chiniofon and Carcinoma--Hepatocellular

Clinical observation of the association between cancer aggressiveness and embryonic development stage implies the importance of developmental signals in cancer initiation and therapeutic resistance. However, the dynamic gene expression during organogenesis and the master oncofetal drivers are still unclear, which impeded the efficient elimination of poor prognostic tumors, including human hepatocellular carcinoma (HCC). In this study, human embryonic stem cells were induced to differentiate into adult hepatocytes along hepatic lineages to mimic liver development in vitro. Combining transcriptomic data from liver cancer patients with the hepatocyte differentiation model, the active genes derived from different hepatic developmental stages and the tumor tissues were selected. Bioinformatic analysis followed by experimental assays was used to validate the tumor subtype-specific oncofetal signatures and potential therapeutic values. Hierarchical clustering analysis revealed the existence of two subtypes of liver cancer with different oncofetal properties. The gene signatures and their clinical significance were further validated in an independent clinical cohort and The Cancer Genome Atlas database. Upstream activator analysis and functional screening further identified E2F1 and SMAD3 as master transcriptional regulators. Small-molecule inhibitors specifically targeting the oncofetal drivers extensively down-regulated subtype-specific developmental signaling and inhibited tumorigenicity. Liver cancer cells and primary HCC tumors with different oncofetal properties also showed selective vulnerability to their specific inhibitors. Further precise targeting of the tumor initiating steps and driving events according to subtype-specific biomarkers might eliminate tumor progression and provide novel therapeutic strategy.

Topics: Aminopyridines; Animals; Biomarkers, Tumor; Carcinoma, Hepatocellular; Cell Differentiation; Cell Line; Cell Transformation, Neoplastic; Cohort Studies; Disease-Free Survival; E2F1 Transcription Factor; Female; Gene Expression Profiling; Gene Expression Regulation, Developmental; Gene Expression Regulation, Neoplastic; Hepatectomy; Hepatocytes; Human Embryonic Stem Cells; Humans; Hydroxyquinolines; Isoquinolines; Kaplan-Meier Estimate; Liver; Liver Neoplasms; Male; Mice; Middle Aged; Prognosis; Pyridines; Pyrroles; Signal Transduction; Smad3 Protein; Xenograft Model Antitumor Assays

Tumour growth is closely related to the development of new blood vessels to supply oxygen and nutrients to cancer cells. Without the neovascular formation, tumour volumes cannot increase and undergo metastasis. Antiangiogenesis is one of the most promising approaches for antitumour therapy. The exploration of new antiangiogenic agents would be helpful in antitumour therapy. Quinoline is an aromatic nitrogen compound characterized by a double-ring structure which exhibits a benzene ring fused to pyridine at two adjacent carbon atoms. The high stability of quinoline makes it preferable in a variety of therapeutic and pharmaceutical applications, including antitumour treatment. This work is to examine the potential antiangiogenic activity of the synthetic compound 2-Formyl-8-hydroxy-quinolinium chloride. We found that 2-Formyl-8-hydroxy-quinolinium chloride could inhibit the growth of human umbilical vein endothelial cells in vitro. Using the diethylnitrosamine-induced hepatocarcinogenesis model, 2-Formyl-8-hydroxy-quinolinium chloride showed strong antiangiogenic activity. Furthermore, 2-Formyl-8-hydroxy-quinolinium chloride could inhibit the growth of large Hep3B xenografted tumour from the nude mice. We assume that 2-Formyl-8-hydroxy-quinolinium chloride could be a potential antiangiogenic and antitumour agent and it is worthwhile to further study its underlying working mechanism.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Carcinogenesis; Carcinoma, Hepatocellular; Cell Death; Cell Proliferation; Diethylnitrosamine; Human Umbilical Vein Endothelial Cells; Humans; Hydroxyquinolines; Liver Neoplasms; Mice, Inbred C57BL; Mice, Nude; Quinolinium Compounds; Tumor Burden; Xenograft Model Antitumor Assays

The synthesis, in vitro antimicrobial and cytotoxic activities of some novel hexahydroquinolines supported with various pharmacophores are described. The results revealed that 18 compounds displayed pronounced activity against Staphylococcus aureus and Escherichia coli bacteria beside a moderate antifungal activity. Compound 25 is the most active candidate with equipotency to ampicillin against S. aureus, E. coli and Pseudomonas aeruginosa, together with an obvious antifungal activity. Additionally, 12 compounds showed remarkable cytotoxic efficiency against human colon carcinoma HT29, hepatocellular carcinoma Hep-G2 and Caucasian breast adenocarcinoma MCF7 cell lines. Among these, the analogs 22 and 25 proved to be the most active cytotoxic members. Collectively, the results would suggest that compounds 22 and 25 could be considered as possible dual antimicrobial-anticancer agents.

Topics: Adenocarcinoma; Anti-Bacterial Agents; Anti-Infective Agents; Antifungal Agents; Antineoplastic Agents; Breast Neoplasms; Carcinoma, Hepatocellular; Cell Line, Tumor; Chemistry Techniques, Synthetic; Cytotoxins; Drug Screening Assays, Antitumor; Escherichia coli; HT29 Cells; Humans; Hydroxyquinolines; Liver Neoplasms; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Staphylococcus aureus; Structure-Activity Relationship

Iron accumulation and iron-related oxidative stress are involved in several pathological conditions and provide a rationale for the development of iron chelators as novel promising therapeutic strategies. Thus, we have recently synthesized multifunctional non-toxic, brain permeable iron chelating compounds, M30 and HLA20, possessing the neuroprotective N-propargyl moiety of the anti-Parkinsonian drug, monoamine oxidase (MAO)-B inhibitor, rasagiline and the antioxidant-iron chelating moiety of an 8-hydroxyquinoline derivative of the iron chelator, VK28. Here, we examined the hepatic regulatory effects of these novel compounds using two experimental approaches: chelation activity and glucose metabolism parameters. The present study demonstrated that M30 and HLA20 significantly decreased intracellular iron content and reduced ferritin expression levels in iron-loaded hepatoma Hep3B cells. In electron microscopy analysis, M30 was shown to reduce the electron-dense deposits of siderosomes by ~30 %, as well as down-regulate cytosolic ferritin particles observed in iron-overloaded cells. In vivo studies demonstrated that M30 administration (1 mg/kg, P.O. three times a week) reduced hepatic ferritin levels; increased hepatic insulin receptor and glucose transporter-1 levels and improved glucose tolerance in C57BL/6 mice and in a mouse model of type-2 diabetes, the ob/ob (leptin(-/-)). The results clearly indicate that the novel multifunctional drugs, especially M30, display significant capacity of chelating intracellular iron and regulating glucose metabolism parameters. Such effects can have therapeutic significance in conditions with abnormal local or systemic iron metabolism, including neurological diseases.

Topics: Animals; Benzofurans; Carcinoma, Hepatocellular; Cell Line, Tumor; Dose-Response Relationship, Drug; Ferric Compounds; Ferritins; Glucose; Glucose Tolerance Test; Humans; Hydroxyquinolines; Iron; Iron Chelating Agents; Leptin; Liver; Male; Mice; Mice, Transgenic; Microscopy, Electron, Transmission; Monoamine Oxidase Inhibitors; Neuroprotective Agents; Piperazines; Quaternary Ammonium Compounds; Quinolines

If a new generation of iron chelators specifically devoted for cancer chemotherapy emerged these last years, any of them has not yet been approved at this time. Accordingly, there is a need to optimize new chelating molecules for iron chelation therapy and cancer treatment. So, the objective of the present investigation was to characterize the antiproliferative activity and the iron chelating capacity of the iron chelator S1 [bis-N-(8-hydroxyquinoline-5-ylmethyl)benzylamine]. Its effects were compared to O-trensox which binds ferric iron with a very high affinity (pFe(3+)=29.5). For this purpose, primary rat hepatocyte stimulated by EGF and human hepatoma HepaRG cell cultures were used. In these models, the anti-proliferative effect, the inhibition of DNA synthesis and the iron-chelating efficiency of increasing concentrations of S1 and O-trensox (0 up to 200 μM) were investigated. In the two cell culture models, we observed that S1 was about 100 times more efficient than O-trensox and the antiproliferative effect of S1 in HepaRG cells appeared at concentrations as low as 0.1 μM without cytotoxicity. Moreover, the stoichiometry of S1 for iron seemed to be in the range S1/Fe(3+)=1. Using the calcein fluorescence assay, we demonstrated that the affinity of S1 for iron was better than that of O-trensox since it was at least two times more effective to restore the fluorescence of calcein previously quenched by iron. So, the iron chelating efficiency of S1 could explain at least partially its higher anti-proliferative effect compared to O-trensox. Finally, these results suggest that molecules such as S1 may constitute a promising starting point to improve cancer treatment.

Topics: Animals; Benzylamines; Carcinoma, Hepatocellular; Cell Proliferation; Dose-Response Relationship, Drug; Ethylamines; Hepatocytes; Humans; Hydroxyquinolines; Iron Chelating Agents; Male; Oxyquinoline; Rats; Rats, Sprague-Dawley; Toxicity Tests

By comparing the antiproliferative effect of the iron chelators ICL670A and O-trensox in the human hepatoma cell line HUH7 and human hepatocyte cultures, we have shown that ICL670A decreased cell viability, inhibited DNA replication and induced DNA fragmentation more efficiently than O-trensox. O-trensox and ICL670A induced a cell cycle blockade in G0-G1 and S phases respectively. In parallel, ICL670A inhibited polyamine biosynthesis by decreasing ornithine decarboxylase and spermidine/spermine N(1)-acetyltransferase activities. O-trensox increased polyamine biosynthesis and particularly putrescine level by stimulating spermidine-spermine N(1)-acetyltransferase activity which could activate the polyamine retro-conversion pathway. Moreover, the two chelators exhibit some cytotoxic effect in the two culture models; ICL670A was more cytotoxic than O-trensox and higher concentrations of the two chelators were necessary to induce a cytotoxicity in primary cultures versus hepatoma cells. These results suggested that ICL670A has the most efficient antitumoral effect, blocks cell proliferation by a pathway different of O-trensox and may constitute a potential drug for anticancer therapy.

Topics: Acetyltransferases; Apoptosis; Benzoates; Biogenic Polyamines; Carcinoma, Hepatocellular; Cell Cycle; Cell Proliferation; Deferasirox; DNA Replication; Ethylamines; Hepatocytes; Humans; Hydroxyquinolines; Iron Chelating Agents; Ornithine Decarboxylase; RNA, Messenger; Triazoles

We investigated the effects of a new iron chelator, O-Trensox (TRX), compared with desferrioxamine (DFO), on proliferation and apoptosis in cultures of the human hepatoblastoma HepG2 and hepatocarcinoma HBG cell lines. Our results show that TRX decreased DNA synthesis in a time- and dose-dependent manner and with a higher efficiency than DFO. Mitotic index was also strongly decreased by TRX and, unexpectedly, DFO inhibited mitotic activity to the same extent as TRX, thus there is a discrepancy between the slight reduction in DNA synthesis and a large decrease in mitotic index after DFO treatment. In addition, we found that TRX induced accumulation of cells in the G(1) and G(2) phases of the cell cycle whereas DFO arrested cells in G(1) and during progression through S phase. These data suggest that the partial inhibition of DNA replication observed after exposure to DFO may be due to a lower efficiency of metal chelation and/or that it does not inhibit the G(1)/S transition but arrests cells in late S phase. The effects of both TRX and DFO on DNA synthesis and mitotic index were reversible after removing the chelators from the culture medium. An apoptotic effect of TRX was strongly suggested by analysis of DNA content by flow cytometry, nuclear fragmentation and DNA degradation in oligonucleosomes and confirmed by the induction of a high level of caspase 3-like activity. TRX induced apoptosis in a dose- and time-dependent manner in proliferating HepG2 cells. In HBG cells, TRX induced apoptosis in proliferating and confluent cells arrested in the G(1) phase of the cell cycle, demonstrating that inhibition of proliferation and induction of apoptosis occurred independently. DFO induced DNA alterations only at concentrations >100 microM and without induction of caspase 3-like activity, indicating that DFO is not a strong inducer of apoptosis. Addition of Fe or Zn to the culture medium during TRX treatment led to a complete restoration of proliferation rate and inhibition of apoptosis, demonstrating that Fe/Zn-saturated TRX was not toxic in the absence of metal depletion. These data show that TRX, at concentrations of 20-50 microM, strongly inhibits cell proliferation and induces apoptosis in proliferating and non-proliferating HepG2 and HBG cells, respectively.

Topics: Apoptosis; Carcinoma, Hepatocellular; Cell Differentiation; Cell Division; DNA, Neoplasm; Ethylamines; Flow Cytometry; G1 Phase; G2 Phase; Hepatoblastoma; Humans; Hydroxyquinolines; Iron Chelating Agents; Liver Neoplasms; Tumor Cells, Cultured

A 54-year-old man was admitted to hospital with a 3-month history of progressive dyspnea with coughing. A giant right atrial mass, originating from a hepatocellular carcinoma, was visualized by computed tomography, and digital subtraction angiography. The volume of the right atrial mass was increasing rapidly. It was therefore essential to determine whether this giant mass was a tumor thrombus or a multiplication of the hepatocellular carcinoma. 111In-oxine labeled platelet scintigraphy revealed active accumulation in the right atrium caused by the presence of active platelet deposition, and slight accumulation in the lung fields probably due to embolic showers originating from the tumor thrombus in the right atrium. This is the first case report showing that 111In-oxine labeled platelet scintigraphy can aid in confirming the nature of a giant tumor thrombus in the right atrium and can clarify the pathogenesis of the respiratory symptoms.

Topics: Blood Platelets; Carcinoma, Hepatocellular; Coronary Disease; Heart Atria; Heart Neoplasms; Humans; Hydroxyquinolines; Indium; Liver Neoplasms; Male; Middle Aged; Organometallic Compounds; Oxyquinoline; Radionuclide Imaging

Topics: Animals; Carboxylic Acids; Carcinoma, Hepatocellular; Cells, Cultured; Depression, Chemical; DNA, Neoplasm; Hydroxyquinolines; Liver Neoplasms; Male; Mice; Neoplasms, Experimental; Oxyquinoline; Rats