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  • The American Association for Cancer Research (AACR)  (4)
  • Blackwell Science Ltd  (1)
  • Munksgaard International Publishers  (1)
  • 1
    Publication Date: 2018-03-06
    Description: Purpose: Aberrant activation of the B-cell receptor (BCR) is implicated in the pathogenesis of mature B-cell tumors, a concept validated in part by the clinical success of inhibitors of the BCR-related kinases BTK (Bruton's tyrosine kinase) and PI3K. These inhibitors have limitations, including the paucity of complete responses, acquired resistance, and toxicity. Here, we examined the mechanism by which the cyclic-AMP/PDE4 signaling axis suppresses PI3K, toward identifying a novel mechanism-based combinatorial strategy to attack BCR-dependency in mature B-cell malignancies. Experimental Design: We used in vitro and in vivo diffuse large B-cell lymphoma (DLBCL) cell lines and primary chronic lymphocytic leukemia (CLL) samples to preclinically evaluate the effects of the combination of the FDA-approved phosphodiesterase 4 (PDE4) inhibitor roflumilast and idelalisib on cell survival and tumor growth. Genetic models of gain- and loss-of-function were used to map multiple signaling intermediaries downstream of the BCR. Results: Roflumilast elevates the intracellular levels of cyclic-AMP and synergizes with idelalisib in suppressing tumor growth and PI3K activity. Mechanistically, we show that roflumilast suppresses PI3K by inhibiting BCR-mediated activation of the P85 regulatory subunit, distinguishing itself from idelalisib, an ATP-competitive inhibitor of the catalytic P110 subunit. Using genetic models, we linked the PDE4-regulated modulation of P85 activation to the oncogenic kinase SYK. Conclusions: These data demonstrate that roflumilast and idelalisib suppress PI3K by distinct mechanisms, explaining the basis for their synergism, and suggest that the repurposing of PDE4 inhibitors to treat BCR-dependent malignancies is warranted. Clin Cancer Res; 24(5); 1103–13. ©2017 AACR .
    Print ISSN: 1078-0432
    Electronic ISSN: 1557-3265
    Topics: Medicine
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  • 2
    Publication Date: 2018-02-09
    Description: Cisplatin-based therapy is highly toxic, but moderately effective in most cancers. Concurrent inhibition of cyclooxygenase-2 (COX-2) and soluble epoxide hydrolase (sEH) results in antitumor activity and has organ-protective effects. The goal of this study was to determine the antitumor activity of PTUPB, an orally bioavailable COX-2/sEH dual inhibitor, in combination with cisplatin and gemcitabine (GC) therapy. NSG mice bearing bladder cancer patient-derived xenografts were treated with vehicle, PTUPB, cisplatin, GC, or combinations thereof. Mouse experiments were performed with two different PDX models. PTUPB potentiated cisplatin and GC therapy, resulting in significantly reduced tumor growth and prolonged survival. PTUPB plus cisplatin was no more toxic than cisplatin single-agent treatment as assessed by body weight, histochemical staining of major organs, blood counts, and chemistry. The combination of PTUPB and cisplatin increased apoptosis and decreased phosphorylation in the MAPK/ERK and PI3K/AKT/mTOR pathways compared with controls. PTUPB treatment did not alter platinum–DNA adduct levels, which is the most critical step in platinum-induced cell death. The in vitro study using the combination index method showed modest synergy between PTUPB and platinum agents only in 5637 cell line among several cell lines examined. However, PTUPB is very active in vivo by inhibiting angiogenesis. In conclusion, PTUPB potentiated the antitumor activity of cisplatin-based treatment without increasing toxicity in vivo and has potential for further development as a combination chemotherapy partner. Mol Cancer Ther; 17(2); 474–83. ©2017 AACR .
    Print ISSN: 1535-7163
    Electronic ISSN: 1538-8514
    Topics: Medicine
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  • 3
    Publication Date: 2018-05-02
    Description: Purpose: Osimertinib is a third-generation inhibitor of the epidermal growth factor receptor used in treatment of non–small cell lung cancer. A full understanding of its disposition and capacity for interaction with other medications will facilitate its effective use as a single agent and in combination therapy. Experimental Design: Recombinant cytochrome P450s and liver microsomal preparations were used to identify novel pathways of osimertinib metabolism in vitro . A panel of knockout and mouse lines humanized for pathways of drug metabolism were used to establish the relevance of these pathways in vivo . Results: Although some osimertinib metabolites were similar in mouse and human liver samples there were several significant differences, in particular a marked species difference in the P450s involved. The murine Cyp2d gene cluster played a predominant role in mouse, whereas CYP3A4 was the major human enzyme responsible for osimertinib metabolism. Induction of this enzyme in CYP3A4 humanized mice substantially decreased circulating osimertinib exposure. Importantly, we discovered a further novel pathway of osimertinib disposition involving CPY1A1. Modulation of CYP1A1/CYP1A2 levels markedly reduced parent drug concentrations, significantly altering metabolite pharmacokinetics (PK) in humanized mice in vivo . Conclusions: We demonstrate that a P450 enzyme expressed in smokers' lungs and lung tumors has the capacity to metabolise osimertinib. This could be a significant factor in defining the outcome of osimertinib treatment. This work also illustrates how P450-humanized mice can be used to identify and mitigate species differences in drug metabolism and thereby model the in vivo effect of critical metabolic pathways on anti-tumor response. Clin Cancer Res; 24(9); 2138–47. ©2018 AACR .
    Print ISSN: 1078-0432
    Electronic ISSN: 1557-3265
    Topics: Medicine
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  • 4
    Publication Date: 2018-01-04
    Description: Purpose: Agents extracted from natural sources with antitumor property have attracted considerable attention from researchers and clinicians because of their safety, efficacy, and immediate availability. Degalactotigonin (DGT), extracted from Solanum nigrum L ., has anticancer properties without serious side effects. Here, we explored whether DGT can inhibit the growth and metastasis of osteosarcoma. Experimental Design: MTT, colony formation, and apoptosis assays were performed to analyze the effects of DGT on osteosarcoma cell viability in vitro . The migration and invasion abilities were measured using a Transwell assay. Animal models were used to assess the roles of DGT in both tumor growth and metastasis of osteosarcoma. Gli1 expression and function were measured in osteosarcoma cells and clinical samples. After DGT treatment, Gli1 activation and the phosphorylation status of multiple cellular kinases were measured with a luciferase reporter and phospho-kinase antibody array. Results: DGT inhibited proliferation, induced apoptosis, and suppressed migration and invasion in osteosarcoma cells. DGT, injected intraperitoneally after tumor inoculation, significantly decreased the volume of osteosarcoma xenografts and dramatically diminished the occurrence of osteosarcoma xenograft metastasis to the lungs. Mechanistically, DGT inhibited osteosarcoma growth and metastasis through repression of the Hedgehog/Gli1 pathway, which maintains malignant phenotypes and is involved in the prognosis of osteosarcoma patients. DGT decreased the activity of multiple intracellular kinases that affect the survival of osteosarcoma patients, including GSK3β. In addition, DGT represses the Hedgehog/Gli1 pathway mainly through GSK3β inactivation. Conclusions: Our studies provide evidence that DGT can suppress the growth and metastasis of human osteosarcoma through modulation of GSK3β inactivation–mediated repression of the Hedgehog/Gli1 pathway. Clin Cancer Res; 24(1); 130–44. ©2017 AACR .
    Print ISSN: 1078-0432
    Electronic ISSN: 1557-3265
    Topics: Medicine
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  • 5
    ISSN: 1365-2133
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Background  Alopecia areata (AA) is hypothesized to be an organ-specific autoimmune disease with genetic predisposition and an environmental trigger. There are few clinical data in Asians.Objectives  To describe the genetic epidemiological features of AA patients in China and to determine the possible genetic model for AA.Methods  Data for 1032 patients with AA were obtained by questionnaire in the Institute of Dermatology of Anhui Medical University in China from 2001 to 2003. Complex segregation analysis and heritability analysis were performed using Falconer's method, EPI INFO 6·0 and SAGE-REGTL programs.Results  In total, 1032 AA patients (male/female ratio 1·1 : 1) were enrolled, representing 0·94% of the total number of cases seen in our outpatient clinic during that time. The mean ± SD age of onset was 28·98 ± 13·43 years. The difference between the mean age of onset in males and females was not significant. Most patients (82·6%) experienced their first episode of AA within the first four decades of life. A positive family history of AA was obtained in 87 patients (8·4%). The prevalence of AA in first-, second- and third-degree relatives of the proband with AA was 1·6%, 0·19% and 0·03%, respectively. These figures were higher than those in controls. A greater severity and longer duration of AA were seen in the early onset group than in the late-onset group. The early onset group also had more affected first- and second-degree relatives. The heritability of AA in first-, second- and third-degree relatives was 47·16%, 42·53% and 22·29%, respectively. Based on the REGTL results, the best model was a polygenic additive model for AA.Conclusions  The effect of genetic factors is strong in AA, but environmental factors such as infection and psychological stress may still play an important role. Our findings on the genetics of AA are consistent with a polygenic additive mode of inheritance.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1600-0765
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: After severe injury to the periodontal ligament (PL), the phenotypes of cells recolonizing root surfaces influence the extent and type of repair processes. In teeth that are replanted following avulsion injury, recolonization of the PL space by osteogenic cells instead of by PL fibroblasts may favor bone formation (i.e. ankylosis) instead of PL regeneration. We consider here that recolonization processes depend in part on the storage conditions of the teeth following avulsion. We used an in vitro cell culture model to assess the effect of storage conditions on immunohistochemical staining of several marker proteins that are expressed by osteogenic cells (osteopontin and alkaline phosphatase) and fibroblasts (α-smooth muscle actin, type III and XII collagens). Prior to cell culture, extracted human premolar teeth were stored in air (“dry”) or in α-MEM (“wet”) for either 30 or 120 min as surrogate conditions for the variations of extra-alveolar tooth storage that may occur following avulsion. Collagenase/trypsin-digested suspensions of PL cells were prepared from the tissue adherent to the extracted root surface. Passage #2 or #3 cultures were immunostained and examined by fluorescence microscopy. For type XII collagen, cells from wet samples displayed perinuclear staining while cells from 30-min dry samples showed only isolated foci. The staining for 120-min dry samples was weak and non-specific. α-Smooth muscle actin was not incorporated into stress fibers in wet samples, whereas dry samples demonstrated prominent stress fibers stained for α-smooth muscle actin. Detached cytoplasmic fragments resembling cell processes that stained for α-smooth muscle actin were abundant in dry samples, indicating the presence of highly contractile cells. The staining for osteopontin was mainly perinuclear but was more intense in dry samples. The focal adhesion pattern of osteopontin staining in 120-min dry samples resembled that of migrating osteogenic cells. The pattern of staining did not vary for type III collagen or alkaline phosphatase, although staining for alkaline phosphatase was more intense in samples stored under dry conditions. We conclude that prolonged extra-alveolar dry storage favors increased in vitro growth of contractile cells expressing osteogenic cell markers while storage in cell culture medium favors growth of cells with the classical phenotype of PL fibroblasts.
    Type of Medium: Electronic Resource
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