chiniofon and Liver-Neoplasms

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

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

The use of In-111 labeled leukocytes for abscess localization is becoming well established. The first report of In-111 imaging following hepatic embolization is presented. A 45-year-old man with adenocarcinoma of the colon and metastatic liver disease was treated for intractable pain using particulate embolization of the hepatic artery. In-111 leukocyte imaging was performed to rule out abscess formation. The distribution of the labeled leukocytes demonstrated hepatic uptake commensurate with Tc-99m sulfur colloid (SC) images. Areas of embolization did not accumulate tracer. Pathologic examination at autopsy correlated with the distribution of the labeled leukocytes. Thus, therapeutic embolization did not alter the normal distribution of this tracer in functional hepatic tissue.

Topics: Adenocarcinoma; Colonic Neoplasms; Embolization, Therapeutic; Hepatic Artery; Humans; Hydroxyquinolines; Indium; Leukocytes; Liver Abscess; Liver Neoplasms; Male; Middle Aged; Organometallic Compounds; Oxyquinoline; Pain, Intractable; Radioisotopes; Radionuclide Imaging

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

One hundred twenty-nine 111In-oxine-labeled leukocyte scintiscans have been performed in 117 patients with cancer in order to diagnose localized infectious disease. Of the 115 contributive scans, 40 were in patients with localizing signs, whereas in 75 fever of unknown origin constituted the indication for this examination. The overall specificity of the method was 95.4%, the overall sensitivity 86%, and the global accuracy 91.3%. In 10 cases with localizing signs, the 111In-oxine granulocyte scintigram allowed exclusion of the diagnosis of infection, whereas in 17 instances without localizing signs, a focal infectious process was demonstrated. Heterologous donor leukocytes were used successfully in five instances. With the exception of accumulation of label at the site of an osteolytic metastasis in one case, no uptake was observed in primary or secondary tumors. It is concluded that 111In-oxine-labeled leukocytes constitute a valuable tool in the diagnosis and localization of infection in patients with malignant disease.

Topics: Bacterial Infections; Bone Neoplasms; Diagnosis, Differential; False Negative Reactions; Female; Humans; Hydroxyquinolines; Indium; Leukemia, Lymphoid; Leukocytes; Liver Neoplasms; Lymphoma; Neoplasms; Organometallic Compounds; Oxyquinoline; Radioisotopes; Radionuclide Imaging; Rectal Neoplasms; Uterine Cervical Neoplasms

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