pyrimidinones and Cell-Transformation--Neoplastic

Topics: Animals; Antineoplastic Agents; Arginase; Benz(a)Anthracenes; Benzopyrenes; Carcinogens; Cell Division; Cell Transformation, Neoplastic; Deoxyribonucleases; DNA; Fluorouracil; Humans; Liver Neoplasms; Methylcholanthrene; Mice; Mutation; Neoplasms; Neoplasms, Experimental; Nucleosides; Oncogenic Viruses; Orotic Acid; Phenanthrenes; Protein Binding; Pyrimidinones; Rats; Skin Neoplasms; Thymine; Uracil

Topics: Cell Transformation, Neoplastic; Child; Chromogranins; Chromosome Deletion; Chromosomes, Human, Pair 10; Dexamethasone; DNA Copy Number Variations; GTP-Binding Protein alpha Subunits, Gs; Humans; Laminectomy; Magnetic Resonance Imaging; Male; Melanosis; Neurocutaneous Syndromes; Pyridones; Pyrimidinones

The chemokine, CXCL11, is highly expressed in different solid tumors and controls tumor growth, metastasis, and lymphocyte infiltration. Although of potential clinical interest, it is presently unknown whether these tumor-promoting activities involve the CXCL11 receptors, CXCR3 and/or CXCR7. This issue is further intrigued by the fact that CXCR3 exists in the two functionally divergent splice variants, CXCR3A and CXCR3B, which exert pro- and anti-tumorigenic influences, respectively. To unravel the role of the various CXCL11 receptors in tumor progression, we have now defined their role in CXCL11-induced chemotaxis of the tumor cell lines, A549, C33-A, DLD-1, MDA-MB-231, and PC-3. CXCL11-induced cell migration was either sensitive to the CXCR3 antagonist, ÀMG487 (DLD-1), the CXCR7 antagonist, CCX771 (C33-A, PC-3), or both (A549, MDA-231). Moreover, in C33-A and PC-3 cells, but not in the other tumor cells, pharmacological activation and inhibition of CXCR3B prevented and potentiated CXCL11-induced cell migration, respectively. Both immunocytochemistry and Western blot analysis finally revealed that the observed cell type specific organization of the CXCL11 system is not the result of differences in expression levels or subcellular location of CXCL11 receptors. Our findings imply that the therapeutic use of CXCR3 antagonists in cancer patients requires exact knowledge of the organization of the CXCR3 system in the respective tumor.

Topics: Acetamides; Cell Line, Tumor; Cell Movement; Cell Transformation, Neoplastic; Chemokine CXCL11; Disease Progression; Humans; Pyrimidinones; Real-Time Polymerase Chain Reaction; Receptors, CXCR; Receptors, CXCR3; RNA Splicing; Signal Transduction

Pediatric high-grade gliomas (pedHGG) belong to the most aggressive cancers in children with a poor prognosis due to a lack of efficient therapeutic strategies. The β-catenin/Wnt-signaling pathway was shown to hold promising potential as a treatment target in adult high-grade gliomas by abrogating tumor cell invasion and the acquisition of stem cell-like characteristics. Since pedHGG differ from their adult counterparts in genetically and biologically we aimed to investigate the effects of β-catenin/Wnt-signaling pathway-inhibition by the β-catenin/CBP antagonist ICG-001 in pedHGG cell lines. In contrast to adult HGG, pedHGG cells displayed minimal detectable canonical Wnt-signaling activity. Nevertheless, low doses of ICG-001 inhibited cell migration/invasion, tumorsphere- and colony formation, proliferation in vitro as well as tumor growth in vivo/ovo, suggesting that ICG-001 affects pedHGG tumor cell characteristics independent of β-catenin/Wnt-signaling. RNA-sequencing analyses support a Wnt/β-catenin-independent effect of ICG-001 on target gene transcription, revealing strong effects on genes involved in cellular metabolic/biosynthetic processes and cell cycle progression. Among these, high mRNA expression of cell cycle regulator JDP2 was found to confer a better prognosis for pedHGG patients. In conclusion, ICG-001 might offer an effective treatment option for pedHGG patients functioning to regulate cell phenotype and gene expression programs in absence of Wnt/β-catenin signaling-activity.

Topics: Adolescent; Animals; beta Catenin; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Cell Movement; Cell Self Renewal; Cell Survival; Cell Transformation, Neoplastic; Chick Embryo; Child; Child, Preschool; CREB-Binding Protein; Databases, Genetic; Disease Models, Animal; Glioma; Humans; Kaplan-Meier Estimate; Neoplastic Stem Cells; Prognosis; Pyrimidinones; Wnt Signaling Pathway; Young Adult

Activation of the phosphoinositide 3-kinase (PI3K) pathway occurs widely in human cancers. Although somatic mutations in the PI3K pathway genes PIK3CA and PTEN are known to drive PI3K pathway activation and cancer growth, the significance of somatic mutations in other PI3K pathway genes is less clear. Here, we establish the signaling and oncogenic properties of a recurrent somatic mutation in the PI3K p110β isoform that resides within its kinase domain (PIK3Cβ(D1067V)). We initially observed PIK3Cβ(D1067V) by exome sequencing analysis of an EGFR-mutant non-small cell lung cancer (NSCLC) tumor biopsy from a patient with acquired erlotinib resistance. On the basis of this finding, we hypothesized that PIK3Cβ(D1067V) might function as a novel tumor-promoting genetic alteration, and potentially an oncogene, in certain cancers. Consistent with this hypothesis, analysis of additional tumor exome data sets revealed the presence of PIK3Cβ(D1067V) at low frequency in other patient tumor samples (including renal cell carcinoma, glioblastoma multiforme, head and neck squamous cell carcinoma, melanoma, thyroid carcinoma and endometrial carcinoma). Functional studies revealed that PIK3Cβ(D1067V) promoted PI3K pathway signaling, enhanced cell growth in vitro, and was sufficient for tumor formation in vivo. Pharmacologic inhibition of PIK3Cβ with TGX-221 (isoform-selective p110β inhibitor) specifically suppressed growth in patient-derived renal-cell carcinoma cells with endogenous PIK3Cβ(D1067V) and in NIH-3T3 and human EGFR-mutant lung adenocarcinoma cells engineered to express this mutant PI3K. In the EGFR-mutant lung adenocarcinoma cells, expression of PIK3Cβ(D1067V) also promoted erlotinib resistance. Our data establish a novel oncogenic form of PI3K, revealing the signaling and oncogenic properties of PIK3Cβ(D1067V) and its potential therapeutic relevance in cancer. Our findings provide new insight into the genetic mechanisms underlying PI3K pathway activation in human tumors and indicate that PIK3Cβ(D1067V) is a rational therapeutic target in certain cancers.

Topics: Animals; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Cell Transformation, Neoplastic; Class I Phosphatidylinositol 3-Kinases; Humans; Mice; Morpholines; Mutation; NIH 3T3 Cells; Phosphatidylinositol 3-Kinases; Protein Isoforms; PTEN Phosphohydrolase; Pyrimidinones; Signal Transduction

We aimed to exploit novel compounds with high selectivity to clear cell renal cell carcinoma (ccRCC) with common mutations. Using the GDSC databases, we searched for compounds with high selectivity for ccRCC with VHL and/or SETD2 mutations. Clinical impact and gene interactions were analysed using TCGA database. In vitro and in vivo studies were performed to validate the inhibitory effects of the compound. We identified the selective PI3Kβ inhibitor TGX221 as a selective inhibitor for ccRCC with both VHL and SETD2 mutations. TGX221 also targeted cancer cells with CDKN2A and PTEN mutations. Changes in PTEN and CDKN2A gene sets were associated with worsened prognosis of ccRCC. TGX221 substantially and selectively inhibited the down stream products of VHL, SETD2, and PTEN in ccRCC cells with VHL and SETD2 mutations. TGX221 also exhibited significant selectivity in inhibiting cell motility and tumourigenesis of ccRCC cells with VHL and SETD2 mutations. TGX221 is a novel inhibitor with high selectivity for ccRCC with VHL and SETD2 mutations. It also targeted PTEN and CDKN2A mutations. How those genes were associated with PI3Kβ warranted further investigations.

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Cell Line, Tumor; Cell Movement; Cell Transformation, Neoplastic; Cyclin-Dependent Kinase Inhibitor p16; Drug Resistance, Neoplasm; Histone-Lysine N-Methyltransferase; Humans; Kidney Neoplasms; Morpholines; Mutation; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; PTEN Phosphohydrolase; Pyrimidinones; Receptor, Notch1; Signal Transduction; Von Hippel-Lindau Tumor Suppressor Protein

The aim of this study was to evaluate the potential of (18)F-fluorodeoxyglucose-positron emission tomography ((18)F-FDG-PET) for monitoring the therapeutic efficacy of TAK-733, an inhibitor of mitogen-activated protein kinase kinase, in nude rats bearing A549 (human lung carcinoma) xenografts.. TAK-733 was administered orally by gavage to nude xenograft rats for 2 weeks, at dosage levels of 0 (0.5% w/v methylcellulose solution), 1, 3, and 10 mg/kg/day (n = 8/dose). Tumor size was measured before treatment (day 0), and on days 1, 3, 7, 9, 11, and 14. PET scans were performed pretreatment (day 0), and on days 2, 4, 7, 10, and 14. Tracer accumulations in tumor tissue were quantified as the mean standard uptake value (SUVmean).. No deaths or treatment-related body weight losses occurred during the study period. TAK-733 showed dose-dependent inhibition of tumor growth and (18)F-FDG uptake in tumor tissue. At a dosage of 10 mg/kg, TAK-733 treatment produced a statistically significant reduction in tumor weight from day 11 compared with the vehicle group (P < 0.05). Tumor growth was inhibited in the 10 mg/kg group with a treated/control value of 31% on day 14. The SUVmean on day 2 in this dosage group was statistically lower than that observed on day 0, and that seen in the vehicle group on day 2 (P < 0.05 for both comparisons). Furthermore, this reduction in SUVmean at 10 mg/kg was maintained over time. In the two lower dosage groups (1 and 3 mg/kg), SUVmean gradually increased over time.. (18)F-FDG-PET enabled early determination of late anti-tumor activity in response to TAK-733 treatment.

Topics: Animals; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Transformation, Neoplastic; Disease Models, Animal; Fluorodeoxyglucose F18; Humans; Lung Neoplasms; Mitogen-Activated Protein Kinase Kinases; Positron-Emission Tomography; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Rats; Treatment Outcome

Cancer-specific mutations in the iSH2 (inter-SH2) and nSH2 (N-terminal SH2) domains of p85alpha, the regulatory subunit of phosphatidylinositide 3-kinase (PI3K), show gain of function. They induce oncogenic cellular transformation, stimulate cellular proliferation, and enhance PI3K signaling. Quantitative determinations of oncogenic activity reveal large differences between individual mutants of p85alpha. The mutant proteins are still able to bind to the catalytic subunits p110alpha and p110beta. Studies with isoform-specific inhibitors of p110 suggest that expression of p85 mutants in fibroblasts leads exclusively to an activation of p110alpha, and p110alpha is the sole mediator of p85 mutant-induced oncogenic transformation. The characteristics of the p85 mutants are in agreement with the hypothesis that the mutations weaken an inhibitory interaction between p85alpha and p110alpha while preserving the stabilizing interaction between p85alpha iSH2 and the adapter-binding domain of p110alpha.

Topics: Adenine; Amino Acid Sequence; Animals; Base Sequence; Blotting, Western; Catalytic Domain; Cell Line; Cell Proliferation; Cell Transformation, Neoplastic; Cells, Cultured; Chick Embryo; Class I Phosphatidylinositol 3-Kinases; Dioxoles; Fibroblasts; Humans; Immunoprecipitation; Morpholines; Mutation; Neoplasms; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Protein Binding; Protein Subunits; Pyrimidinones; Quinazolines; Thiazolidinediones; Transfection

The effects of two cyclic nucleotide phosphodiesterase type 4 (PDE4) inhibitors on proliferation of cell lines representing different stages of mouse skin tumorigenesis were studied. Skin papillomas and carcinomas become resistant to the growth inhibition by glucocorticoids. Their control of cellular functions is mediated by a well-known transcription factor, glucocorticoid receptor. The primary aim of the present study was to determine whether the PDE4 inhibitors, that raise intracellular cAMP levels, can increase the sensitivity of mouse skin papillomas and carcinomas to the glucocorticoids. We sought to establish the effect of cAMP signaling on the glucocorticoid receptor function using well-known model representing non-tumorigenic keratinocyte cell line (3PC), papilloma (MT1/2) and squamous cell carcinoma cell line (Ca3/7). These cells were treated with the glucocorticoid fluocinolone acetonide (FA) alone or in concert with PDE4 inhibitors--rolipram or YM976. Results of our study revealed that both PDE4 inhibitors may increase the sensitivity of transformed cell lines to the growth inhibitory effect of FA. In the transformed cell lines, changes in the viability of cells were accompanied by an increase in mRNA level of two negative regulators of the cell cycle--p21 and p27 proteins. Co-treatment with PDE4 inhibitors and FA caused inhibition of an endogenous glucocorticoid-responsive gene (MT-1) expression. Thus, the PDE4 inhibitors exerted a differential effect on non-transformed and transformed keratinocytes and on glucocorticoid receptor signal transduction. These findings warrant further studies to clarify the mechanism by which PDE4 inhibitors modulate glucocorticoid receptor signal transduction in transformed cells.

Topics: Animals; Carcinoma, Squamous Cell; Cell Line; Cell Line, Tumor; Cell Transformation, Neoplastic; Dose-Response Relationship, Drug; Drug Interactions; Fluocinolone Acetonide; Glucocorticoids; Keratinocytes; Mice; Papilloma; Phosphodiesterase Inhibitors; Pyridines; Pyrimidinones; Rolipram; Skin; Skin Neoplasms; Time Factors

Three pyrimidinylpropanamide antibiotics sparsomycin (1), sparoxomycins A1, A2 (2, 3), and also six analogues (4-9) have been synthesized by employing asymmetric sulfide oxidation conditions as a key step. Sparsomycin (1) and its alkyl analogues (5-7) showed higher morphological reversion activities on srctsNRK cells than 2 and 3.

Topics: Antibiotics, Antineoplastic; Avian Sarcoma Viruses; Cell Line; Cell Transformation, Neoplastic; Pyrimidinones; Sparsomycin

Sparoxomycins A1 and A2, isolated from the fermentation broth and mycelium of Streptomyces sparsogenes SN2325, are new inducers of the flat reversion of NRK cells transformed by temperature sensitive Rous sarcoma virus. Sparoxomycins A1 and A2 were isolated by active carbon chromatography, centrifugal partition chromatography (CPC), ODS column chromatography and preparative HPLC. The structure of sparoxomycins were determined by spectroscopic evidences. Stereochemical assignments of these inducers were executed from the analyses of CD spectra.

Topics: Antibiotics, Antineoplastic; Avian Sarcoma Viruses; Cell Transformation, Neoplastic; Molecular Conformation; Pyrimidinones; Temperature

We tested the effect of three different interferon-(IFN) inducing pyrimidinone molecules with cancer therapeutic potential on natural killer (NK) cells. Peritoneal exudate (PE) cells were selected for these studies because their NK cell cytotoxicity is very low. Augmentation of PE-NK cell cytotoxicity was observed in eight different strains of mice after i.p. administration of 250 mg/kg of each of the pyrimidinones. NK cell induction occurred as early as 6 hr after pyrimidinone administration and peaked 2 to 4 days after treatment; at that time, cytotoxicity was as high as 60 to 90%. Augmentation of NK cell activity was independent of IFN serum levels induced by pyrimidinones and murine H-2 haplotype, and did not exhibit any histocompatibility or species-specific restriction, because it was expressed to syngeneic, allogeneic, and xenogeneic tumor target cells. Characterization studies demonstrated that the cytolytic cells were not macrophages, T cells, or B cells and exhibited NK cell characteristics. NK cell tumor-binding and tumor-killing studies demonstrated that NK cell augmentation was accomplished via both activation and recruitment of NK cells. If one considers NK cells as an important part of tumor immunity (as indicated by murine studies), pyrimidinone molecules may be effective anticancer agents.

Topics: Animals; Antibodies, Monoclonal; Ascitic Fluid; Cell Transformation, Neoplastic; Cytotoxicity, Immunologic; Female; Interferon Inducers; Killer Cells, Natural; Lymphocyte Activation; Mice; Mice, Inbred A; Mice, Inbred AKR; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Inbred CBA; Mice, Inbred DBA; Pyrimidinones; Species Specificity