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  • 1
  • 2
    Keywords: APOPTOSIS ; CELLS ; METABOLISM ; ACTIVATION ; GEMCITABINE ; NUCLEAR RECEPTORS ; HYPERFORIN ; ST-JOHNS-WORT ; DRUG-INTERACTIONS ; PREGNANE-X RECEPTOR
    Abstract: Pancreatic cancer is one of the leading cancer-related causes of death in the western world with an urgent need for new treatment strategies. Recently, hyperforin and nemorosone have been described as promising anti-cancer lead compounds. While hyperforin has been thoroughly investigated in vitro and in vivo, in vivo data for nemorosone are still missing. Thus, we investigated the growth-inhibitory potential of nemorosone on pancreatic cancer xenografts in NMRI nu/nu mice and determined basic pharmacokinetic parameters. Xenograft tumors were treated with nemorosone and gemcitabine, the current standard of care. Tumor sections were subjected to H&E as well as caspase 3 and Ki-67 staining. Nemorosone plasma kinetics were determined by HPLC and mass spectrometry. Induction of CYP3A4 and other metabolizing enzymes by nemorosone and hyperforin was tested on primary hepatocytes using qRT-PCR. At a dose of 50 mg/kg nemorosone per day, a significant growth-inhibitory effect was observed in pancreatic cancer xenografts. The compound was well tolerated and rapidly absorbed into the bloodstream with a half-life of approximately 30 min. Different metabolites were detected, possibly resembling CYP3A4-independent oxidation products. It is concluded that nemorosone is a potential anti-cancer lead compound with good bioavailability, little side-effects and promising growth-inhibitory effects, thus representing a valuable compound for a combination therapy approach.
    Type of Publication: Journal article published
    PubMed ID: 24040280
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  • 3
    Keywords: APOPTOSIS ; CANCER ; EXPRESSION ; GROWTH ; proliferation ; MICROSCOPY ; PATHWAY ; NETWORK ; DEATH ; GENE-EXPRESSION ; ACTIVATION ; IDENTIFICATION ; MITOCHONDRIA ; pancreatic cancer ; unfolded protein response ; endoplasmic reticulum stress ; ENDOPLASMIC-RETICULUM-STRESS ; GARCINOL ; HYPERFORIN ; mitochondrial membrane potential ; nemorosone ; polycyclic polyprenylated acylphloroglucinols ; ST-JOHNS-WORT ; THAPSIGARGIN
    Abstract: BACKGROUND AND PURPOSE Pancreatic cancer is one of the leading cancer-related causes of death due to high chemo-resistance and fast metastasation. Nemorosone, a polycyclic polyprenylated acylphloroglucinol, has recently been identified as a promising anticancer agent. Here, we examine its growth-inhibitory effects on pancreatic cancer cells. Based on transcription profiling, a molecular mode of action is proposed. EXPERIMENTAL APPROACH Nemorosone cytotoxicity was assessed by the resazurin proliferation assay on pancreatic cancer cells and fibroblasts. Apoptosis was determined by Annexin V/propidium iodide staining as well as cytochrome c and caspase activation assays. Staining with the voltage-dependent dye JC-1 and fluorescence microscopy were used to detect effects on mitochondrial membrane potential. Total RNA was isolated from treated cell lines and subjected to microarray analysis, subsequent pathway identification and modelling. Gene expression data were validated by quantitative polymerase chain reaction and siRNA-mediated gene knock-down. KEY RESULTS Nemorosone significantly inhibited cancer cell growth, induced cytochrome c release and subsequent caspase-dependent apoptosis, rapidly abolished mitochondrial membrane potential and elevated cytosolic calcium levels, while fibroblasts were largely unaffected. Expression profiling revealed 336 genes to be affected by nemorosone. A total of 75 genes were altered in all three cell lines, many of which were within the unfolded protein response (UPR) network. DNA damage inducible transcript 3 was identified as a key regulator in UPR-mediated cell death. CONCLUSIONS AND IMPLICATIONS Nemorosone could be a lead compound for the development of novel anticancer drugs amplifying the already elevated UPR level in solid tumours, thus driving them into apoptosis. This study forms the basis for further investigations identifying nemorosone's direct molecular target(s)
    Type of Publication: Journal article published
    PubMed ID: 21091652
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  • 4
    Keywords: EXPRESSION ; IN-VIVO ; THERAPY ; GENE ; GENE-EXPRESSION ; GENES ; GENOME ; PROTEIN ; DNA ; INFECTION ; cell cycle ; CELL-CYCLE ; IDENTIFICATION ; MICROARRAY DATA ; VECTOR ; CANCER-CELLS ; ORIGIN ; COMPETENT ADENOVIRUS ; E1A
    Abstract: Adenoviruses (Ads), especially HAdV-5, have been genetically equipped with tumor-restricted replication potential to enable applications in oncolytic cancer therapy. Such oncolytic adenoviruses have been well tolerated in cancer patients, but their anti-tumor efficacy needs to be enhanced. In this regard, it should be considered that cancer cells, dependent on their tissue of origin, can differ substantially from the normal host cells to which Ads are adapted by complex virus-host interactions. Consequently, viral replication efficiency, a key determinant of oncolytic activity, might be suboptimal in cancer cells. Therefore, we have analyzed both the replication kinetics of HAdV-5 and the virus-induced transcriptome in human bronchial epithelial cells (HBEC) in comparison to cancer cells. This is the first report on genome-wide expression profiling of Ads in their native host cells. We found that E1A expression and onset of viral genome replication are most rapid in HBEC and considerably delayed in melanoma cells. In squamous cell lung carcinoma cells, we observed intermediate HAdV-5 replication kinetics. Infectious particle production, viral spread and lytic activity of HAdV-5 were attenuated in melanoma cells versus HBEC. Expression profiling at the onset of viral genome replication revealed that HAdV-5 induced the strongest changes in the cellular transcriptome in HBEC, followed by lung cancer and melanoma cells. We identified prominent regulation of genes involved in cell cycle and DNA metabolism, replication and packaging in HBEC, which is in accord with the necessity to induce S phase for viral replication. Strikingly, in melanoma cells HAdV-5 triggered opposing regulation of said genes and, in contrast to lung cancer cells, no weak S phase induction was detected when using the E2F promoter as reporter. Our results provide a rationale for improving oncolytic adenoviruses either by adaptation of viral infection to target tumor cells or by modulating tumor cell functions to better support viral replication
    Type of Publication: Journal article published
    PubMed ID: 22140489
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  • 5
    Keywords: CANCER ; CELLS ; INHIBITOR ; leukemia ; COMPOUND ; HYPERFORIN ; polycyclic polyprenylated acylphloroglucinols ; BRIDGEHEAD LITHIATION
    Abstract: The synthesis of an unnatural polyprenylated acylphloroglucinol (PPAP), regioisomeric with nemorosone and clusianone, has been accomplished. The separated enantiomers of this new PPAP, along with those of nemorosone and clusianone, have been screened for activity against HeLa (cervix carcinoma), MIA-PaCa-2 (pancreatic carcinoma), and MCF7 (mamma carcinoma) cancer cell lines. All of the isomers examined gave surprisingly similar results in the screens.
    Type of Publication: Journal article published
    PubMed ID: 22944119
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  • 6
    ISSN: 1435-1536
    Keywords: Key words Benzoylterryleneimide ; Molecular packing ; Electron diffraction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics
    Notes: Abstract  The packing behavior of benzoylterryleneimide was determined by X-ray powder and electron diffraction. The latter was applied to a material solidified from a solution after spreading it onto a water surface. By this procedure various nonequilibrium structures were prepared: crystalline lamellae are embedded in a structure of lower order, the texture of which looks similar to a texture seen in rigid liquid-crystalline polymers. The transition between both regimes is gradual. X-ray diffraction was applied to an annealed crystalline powder. The crystalline packing of the dark-blue compound can be described by a monoclinic unit cell with lattice parameters a = 11.25 Å, b = 10.93 Å, c = 27.78 Å, β = 91.0°, ρ = 1.38 g/cm3 and Z = 4 at ambient temperature. In order to enable optimum space-filling, the molecules are arranged parallel two by two with the planes of the aromatic ring systems 3.47 Å apart in centrosymmetrical relation and shifted longitudinally so that the diisopropylphenyl group of one molecule fits into the cavity at the carbonyl oxygen of the adjacent molecule.
    Type of Medium: Electronic Resource
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