), increased the expression of p53, and induced cytochrome c release into the cytoplasm to activate caspase-3. PIP is a promising potential candidate for the therapeutic treatment of hepatic carcinoma via the ROS-mediated mitochondrial apoptosis pathway.

Exosomal miRNA in early-stage hepatocellular carcinoma.

The incidence and mortality of hepatic carcinoma (HCC) remain high, and early diagnosis of HCC is seen as a key approach in improving clinical outcomes. However, the sensitivity and specificity of current early screening methods for HCC are not satisfactory. In recent years, research around exosomal miRNA has gradually increased, and these molecules have emerged as attractive candidates for early diagnosis and treatment of HCC. This review summarizes the feasibility of using miRNAs in peripheral blood exosomes as early diagnostic tools for HCC.

Bioimaging of glutathione variation for early diagnosis of hepatocellular carcinoma using a liver-targeting ratiometric near-infrared fluorescent probe.

Reliable biomarkers are crucial for early diagnosis of diseases and precise therapy. Biological thiols (represented by glutathione, GSH) play vital roles in the antioxidant defense system for maintaining intracellular redox homeostasis in organisms. However, the aberrant variation in the cellular concentration of GSH correlates with diverse diseases including cancer. Here, a ratiometric near-infrared fluorescent probe CyO-Disu is constructed for the specific sensing of GSH variation in live cells and mice models of hepatic carcinoma (HCC). CyO-Disu features three key elements, a response moiety of bis(2-hydroxyethyl) disulfide, a near-infrared fluorescence signal transducer of heptamethine ketone cyanine, and a targeting moiety of D-galactose. By virtue of its liver-targeting capability, CyO-Disu was utilized for evaluating GSH fluctuations in primary and metastatic hepatoma living cells. To evaluate the efficacy of CyO-Disuin vivo, orthotopic HCC and pulmonary metastatic hepatoma mice models were employed for GSH imaging using two-dimensional and three-dimensional fluorescence molecular tomographic imaging systems. The bioimaging results offered direct evidence that GSH displayed varied concentrations during the progression of HCC. Therefore, the as-synthesized probe CyO-Disu could serve as a potential powerful tool for the early diagnosis and precise treatment of HCC using GSH as a reliable biomarker.

Identification of copper metabolism and cuproptosis-related subtypes for predicting prognosis tumor microenvironment and drug candidates in hepatocellular carcinoma.

Copper (Cu) is an essential element of organisms, which can affect the survival of cells. However, the role of copper metabolism and cuproptosis on hepatic carcinoma is still unclear. In this study, the TCGA database was used as the test set, and the ICGC database and self-built database were used as the validation set. We screened out a class of copper metabolism and cuproptosis-related genes (CMCRGs) that could influence hepatic carcinoma prognosis by survival analysis and differential comparison. Based on CMCRGs, patients were divided into two subtypes by cluster analysis. The C2 subtype was defined as the high copper related subtype, while the C1 subtype was defied as the low copper related subtype. At the clinical level, compared with the C1 subtype, the C2 subtype had higher grade pathological features, risk scores, and worse survival. In addition, the immune response and metabolic status also differed between C1 and C2. Specifically, C2 subtype had a higher proportion of immune cell composition and highly expressed immune checkpoint genes. C2 subtype had a higher TIDE score with a higher proportion of tumor immune dysfunction and exclusion. At the molecular level, the C2 subtype had a higher frequency of driver gene mutations (TP53 and OBSCN). Mechanistically, the single nucleotide polymorphisms of C2 subtype had a very strong transcriptional strand bias for C>A mutations. Copy number variations in the C2 subtype were characterized by LOXL3 CNV gain, which also showed high association with PDCD1/CTLA4. Finally, drug sensitivity responsiveness was assessed in both subtypes. C2 subtype had lower IC50 values for targeted and chemotherapeutic agents (sorafenib, imatinib and methotrexate, etc.). Thus, CMCRGs related subtypes showed poor response to immunotherapy and better responsiveness to targeted agents, and the results might provide a reference for precision treatment of hepatic carcinoma.

Co-Delivery of Dihydroartemisinin and Indocyanine Green by Metal-Organic Framework-Based Vehicles for Combination Treatment of Hepatic Carcinoma.

Dihydroartemisinin (DHA), a widely used antimalarial agent, has clinical potential for the treatment of hepatic carcinoma. Although chemotherapy is indispensable for tumor therapy, it is generally limited by poor solubility, low efficiency, rapid clearance, and side effects. As an emerging treatment method, photothermal therapy (PTT) has many outstanding properties, but suffers from poor photostability of photosensitizer and incomplete ablation. Multimodal therapies could combine the advantages of different therapy methods to improve antitumor efficiency. Hence, we designed a nano-delivery system (ICG&DHA@ZIF-8) using zeolitic imidazolate framework-8 (ZIF-8) with a high porous rate and pH sensitivity property, to co-load DHA and indocyanine green (ICG). Dynamic light scattering and transmission electron microscopy were used to characterize the prepared nanoparticles. The photothermal conversion and drug release performances of ICG&DHA@ZIF-8 were investigated. In vitro antitumor efficacy and cellular uptake were studied. The mechanism of the combination treatment was studied by reactive oxygen species level detection and western blot assays. In vivo antitumor assays were then studied with the guidance of ex vivo imaging. The results showed that the ICG&DHA@ZIF-8 based combination therapy could efficiently kill hepatic carcinoma cells and suppress tumor growth. This research provides a potential nanodrug for the treatment of hepatic carcinoma.

Anti-hepatic carcinoma mechanisms of calycosin through targeting ferroptosis

BackgroundFerroptosis, a pathologic state induced by lipid-driven oxidative stress, is associated with the development of human cancers. Calycosin, a natural compound with antioxidant and anti-inflammatory activities, has promising antitumor effects. However, the ferroptosis-related mechanism of calycosin in the treatment of hepatic carcinoma has not been reported. MethodsThis study applied network pharmacology and bioinformatic approaches (including Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis) to investigate the pharmacologic targets and mechanism of action of calycosin in the treatment of hepatic carcinoma through targeting ferroptosis. By searching online databases including The Cancer Genome Atlas, FerrDb, GeneCards, SwissTargetPrediction, SuperPred, BindingDB, TargetNet, BATMAN-TCM, and Drugbank, we identified 13 ferroptosis-related putative target genes of calycosin against hepatic carcinoma including IL-6, PTGS2, SRC, HRAS, NQO1, NOX4, PGK1, G6PD, GPI, MIF, NOS2, ALDOA, and SQSTM1. ResultsMolecular docking analysis revealed that calycosin potentially binded directly with the target proteins IL-6, PTGS2, and SRC. Functional enrichment analysis of these proteins indicated that they were involved in gluconeogenesis and apoptosis through regulation of ERK1, ERK2, and MAPK activities (P < 0.05). ConclusionCalycosin exerts antitumor effects in hepatic carcinoma by targeting ferroptosis through regulation of IL-6, PTGS2, and SRC.

Albumin-Stabilized Manganese Oxide/Semiconducting Polymer Nanocomposites for Photothermal-Chemodynamic Therapy of Hepatic Carcinoma.

Hepatic carcinoma is one of the most common cancers worldwide, while its treatment remains a great challenge. Traditional therapeutic methods often have disadvantages such as limited therapeutic efficacy and potential side effects. In this study, we report the construction of bovine serum albumin (BSA)–stabilized manganese oxide (MnO2)/semiconducting polymer (SP) nanocomposites to combine photothermal therapy (PTT) and chemodynamic therapy (CDT) for treatment of hepatic carcinoma in living mouse models. Such nanocomposites are composed of BSA, SP, and MnO2 as the stabilizer, PTT, and CDT agent, respectively. SP produced local heat under near-infrared (NIR) laser irradiation for PTT, and MnO2 nanoparticles mediated CDT in the tumor microenvironment, leading to apoptosis of cancer cells. Such nanocomposite-mediated combinational therapy showed a much higher efficacy in inhibiting growth of subcutaneous HepG2 tumors in nude mice than sole treatment. This study thus provides a multifunctional nanoplatform for safe and effective treatment of hepatic carcinoma.

Molecular mechanism of atractylon in the invasion and migration of hepatic cancer cells based on high‑throughput sequencing.

The aim of the present study was to investigate the molecular mechanisms of atractylon in the inhibition of invasion and migration of hepatic cancer cells. High-throughput sequencing was used to compare the expression of long non-coding (lnc)RNAs between hepatic carcinoma and healthy controls. A competing endogenous RNA network was constructed. The top significantly differentially expressed lncRNAs were screened and verified by reverse transcription-quantitative PCR in vitro and in vivo. Small interfering (si)RNA against thymopoietin-antisense 1 (TMPO-AS1) or coiled-coil domain-containing 183-antisense 1 (CCDC183-AS1) overexpression (oe) vectors were transfected into cells following atractylon treatment. Wound healing and Matrigel assays were used to determine the effects of migration and invasion, respectively. Western blot analysis was used to detect the expression levels of invasion- and migration-related proteins, including N-cadherin, E-cadherin and MMP-2. Flow cytometry analysis was used to detect apoptosis. Based on transcriptome sequencing and analysis, the top seven upregulated [(FAM201A, RP11-640M9.2, AL589743.1, TMEM51-AS1, clathrin heavy chain-like 1 (CLTCL1), TMPO-AS1 and LINC00652] and top six downregulated lncRNAs (RP11-465B22.5, CCDC183-AS1, TCONS_00072529, RP11-401F2.3, RP11-290F20.1 and TCONS_00070568) were identified. Only TMPO-AS1 and CCDC183-AS1 were differently regulated by atractylon in vivo. The proliferative ability of HepG2 liver cancer cells decreased, whereas the apoptotic rate improved after atractylon treatment. Notably, the invasive and migratory ability of HepG2 cells significantly declined. In addition, siTMPO-AS1 and oeCCDC183-AS1 reduced the effect of atractylon in vitro. Atractylon was demonstrated to regulate the expression of TMPO-AS1 and CCDC183-AS1 and inhibited the invasion and migration of liver cancer cells. Thus, TMPO-AS1 and CCDC183-AS1 may be potential targets for diagnosis and treatment of hepatic carcinoma.

Investigation of the Role of TCM in the Treatment of Hepatic Carcinoma Based on JAK/STAT Signaling Pathway

JAK/STAT signaling pathway is one of the classical signaling pathways. Numerous studies have shown that this signaling pathway provides a suitable microenvironment for tumors by inducing inflammatory responses, and it is closely related to tumorigenesis, development and invasion. Given the fact that targeted therapies for hepatic carcinoma have limited efficacy, perhaps this pathway may serve as an entry point for new targeted therapies for hepatic carcinoma in the future. Due to the above considerations, in recent years, there have been many articles reporting that TCM monomers and compound preparations act on this pathway and have prominent effects in the clinical treatment of hepatic carcinoma with few side effects. This paper focuses on the systematic discussion of Chinese herbal medicines acting on this mechanism, aiming to provide more ideas and basis for the treatment of hepatic carcinoma in Chinese medicine.

Additive role of dynamic subtraction MRI in assessment of unresolved HCC post-radiofrequency ablation

BackgroundMalignant Hepatocellular carcinoma (HCC) is one amongst the foremost widespread cancers within the world. Radiofrequency ablation (RFA) is that the most generally used substitute tool for hepatic carcinoma treatment. Monitoring tumoral response to loco-regional therapy is a vital mission in oncological imaging. Dynamic contrast enhanced MR and recently added subtraction imaging technique improve assessment of the ablated hepatic focal lesions. The aim of this study is that the evaluation of the role of Subtraction MRI within the detection of recurrent or residual tumoral viability after RF ablation.ResultsFifty patients were conducted during this retrospective study, all underwent RFA for 76 hepatic focal lesions and underwent Dynamic MRI study 1 month after ablation. Subtraction imaging was then performed. MRI images were interpreted by two readers who are experienced in hepatic imaging. The primary reader interpreted the standard Dynamic MRI and was blinded to the subtraction sequences; the second reader interpreted both Dynamic and Subtraction MRI images. the primary reader detected 49 resolved cases by dynamic MRI, while the second reader detected residual activity in 6 cases out of 49 via subtraction dynamic MRI (added value). The second reader agreed with first reader in 43 cases (agreement).The first reader detected 27 residual cases by dynamic MRI. The second reader disagreed with first reader in 11 cases appeared resolved out of 27 via subtraction dynamic MRI (added value). The second reader agreed with first reader in residual activity in 16 cases (agreement).The statistical analysis of those results revealed a big additive value of the subtraction imaging to the dynamic MRI (P < 0.001) with moderate degree of agreement between the 2 diagnostic tools (Kappa value = 0.491). This implies that Subtraction MRI significantly improves the reader confidence level within the assessment of treatment response following loco-regional therapies for HCC.ConclusionDynamic Subtraction MRI is a powerful detector for real enhancement in treated HCC lesions after radiofrequency ablation and hence increasing the degree of readers’ confidence and accuracy of treated lesions in follow-up studies. So it's recommended to feature this powerful tool as a routine to any or all Dynamic MRI studies of the Liver.

Preparation of Near-Infrared/Photoacoustic Dual-Mode Imaging and Photothermal/Chemo Synergistic Theranostic Nanoparticles and Their Imaging and Treating of Hepatic Carcinoma.

At present, the clinical diagnosis of and treatment methods for hepatic carcinoma still fail to fully meet the needs of patients. The integrated theranostic system, in which functional materials are used to load different active molecules, created a new developmental direction for the combination treatment of hepatic carcinoma, realizing the synchronization of diagnosis and treatment. In this study, polydopamine (PDA), which has the functions of self-assembly, encapsulation, photothermal conversion, and photoacoustic interaction, was used as the carrier material. The IR780, a near-infrared fluorescence imaging (NIFI), photoacoustic imaging (PAI), and photothermal therapy (PTT) agent, and paclitaxel (PTX), a broad-spectrum chemotherapy drug, were selected to build the NIF/PA dual-mode imaging and PTT/chemo synergistic theranostic nanoparticles (DIST NPs). The DIST NPs have a 103.4 ± 13.3 nm particle size, a weak negative charge on the surface, good colloidal stability, slow and controlled drug release, and high photothermal conversion ability. The experiments results showed that the DIST NPs have a long circulation in vivo, high bioavailability, high biocompatibility, and low effective dose. DIST NPs showed an excellent NIFI/PAI dual-mode imaging and significant synergistic antitumor effect in hepatic carcinoma models. DIST NPs met the initial design requirements. A set of fast and low-cost preparation methods was established. This study provides an experimental basis for the development of new clinical theranostic methods for hepatic carcinoma.

Tumor Cell-Derived Exosomal Circ-0072088 Suppresses Migration and Invasion of Hepatic Carcinoma Cells Through Regulating MMP-16

Background: Tumor-derived exosomes (EXOs), commonly differentially expressed in circular RNAs, have been shown to be crucial determinants of tumor progression and may regulate the development and metastasis of hepatic carcinoma (HCC).Methods: Possibly differentially expressed circRNAs in patients with HCC were screened out from the Gene Expression Omnibus (GEO). EXOs were isolated from the culture medium of HCC cells and plasma of patients with HCC, followed by characterization by transmission electron microscope, NanHCCight, and western blotting. Additionally, RNA immunoprecipitation and luciferase reporter gene assays were carried out to explore the molecular mechanism of hsa_circRNA_103809 (circ-0072088) in HCC cells.Results: The screening results showed that circ-0072088 was highly expressed in patients with HCC, and its increase indicated unfavorable prognosis of patients according to quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Additionally, circ-0072088 was mainly secreted by HCC cells via EXOs in plasma of such patients, and its high level in plasma EXOs was closely associated with tumor node metastasis (TNM) staging and tumor size. Moreover, HCC-secreted EXOs mediated the degradation of miR-375 via circ-0072088 and upregulated MMP-16, thus suppressing the metastasis of HCC.Conclusion: Upregulated in patients with HCC, circ-0072088 may be an index for diagnosis and prognosis of HCC. In addition, HCC-derived EXOs coated with circ-0072088 might be a treatment for HCC, with the ability to inhibit the metastasis of HCC cells.

Anticancer effect of myristicin on hepatic carcinoma and related molecular mechanism

Context Myristicin is a natural active compound that has inflammatory, antimicrobial and anti-proliferative properties. Yet, its effect on hepatic carcinoma has not been investigated. Objective To explore the role and related molecular mechanism of myristicin in hepatic carcinoma in vitro. Materials and methods Human hepatic carcinoma cell lines (Huh-7 and HCCLM3 cells) were treated with different concentrations of myristicin (0.5, 1 and 5 mM) for 24, 48 and 72 h. Then, (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) tetrazolium assay (MTT), flow cytometer (FCM) analysis and transwell assay were performed to determine cell proliferation, apoptosis and migration/invasion, respectively. Protein levels of B-cell lymphoma-2 (Bcl-2), Bcl-2 associated X (Bax), E-cadherin, N-cadherin and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signalling pathway-related proteins were detected using Western blot assay. Gene expression was determined using quantitative real time-polymerase chain reaction (qRT-PCR). Results Myristicin inhibited cell proliferation and induced apoptosis in Huh-7 and HCCLM3 cells; suppressed cell migration and invasion ability, and increased E-cadherin expression and decreased N-cadherin expression, thereby inhibiting epithelial–mesenchymal transition (EMT). Finally, the findings indicated that myristicin decreased phosphorylated (p)-mTOR and p-AKT expression at the protein level. Discussion and conclusions Myristicin exerts an efficient therapeutic effect on hepatic carcinoma by suppressing PI3K/Akt/mTOR signalling pathway; thus, it may be used as a new potential drug for hepatic carcinoma treatment.

Construction and characterization of folate-functionalized curdlan-trilysine siRNA delivery platform for in vivo hepatic carcinoma treatment

RNA interference technology is a powerful tool with substantially clinical prospects for carcinoma therapy, in which efficiency and specificity of delivery of dsRNA remains a critical issue. Herein, aiming at delivery of dsRNA in efficient and safe way, we constructed targeting delivery platform (CTL-PEG-FA) by grafting curdlan with trilysine through click reaction, then modifying with PEG linked folic acid. The CTL-PEG-FA vector exhibited excellent gene binding capacity to condense siRNA and dramatically reduced cytotoxicity. Increased cell uptake of CTL-PEG-FA/Bcl-2 siRNA was achieved by the synergism of folate mediated endocytosis and charge interaction, and further causing severe HepG2 cells injury through apoptosis mechanism after down-regulation of Bcl-2 protein. In vivo experiments, CTL-PEG-FA/Bcl-2 siRNA complex distinctly accumulated in tumor site and significantly inhibited the growth of tumor, while no obvious toxicity was observed. Therefore, well-performed CTL-PEG-FA with excellent biocompatibility, has the potential to be the candidate of gene therapy for clinical applications.

Plantamajoside Inhibits Hepatic Carcinoma Cell Proliferation, Migration, Invasion and Induces Apoptosis Through Regulating Phosphatidylinositol-3-Kinase/ Protein Kinase B Pathway

Background: Plantamajoside (PMS) is the main active compound of Plantago asiatica . It is a traditional Chinese medicine and has been reported to have various biological activities. However, the function of PMS on hepatic carcinoma cells (HCC) and the potential mechanism of action still remains unevaluated. Here, we investigated the effect of PMS on HCC cells and the potential molecular mechanism. Methods: Firstly, HCC cells were treated with different dose of PMS (0, 20, 80 and 160 g/ml). Then, cell viability was determined by MTT assay. Furthermore, we investigated the cell apoptosis, migration and invasion by flow cytometry assay and Transwell assay. In addition, PI3K/AKT related proteins p-AKT and AKT were determined via Western blotting assay. Results: Our results showed that PMS dose-dependently reduced HCC cell viability. PMS also induced HCC cell apoptosis, up-regulated the expression of Bax and down-regulated expression of Bcl-2. In addition, the Bcl-2/Bax ratio was also decreased. The migration and invasion of HCC cells were also consistently suppressed by PMS treatment in a dose-dependent manner. Subsequently, the results indicated that PMS down-regulated the expression of p-AKT, suggesting the inhibition of the PI3K/AKT pathway in HCC progression. Conclusion: The results indicated that PMS could inhibit HCC progression through regulating cell viability, apoptosis, migration, invasion and PI3K/AKT pathway. Thus, PMS might be a hopeful pharmacological agent for the treatment of hepatic carcinoma.

Supramolecular hybrids of carbon dots and dihydroartemisinin for enhanced anticancer activity and mechanism analysis.

Dihydroartemisinin (DHA) has been regarded as a potential anticancer agent in recent years. Nevertheless, the clinical applications of DHA are seriously restricted as a result of its intrinsic characteristics, such as poor water solubility, instability, and fast clearance. Herein, a type of fluorescent nanoparticles was successfully fabricated via supramolecular assembling of carbon dots (CDs) and DHA. The formulated CDs-DHA fluorescent nanoparticles not only significantly improve the solubility and stability of DHA, but also possess favorable biocompatibility and pH-dependent drug release behavior. In particular, the hybrids of CDs and DHA as nanocarriers can effectively promote the endocytosis of DHA and exhibit enhanced antitumor effects compared with free DHA in vitro and in vivo. In addition, we also explore the possible action mechanism of CDs-DHA through flow cytometric assay, transfection and western blot analysis. The results indicate that CDs-DHA nanoparticles suppress the progression of hepatic carcinoma through inducing apoptosis and inhibiting glucose metabolism, and the mechanism is related to the downregulation of PKM2 expression and the suppression of the Akt/mTOR signaling pathway, which may provide a potential therapeutic target for hepatic carcinoma treatment. This work emphasizes the great potential of utilizing CDs as a safe and convenient platform to deliver DHA for efficient cancer therapy, and the study on the anticancer mechanism can also offer theoretical support for the clinical application of DHA.

Surgical Resection of Hepatocellular Carcinoma in Compensated Cirrhotic Liver: The Benefits and Selection Criteria

Ab

Development of 11-DGA-3-O-Gal-Modified Cantharidin Liposomes for Treatment of Hepatocellular Carcinoma.

Background: Liver cancer is a common malignant tumor worldwide, and its morbidity and mortality increase each year. The disease has a short course and high mortality, making it a serious threat to human health. Purpose: The objective of this study was to create novel liver-targeting nanoliposomes to encapsulate cantharidin (CTD) as a potential treatment for hepatic carcinoma. Methods: 3-Galactosidase-30-stearyl deoxyglycyrrhetinic acid (11-DGA-3-O-Gal)-modified liposomes (11-DGA-3-O-Gal-CTD-lip) for the liver-targeted delivery of CTD were prepared via the film-dispersion method and characterized. In vitro analyses of the effects on cellular cytotoxicity, cell migration, cell cycle, and cell apoptosis were carried out and an in vivo pharmacokinetics study and tissue distribution analysis were performed. Results: Compared with unmodified liposomes (CTD-lip), 11-DGA-3-O-Gal-CTD-lip showed higher cytotoxicity and increased the inhibition of HepG2 cell migration, but they did not increase the apoptotic rate of cells. The inhibition mechanism of 11-DGA-3-O-Gal-CTD-lip on hepatocellular carcinoma was partly through cell cycle arrest at the S phase. Analysis of pharmacokinetic parameters indicated that 11-DGA-3-O-Gal-CTD-lip were eliminated more rapidly than CTD-lip. Regarding tissue distribution, the targeting efficiency of 11-DGA-3-O-Gal-CTD-lip to the liver was (41.15 ± 3.28)%, relative targeting efficiency was (1.53 ± 0.31)%, relative uptake rate was( 1.69 ± 0.37)%, and peak concentration ratio was (2.68 ± 0.12)%. Conclusion: 11-DGA-3-O-Gal-CTD-lip represent a promising nanocarrier for the liver-targeted delivery of antitumor drugs to treat hepatocellular carcinoma.