Farnesoid X receptor (FXR) agonists induce hepatocellular apoptosis and impair hepatic functions via FXR/SHP pathway.

Farnesoid X receptor (FXR) plays an indispensable role in liver homeostasis and has been a promising drug target for hepatic diseases. However, the concerns of undesired biological actions limit the clinical applications of FXR agonists. To reveal the intrinsic mechanism of FXR agonist-induce hepatotoxicity, two typical FXR agonists with different structures (obeticholic acid (OCA) and Px-102) were investigated in the present study. By detecting MMP, ROS, and ATP and analyzing the fate of cells, we found that both OCA and Px-102 reduced the mitochondrial function of hepatocytes and promoted cell apoptosis. Gene ablation or inhibition of FXR or SHP ameliorated the cytotoxicities of OCA and Px-102, which indicated the adverse actions of FXR/SHP activation including down-regulation of phosphorylation of PI3K/AKT and functional hepatic genes. The dose-related injurious effects of OCA (10 mg/kg and 30 mg/kg) and Px-102 (5 mg/kg and 15 mg/kg) on the liver were confirmed on a high-fat diet mouse model. The decrease of hepatocyte-specific genes and augmenter of liver regeneration in the liver caused by OCA or Px-102 suggested an imbalance of liver regeneration and a disruption of hepatic functions. Exploration of intestinally biased FXR agonists or combination of FXR agonist with apoptosis inhibitor may be more beneficial strategies for liver diseases.

6-Amino-2,4,5-trimethylpyridin-3-ol and 2-amino-4,6-dimethylpyrimidin-5-ol derivatives as selective fibroblast growth factor receptor 4 inhibitors: design, synthesis, molecular docking, and anti-hepatocellular carcinoma efficacy evaluation.

A novel series of aminotrimethylpyridinol and aminodimethylpyrimidinol derivatives were designed and synthesised for FGFR4 inhibitors. Structure-activity relationship on the FGFR4 inhibitory activity of the new compounds was clearly elucidated by an intensive molecular docking study. Anti-cancer activity of the compounds was evaluated using hepatocellular carcinoma (HCC) cell lines and a chick chorioallantoic membrane (CAM) tumour model. Compound 6O showed FGFR4 inhibitory activity over FGFR1 - 3. Compared to the positive control BLU9931, compound 6O exhibited at least 8 times higher FGFR4 selectivity. Strong anti-proliferative activity of compound 6O was observed against Hep3B, an HCC cell line which was a much more sensitive cell line to BLU9931. In vivo anti-tumour activity of compound 6O against Hep3B-xenografted CAM tumour model was almost similar to BLU9931. Overall, compound 6O, a novel derivative of aminodimethylpyrimidinol, was a selective FGFR4 kinase inhibitor blocking HCC tumour growth.

Preparation and structural properties of selenium modified heteropolysaccharide from the fruits of Akebia quinata and in vitro and in vivo antitumor activity.

Cancer is a complex disease, and blocking tumor angiogenesis has become one of the most promising approaches in cancer therapy. Here, an exopoly heteropolysaccharide (AQP70-2B) was firstly isolated from Akebia quinata. Monosaccharide composition indicated that the AQP70-2B was composed of rhamnose, glucose, galactose, and arabinose. The backbone of AQP70-2B consisted of →1)-l-Araf, →3)-l-Araf-(1→, →5)-l-Araf-(1→, →3,5)-l-Araf-(1→, →2,5)-l-Araf-(1→, →4)-d-Glcp-(1→, →6)-d-Galp-(1→, and →1)-d-Rhap residues. Based on the close relationship between selenium and anti-tumor activity, AQP70-2B was modified with selenium to obtain selenized polysaccharide Se-AQP70-2B. Then, a series of methods for analysis and characterization, especially scanning electron microscopy coupled with energy dispersive spectrometry (SEM-EDS), indicated that Se-AQP70-2B was successfully synthesized. Furthermore, zebrafish xenografts and anti-angiogenesis experiments indicated that selenization could improve the antitumor activity by inhibiting tumor cell proliferation and migration and blocking angiogenesis.

Mimic Lipoproteins Responsive to Intratumoral pH and Allosteric Enzyme for Efficient Tumor Therapy.

Discoid-reconstituted high-density lipoprotein (d-rHDL) is advantageous for tumor-targeted drug delivery due to its small size, long circulation, and efficient internalization into cancer cells. Nevertheless, an allosteric reaction catalyzed by serum lecithin-cholesterol acyltransferase (LCAT) may cause drug leakage from d-rHDL and reduce its targeting efficiency. Conversely, similar "structural weakening" catalyzed by acyl-coenzyme A-cholesterol acyltransferase (ACAT) inside tumor cells can stimulate precise intracellular drug release. Therefore, we synthesized and characterized a pH-sensitive n-butyraldehyde bi-cholesterol (BCC) to substitute for cholesterol in the d-rHDL particle, and bovine serum albumin (BSA) was used as the targeting agent. This dual pH- and ACAT-sensitive d-rHDL (d-d-rHDL) was small with a disk-like appearance. Morphological transformation observation, in vitro release assays, and differences in internalization upon LCAT treatment confirmed that BCC effectively inhibited the remodeling behavior and enhanced the tumor-targeting efficiency. The accumulation of d-d-rHDL in HepG2 cells was significantly higher than that in LO2 cells, and accumulation was inhibited by free BSA. The pH sensitivity was verified, and d-d-rHDL achieved efficient drug release in vitro and inside tumor cells after exposure to acidic conditions and ACAT. Confocal laser scanning microscopy demonstrated that d-d-rHDL escaped from lysosomes and became distributed evenly throughout cells. Moreover, in vivo imaging assays in a tumor-bearing mouse model demonstrated tumor-targeting properties of d-d-rHDL, and paclitaxel-loaded d-d-rHDL showed strong anticancer activity in these mice. This dual-sensitive d-d-rHDL thus combines structural stability in plasma and an intracellular pH/ACAT-triggered drug release to facilitate inhibition of tumor growth.

Hepatocellular carcinoma induces body mass loss in parallel with osmolyte and water retention in rats.

AIMS: The number of cancer survivors with cardiovascular disease is increasing. However, the effect of cancer on body fluid regulation remains to be clarified. In this study, we evaluated body osmolyte and water imbalance in rats with hepatocellular carcinoma. MAIN METHODS: Wistar rats were administered diethylnitrosamine, a carcinogenic drug, to establish liver cancer. We analyzed tissue osmolyte and water content, and their associations with aldosterone secretion. KEY FINDINGS: Hepatocellular carcinoma rats had significantly reduced body mass and the amount of total body sodium, potassium, and water. However, these rats had significantly increased relative tissue sodium, potassium, and water content per tissue dry weight. Furthermore, these changes in sodium and water balance in hepatocellular carcinoma rats were significantly associated with increased 24-h urinary aldosterone excretion. Supplementation with 0.25% salt in drinking water improved body weight reduction associated with sodium and water retention in hepatocellular carcinoma rats, which was suppressed by treatment with spironolactone, a mineralocorticoid receptor antagonist. Additionally, the urea-driven water conservation system was activated in hepatocellular carcinoma rats. SIGNIFICANCE: These findings suggest that hepatocellular carcinoma induces body mass loss in parallel with activation of the water conservation system including aldosterone secretion and urea accumulation to retain osmolyte and water. The osmolyte and water retention at the tissue level may be a causative factor for ascites and edema formation in liver failure rats.

A branched small molecule-drug conjugate nanomedicine strategy for the targeted HCC chemotherapy.

Off-target toxicity is one of the main challenges faced by anticancer chemotherapeutics. For tumor targeted and precision chemotherapy, we take the advantages of the ligand directed tumor active targeting of small molecule drug conjugates (SMDCs) and the passive tumor targeting of nanoparticles via the enhanced penetration and retention (EPR) effects, put forward a branched small molecule drug conjugate (BSMDC) nanomedicine design concept. In a proof of concept, we used pentaerythritol as the branched moiety, galactosamine (GalN) as the hepatocellular carcinoma (HCC) directing ligands, PTX as a payload, and a stearoyl moiety as the amphiphilic property adjusting group, designed and synthesized BSMDC 1 and prepared its NPs. In cellular level, the BSMDC 1 NPs targeted asialoglycoprotein receptor (ASGPR)-overexpressing HepG2 cells, were effectively taken up in the cells and released in tumor microenvironments, inhibited the HepG2 cell proliferation, arrested HepG2 cell in G2/M phase and induced tumor cell apoptosis. In HepG2 xenograft nude mice, the BSMDC 1 NPs were high specific to target the tumor and demonstrated a higher antitumor efficiency than BSMDC 1, having no apparent influences on mice body weights and major organs, supporting our BSMDC nanomedicine design concept. Therefore, this new strategy may find applications for cancer targeted and precision chemotherapy.

pH-Sensitive nanoparticles based on amphiphilic imidazole/cholesterol modified hydroxyethyl starch for tumor chemotherapy.

pH-Responsive nanoparticles (NPs) have emerged as an effective antitumor drug delivery system, promoting the drugs accumulation in the tumor and selectively releasing drugs in tumoral acidic microenvironment. Herein, we developed a new amphiphilic modified hydroxyethyl starch (HES) based pH-sensitive nanocarrier of antitumor drug delivery. HES was first modified by hydrophilic imidazole and hydrophobic cholesterol to obtain an amphiphilic polymer (IHC). Then IHC can self-assemble to encapsulate doxorubicin (DOX) and form doxorubicin-loaded nanoparticles (DOX/IHC NPs), which displayed good stability for one week storage and acidic sensitive long-term sustained release of DOX. As a result, cancer cell endocytosed DOX/IHC NPs could continuously release doxorubicin into cytoplasm and nucleus to effectively kill cancer cells. Additionally, DOX/IHC NPs could be effectively enriched in the tumor tissue, showing enhanced tumor growth inhibition effect compared to free doxorubicin. Overall, our amphiphilic modified HES-based NPs possess a great potential as drug delivery system for cancer chemotherapy.

Improvement in phenotype homeostasis of macrophages by chitosan nanoparticles and subsequent impacts on liver injury and tumor treatment.

When organic polymer-based drug nanocarriers become concentrated in macrophages, their influence on macrophage polarization has been rarely reported. This study prepared chitosan-based nanoparticles (CNs, 181.5 nm, +14.83 mV) and detected their impacts on macrophage reprogram. RT-PCR results showed in M1-like RAW264.7 cells (Mφ1), CNs decreased CD86 and iNOS expressions by 53.8% and 57.1%, and increased Arg-1 and IL-10 by 642.9% and 102.1%; in M2-like cells (Mφ2), CNs reduced Arg-1 and MR expressions by 70.7% and 93.0%, but increased CD86, iNOS and TNF-α by 290.4%, 86.2% and 728.6%; these results, consistent with cytokine secretions and surface CD86/CD206 expressions, showed CNs polarized Mφ1 and Mφ2 toward opposite type so as to improve the macrophage polarization homeostasis. In CCl4-induced mouse liver injury model, CNs reduced the hepatic Mφ1/Mφ2 ratio from 1.1 (model group) to 0.3, and then reduced the serum AST and ALT level by 42.3% and 39.0%; in mouse model of hepatocellular carcinoma, CNs decreased the number of CD163-positive cells and increased CD86-positive ones in tumor, and subsequently inhibited the tumor growth and metastasis. This study suggests CNs can improve the phenotype homeostasis of macrophages and subsequently promote the treatment of certain diseases such as liver injury and tumor.

Development of oral curcumin based on pH-responsive transmembrane peptide-cyclodextrin derivative nanoparticles for hepatoma.

Herein, a pH-responsive cyclodextrin derivative (R6H4-CMßCD) with cell-penetrating ability was successfully synthesized, and curcumin-loaded nanoparticles (R6H4-CMßCD@CUR NPs, RCCNPs) were developed to improve its efficacy in hepatoma. RCCNPs could improve the cell uptake compared with CMßCD@CUR NPs (CCNPs) and were internalized into cells mainly through endocytosis mediated by reticulin and macropinocytosis. Furthermore, the accumulation of RCCNPs in hepatoma cells at pH 6.4 was higher than that at pH 7.4, indicating a pH-responsive uptake. Additionally, RCCNPs could escape from the lysosomes via the "proton sponge effect", and a high apoptosis rate was detected. Importantly, in vivo experiments revealed that orally administered RCCNPs could exert excellent anti-cancer effects in tumor-bearing mice. Hematoxylin-eosin staining did not show significant histological changes in the major organs. Thus, our findings indicate the potential of R6H4-CMßCD as a nanopharmaceutical material, and RCCNPs as an effective delivery system for oral curcumin in cancer management.

The Discovery of Potential MDM2 Inhibitors: A Combination of Pharmacophore Modeling, Virtual Screening, Molecular Docking Studies, and in†vitro/in†vivo Biological Evaluation.

Small-molecule inhibitors of MDM2 that block the MDM2-p53 protein-protein interaction have been considered as potential therapeutic agents for the treatment of cancer. Here, we identify five highly potent inhibitors of MDM2 (termed as WY 1-5) that display significant inhibitory effects on MDM2-p53 interaction by using a combined strategy of pharmacophore modeling, virtual screening, and molecular docking studies. Among them, WY-5 is the most active MDM2 inhibitor with an IC50 value of 14.1±2.8 nM. Moreover, WY-5 significantly up-regulate the protein level of p53 in SK-Hep-1 cells harboring wild-type p53. In vitro anticancer study reveals that WY-5 markedly inhibits the survival of SK-Hep-1 cells. In vivo anticancer study suggests that WY-5 significantly inhibits the growth of SK-Hep-1 cells-derived xenograft in nude mice, with no observable toxicity. Our results demonstrate that WY-5 may be a promising candidate for the treatment of cancer harboring wild-type p53.

Therapeutic Potential of Cucumis melo (L.) Fruit Extract and Its Silver Nanopartciles Against DEN-Induced Hepatocellular Cancer in Rats.

Biosynthesized silver nanoparticles have a wide range of biological activities and using nanoparticles as one of the novel approaches in cancer therapy. In this present research work, the anti-cancer efficacy of Cucumis melo fruit extract and its silver nanoparticles was explored. Wistar rats were divided into six groups and hepatic cancer was induced with 0.01% DEN (diethylnitrosamine) through drinking water for 16 weeks. Cyclophosphamide was given as the standard drug at the dose of 50 mg/kg body weight. Hematological parameters showed a decrease in the levels of hemoglobin (Hb), packed cell volume (PCV), red blood cells (RBC), mean corpuscular volume (MCV), mean corpuscular Hb (MCH), mean corpuscular Hb concentration (MCHC), and platelets (PLTS) levels except white blood cell (WBC) in DEN-induced cancer animals. Significant alterations in the hematological parameters were observed after treatment which indicate the protective effect of Cucumis melo fruit on the hemopoietic system. The structural integrity of the cells has been damaged in cancer-induced animals, and this results in cytoplasmic leakage of enzyme into the blood stream, leads to the elevated levels of these enzymes in blood with subsequent fall in the tissues. Hence, the levels of liver function markers such as AST ALT, ALP, LDH, GGT, and 5'NT were significantly elevated in serum and the liver of cancer-induced rats. The levels of serum tumor markers, viz., alpha-fetoprotein (AFP) and carcinoembryonic antigen (CEA), elevated in rats induced with DEN, which then were reduced following Cucumis melo fruit treatment, indicating the anti-cancer activity of the drug. Histological evaluation of the liver and kidney was also performed to authenticate the present work. Treatment with crude extract and silver nanoparticles of Cucumis melo fruit indicates that Cucumis melo fruit could have exerted its protective effect.

Preparation and synergistic chemo-photothermal therapy of redox-responsive carboxymethyl cellulose/chitosan complex nanoparticles.

Chemo-photothermal combination therapy has great promise for enhanced tumor treatment. Hereby, we developed a complex nanoparticle using electrostatic absorption method, in which the inner chitosan (CS) NPs loaded polypyrrole (PPy) nanoparticles and 5-fluorouracil (5Fu), the outer shell was carboxymethyl cellulose (CMC) crosslinked with disulfide. The drug loaded polysaccharide complex nanoparticles displayed good photothermal effects, and the drug release would be triggered by multi-model response of NIR irradiation, high glutathione (GSH) and weak acidity in tumor environment. In vitro biological studies indicated the nanopartiles could be effectively internalized by HepG2 cancer cells. Moreover, the remarkable inhibition of the CMC complex PPy and 5Fu loaded CS nanoparticles (CMC/CS@PPy + 5Fu NPs) against tumor growth was achieved in HepG2-bearing mice model, suggesting its great potential for synergetic chemo-photothermal therapy.

Chamaejasmenin E from Stellera chamaejasme induces apoptosis of hepatocellular carcinoma cells by targeting c-Met in vitro and in vivo.

Hepatocellular carcinoma (HCC), the most prevalent liver cancer, is considered one of the most lethal malignancies with a dismal outcome. There is an urgent need to find novel therapeutic approaches to treat HCC. At present, natural products have served as a valuable source for drug discovery. Here, we obtained five known biflavones from the root of Stellera chamaejasme and evaluated their activities against HCC Hep3B cells in vitro. Chamaejasmenin E (CE) exhibited the strongest inhibitory effect among these biflavones. Furthermore, we found that CE could suppress the cell proliferation and colony formation, as well as the migration ability of HCC cells, but there was no significant toxicity on normal liver cells. Additionally, CE induced mitochondrial dysfunction and oxidative stress, eventually leading to cellular apoptosis. Mechanistically, the potential target of CE was predicted by database screening, showing that the compound might exert an inhibitory effect by targeting at c-Met. Next, this result was confirmed by molecular docking, cellular thermal shift assay (CETSA), as well as RT-PCR and Western blot analysis. Meanwhile, CE also reduced the downstream proteins of c-Met in HCC cells. In concordance with above results, CE is efficacious and non-toxic in tumor xenograft model. Taken together, our findings revealed an underlying tumor-suppressive mechanism of CE, which provided a foundation for identifying the target of biflavones.

Aidi injection altered the activity of CYP2D4, CYP1A2, CYP2C19, CYP3A2, CYP2E1 and CYP2C11 in normal and diethylnitrosamine-induced hepatocellular carcinoma in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Aidi injection (ADI), a traditional chinese medicine preparation, is widely used in combination with chemotherapy for the treatment of various malignant tumors, such as hepatocellular carcinoma (HCC). Studies have shown that changes in cytochrome P450 (CYP450) activity in disease states would affect the metabolism of drugs in vivo, especially liver diseases. However, the changes of Aidi injection on the activities of CYP2D4, CYP1A2, CYP2C19, CYP3A2, CYP2E1 and CYP2C11 in normal and HCC states are still unknown. AIM OF THE STUDY: The cocktail probe drugs method was used to investigate the effects of ADI on the activity of CYP2D4, CYP1A2, CYP2C19, CYP3A2, CYP2E1 and CYP2C11 in normal and HCC rats. MATERIALS AND METHODS: The HCC rats was induced by diethylnitrosamine (DEN). Then, both normal and HCC rats were randomly divided into 2 groups (n = 6). They were given saline or ADI (10 mL/kg/d, i.p) for 2 weeks, respectively. On the fifteenth day, cocktail probe mixing solution, including metoprolol (10 mg/kg), caffeine (1.0 mg/kg), omeprazole (2.0 mg/kg), midazolam (2.0 mg/kg), chlorzoxazone (4.0 mg/kg) and tolbutamide (0.5 mg/kg), was injected into tail vein of all rats in each group. The blood sample was obtained at specified time. After the protein is precipitated, six probe drugs are analyzed by ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). RESULTS: Compared with control group, the activity of CYP3A2 and CYP2E1 was significantly lower in the ADI group. Compared with the model group, the activities of CYP1A2, CYP3A2, CYP2E1, and CYP2C11 enzymes in the ADI model group were significantly reduced. Additionally, the activity of CYP2D4, CYP1A2, CYP2C19, CYP3A2, CYP2E1 and CYP2C11 enzymes in model group was significantly lower than control group. CONCLUSIONS: ADI can inhibit a lot of CYP450 enzyme, so it may reduce the dosage of chemotherapeutic drugs to reach the required plasma concentration of chemotherapeutic drugs, which is of great significance for the combination of anti-tumor chemotherapeutic drugs and is worthy of further in-depth study and clinical attention.

Structure modification and biological evaluation of indole-chalcone derivatives as anti-tumor agents through dual targeting tubulin and TrxR.

Microtubule target agents (MTAs) are widely-used clinical anti-cancer drugs for decades, but the acquired drug resistance severely restricted their application. Thioredoxin reductases (TrxR) was reported to be overexpressed in most tumors and closely related to high risk of cancer recurrence and drug resistance, making it a potential target for anticancer drug discovery. Multi-target-directed ligands (MTDLs) by a single molecule provide a logical and alternative approach to drug combinations. In this work, based on the structure-activity relationships obtained in our previous study, some structure modifications were performed. On one hand, the retained skeleton structure of MTAs endowed its tubulin polymerization inhibition activity, on the other hand, the selenium-containing structure and α,ß-unsaturated ketone moiety endowed the TrxR inhibition activity. As results, the newly obtained compounds exhibited superior anti-proliferative activities towards various human cancer cells and drug-resistance cells, and displayed high selectivity towards various human normal cells. The mechanism study revealed that the dual effect of cell cycle arrest triggered by targeting tubulin and the abnormal accumulation of ROS caused by TrxR inhibition eventually lead to cell apoptosis. Notably, compared with the MTA agents CA-4P, and the TrxR inhibitor Ethaselen, the optimized compound 14c, which served as dual-targeting inhibitor of tubulin and TrxR, exerted greatly improved in vivo anti-tumor activity. In summary, 14c deserved further consideration for cancer therapy.

Assembly Transformation Jointly Driven by the LAP Enzyme and GSH Boosting Theranostic Capability for Effective Tumor Therapy.

Developing intelligent and morphology-transformable nanomaterials that can spatiotemporally undergo stimulus-responsive size transformation holds great promise for improving the tumor delivery efficiency of drugs in vivo. Here, we report a smart size-transformable theranostic probe Ce6-Leu consisting of a leucine amino peptidase (LAP) and glutathione (GSH) dual-responsive moiety, an 1,2-aminothiol group, and a clinically used photosensitizer Ce6. This probe tends to self-assemble into uniform nanoparticles with an initial size of ∼80 nm in aqueous solution owing to the amphiphilic feature. Surprisingly, taking advantage of the biocompatible CBT-Cys condensation reaction, the large nanoprobes can be transformed into tiny nanoparticles (∼23 nm) under the joint action of LAP and GSH in a tumor microenvironment, endowing them with great tumor accumulation and deep tissue penetration. Concomitantly, this LAP/GSH-driven disassembly and size shrinkage of Ce6-Leu can also activate the fluorescence/magnetic resonance signals and the photodynamic effect for enhanced multimodal imaging-guided photodynamic therapy of human liver HepG2 tumors in vivo. More excitingly, the Mn2+-chelating probe (Ce6-Leu@Mn2+) was demonstrated to have the capability to catalyze endogenous H2O2 to persistently release O2 at the hypoxic tumor site, as a consequence improving the oxygen supply to boost the radiotherapy effect. We thus believe that this LAP/GSH-driven size-transformable nanosystem would offer a novel advanced technology to improve the drug delivery efficiency for achieving precise tumor diagnosis and treatment.

Ventilagolin Suppresses Migration, Invasion and Epithelial-Mesenchymal Transition of Hepatocellular Carcinoma Cells by Downregulating Pim-1.

OBJECTIVE: Inhibition of tumor metastasis is a useful strategy to improve the efficacy of cancer therapy. Ventilagolin, a natural 1, 4-naphthoquinone derivative extracted from Ventilago leiocarpa Benth, has shown promising antitumor effects in previous studies. However, the effects and underlying mechanisms of Ventilagolin against migration, invasion and epithelial-mesenchymal transition (EMT) of hepatocellular carcinoma (HCC) remain unclear. The present study has examined these effects and determined whether the proto-oncogene Pim-1 is involved. METHODS: The effects of Ventilagolin on migration, invasion, Pim-1 and EMT-related proteins (eg, E-cadherin, N-cadherin, Vimentin) expression were assessed by scratch wound healing, Transwell, qRT-PCR and Western blot assays, respectively. Pim-1 stably overexpressed HepG2 and SMMC-7721 cells were generated to explore whether Ventilagolin inhibited migration, invasion and EMT of HCC cells via regulating Pim-1. Subcutaneous xenograft tumor model in nude mice was established. Histopathological changes of tumor tissues were examined by H&E staining and expressions of Pim-1 and EMT-related proteins were detected by immunohistochemistry. RESULTS: Ventilagolin significantly (P < 0.01) reduced the expression of Pim-1 levels in HepG2 and SMMC-7721 cells. Compared with the control group, the migration and invasion abilities of Pim-1-overexpressing HepG2 and SMMC-7721 cells were significantly (P < 0.05, P < 0.01) enhanced, the expression of E-cadherin was decreased (P < 0.01), and the levels of N-cadherin and Vimentin were upregulated (P < 0.05, P < 0.01). Ventilagolin treatment effectively reversed these effects of Pim-1 overexpression. In vivo experiments showed that Ventilagolin could effectively suppress HCC tumor growth, downregulate Pim-1, N-cadherin and Vimentin expression, and upregulate E-cadherin expression. CONCLUSION: Ventilagolin suppresses HCC cell proliferation, migration and invasion and reverses EMT process by downregulating Pim-1, suggesting Ventilagolin is a potential therapeutic agent for treatment of HCC.

Dendritic cell paucity in mismatch repair-proficient colorectal cancer liver metastases limits immune checkpoint blockade efficacy.

Liver metastasis is a major cause of mortality for patients with colorectal cancer (CRC). Mismatch repair-proficient (pMMR) CRCs make up about 95% of metastatic CRCs, and are unresponsive to immune checkpoint blockade (ICB) therapy. Here we show that mouse models of orthotopic pMMR CRC liver metastasis accurately recapitulate the inefficacy of ICB therapy in patients, whereas the same pMMR CRC tumors are sensitive to ICB therapy when grown subcutaneously. To reveal local, nonmalignant components that determine CRC sensitivity to treatment, we compared the microenvironments of pMMR CRC cells grown as liver metastases and subcutaneous tumors. We found a paucity of both activated T cells and dendritic cells in ICB-treated orthotopic liver metastases, when compared with their subcutaneous tumor counterparts. Furthermore, treatment with Feline McDonough sarcoma (FMS)-like tyrosine kinase 3 ligand (Flt3L) plus ICB therapy increased dendritic cell infiltration into pMMR CRC liver metastases and improved mouse survival. Lastly, we show that human CRC liver metastases and microsatellite stable (MSS) primary CRC have a similar paucity of T cells and dendritic cells. These studies indicate that orthotopic tumor models, but not subcutaneous models, should be used to guide human clinical trials. Our findings also posit dendritic cells as antitumor components that can increase the efficacy of immunotherapies against pMMR CRC.

Supramolecular Drug Delivery System from Macrocycle-Based Self-Assembled Amphiphiles for Effective Tumor Therapy.

Intelligent drug delivery systems (DDSs) that can improve therapeutic outcomes of antitumor agents and decrease their side effects are urgently needed to satisfy special requirements of treatment of malignant tumors in clinics. Here, the fabrication of supramolecular self-assembled amphiphiles based on the host-guest recognition between a cationic water-soluble pillar[6]arene (WP6A) host and a sodium decanesulfonate guest (G) is reported. The chemotherapeutic agent doxorubicin hydrochloride (DOX) can be encapsulated into the formed vesicle (G/WP6A) to construct supramolecular DDS (DOX@G/WP6A). WP6A affords strong affinities to G to avoid undesirable off-target leakage during delivery. Nanoscaled DOX@G/WP6A is capable of preferentially accumulating in tumor tissue via enhanced permeability and retention (EPR) effect. After internalization by tumor cells, the abundant adenosine triphosphate (ATP) binds competitively with WP6A to trigger the disintegration of self-assembled vesicles with the ensuing release of DOX. In vitro and in vivo research confirmed that DOX@G/WP6A is not only able to promote antitumor efficacy but also reduce DOX-related systemic toxicity. The above favorable findings are ascribed to the formation of ternary self-assembly, which profits from the combination of the factors of the EPR effect and the ATP-triggered release.

Ligand Engineering of Titanium-Oxo Nanoclusters for Cerenkov Radiation-Reinforced Photo/Chemodynamic Tumor Therapy.

The therapeutic effect of general photodynamic therapy (PDT) is gravely limited by the poor penetration depth of exogenous light radiation. In recent years, Cerenkov radiation (CR) has been exploringly applied to overcome this critical defect. However, the currently reported type I photosensitizers for CR-induced PDT (CRIT) are only TiO2 nanoparticle-based agents with numerous fatally intrinsic drawbacks. Herein, we developed NH2-Ti32O16 nanocluster (NTOC)-derived ultrasmall nanophotosensitizers (NPSs, denoted as TDPs) via innovate ligand engineering. The introduced dopamine (DA) ligands not only facilitate the water solubility and photocatalytic properties of NPSs but also involve the tumor-targeting behavior through the binding affinity with DA receptors on cancer cells. Under CR irradiation, TDPs enable efficient hydroxyl radical (·OH) generation benefiting from the enhanced separation of hole (h+)-electron (e-) pairs, where the h+ will react with H2O to execute type I PDT and the transferred e- can realize the augmentation of Ti3+ to substantially promote the therapeutic index of chemodynamic therapy. This study provides an easy but feasible strategy for constructing versatile NPSs with an ultrasmall framework structure, propounding a refreshing paradigm for implementing efficient CR-induced combined therapy (CRICT) and spurring the development of CR and titanium-familial nanoplatforms in the fields of photocatalysis and nanocatalytic medicine.