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1.
Oncotarget ; 7(46): 74860-74871, 2016 Nov 15.
Article in English | MEDLINE | ID: mdl-27556862

ABSTRACT

Temozolomide (TMZ) is an alkylating agent that has become the mainstay treatment of the most malignant brain cancer, glioblastoma multiforme (GBM). Unfortunately only a limited number of patients positively respond to it. It has been shown that zinc metal reestablishes chemosensitivity but this effect has not been tested with TMZ. Using both in vitro and in vivo experimental approaches, we investigated whether addition of zinc to TMZ enhances its cytotoxicity against GBM. In vitro cell viability analysis showed that the cytotoxic activity of TMZ was substantially increased with addition of zinc and this response was accompanied by an elevation of p21, PUMA, BAX and Caspase-3 expression and a decrease in growth fraction as manifested by low ki67 and lower colony formation. Analysis of GBM as intracranial xenografts in athymic mice and administration of concurrent TMZ and zinc yielded results consistent with those of the in vitro analyses. The co-treatment resulted in significant reduction in tumor volume in TMZ/zinc treated mice relative to treatment with TMZ alone. Our results suggest that zinc may serve as a potentiator of TMZ therapy in GBM patients.


Subject(s)
Antineoplastic Agents, Alkylating/pharmacology , Brain Neoplasms/pathology , Dacarbazine/analogs & derivatives , Glioblastoma/pathology , Zinc/pharmacology , Animals , Apoptosis/drug effects , Apoptosis/genetics , Apoptosis Regulatory Proteins/genetics , Apoptosis Regulatory Proteins/metabolism , Brain Neoplasms/drug therapy , Brain Neoplasms/genetics , Brain Neoplasms/metabolism , Caspase 3/genetics , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Cell Survival/genetics , Dacarbazine/pharmacology , Disease Models, Animal , Drug Synergism , Glioblastoma/drug therapy , Glioblastoma/genetics , Glioblastoma/metabolism , Humans , Ki-67 Antigen/genetics , Ki-67 Antigen/metabolism , Mice , Temozolomide , Tumor Burden , Xenograft Model Antitumor Assays , bcl-2-Associated X Protein/genetics , bcl-2-Associated X Protein/metabolism
3.
PLoS One ; 11(5): e0155711, 2016.
Article in English | MEDLINE | ID: mdl-27196668

ABSTRACT

Inhibitors of poly[ADP-ribose] polymerase 1 (PARPis) show promise for treatment of cancers which lack capacity for homologous recombination repair (HRR). However, new therapeutic strategies are required in order to overcome innate and acquired resistance to these drugs and thus expand the array of cancers that could benefit from them. We show that human cancer cell lines which respond poorly to ABT-888 (a PARPi), become sensitive to it when co-treated with vorinostat (a histone deacetylase inhibitor (HDACi)). Vorinostat also sensitized PARPis insensitive cancer cell lines to 6-thioguanine (6-TG)-a drug that targets PARPis sensitive cells. The sensitizing effect of vorinostat was associated with increased phosphorylation of eukaryotic initiation factor (eIF) 2α which in and of itself increases the sensitivity of cancer cells to ABT-888. Importantly, these drug combinations did not affect survival of normal fibroblasts and breast cells, and significantly increased the inhibition of xenograft tumor growth relative to each drug alone, without affecting the mice weight or their liver and kidney function. Our results show that combination of vorinostat and ABT-888 could potentially prove useful for treatment of cancer with innate resistance to PARPis due to active HRR machinery, while the combination of vorinostat and 6-TG could potentially overcome innate or acquired resistance to PARPis due to secondary or reversal BRCA mutations, to decreased PARP-1 level or to increased expression of multiple drug resistant proteins. Importantly, drugs which increase phosphorylation of eIF2α may mimic the sensitizing effect of vorinostat on cellular response to PARPis or to 6-TG, without activating all of its downstream effectors.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Benzimidazoles/administration & dosage , Drug Resistance, Neoplasm , Hydroxamic Acids/administration & dosage , Poly (ADP-Ribose) Polymerase-1/antagonists & inhibitors , Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use , Animals , BRCA1 Protein/metabolism , Carrier Proteins/metabolism , Cell Line, Tumor , Cellular Senescence , Eukaryotic Initiation Factor-2/metabolism , Female , Fibroblasts/metabolism , Humans , MCF-7 Cells , Mice , Mice, Nude , Neoplasm Transplantation , Phosphorylation , Plasmids/metabolism , Rad51 Recombinase/metabolism , Recombination, Genetic , Thioguanine/administration & dosage , Vorinostat , Weight Loss
4.
BMC Genomics ; 17: 56, 2016 Jan 14.
Article in English | MEDLINE | ID: mdl-26768750

ABSTRACT

BACKGROUND: The genetic mechanisms underlying hemangioblastoma development are still largely unknown. We used high-resolution single nucleotide polymorphism microarrays and droplet digital PCR analysis to detect copy number variations (CNVs) in total of 45 hemangioblastoma tumors. RESULTS: We identified 94 CNVs with a median of 18 CNVs per sample. The most frequently gained regions were on chromosomes 1 (p36.32) and 7 (p11.2). These regions contain the EGFR and PRDM16 genes. Recurrent losses were located at chromosome 12 (q24.13), which includes the gene PTPN11. CONCLUSIONS: Our findings provide the first high-resolution genome-wide view of chromosomal changes in hemangioblastoma and identify 23 candidate genes: EGFR, PRDM16, PTPN11, HOXD11, HOXD13, FLT3, PTCH, FGFR1, FOXP1, GPC3, HOXC13, HOXC11, MKL1, CHEK2, IRF4, GPHN, IKZF1, RB1, HOXA9, and micro RNA, such as hsa-mir-196a-2 for hemangioblastoma pathogenesis. Furthermore, our data implicate that cell proliferation and angiogenesis promoting pathways may be involved in the molecular pathogenesis of hemangioblastoma.


Subject(s)
DNA Copy Number Variations/genetics , Hemangioblastoma/genetics , Loss of Heterozygosity/genetics , Neoplasm Proteins/genetics , Adult , Aged , Cell Proliferation/genetics , Chromosome Aberrations , Female , Genetic Association Studies , Hemangioblastoma/pathology , Humans , Male , MicroRNAs/genetics , Middle Aged , Oligonucleotide Array Sequence Analysis , Polymerase Chain Reaction/methods , Polymorphism, Single Nucleotide/genetics , Signal Transduction/genetics
5.
BMC Med Genomics ; 8: 68, 2015 Oct 22.
Article in English | MEDLINE | ID: mdl-26493598

ABSTRACT

BACKGROUND: Glioblastoma multiforme (GBM) is the most common and aggressive malignant brain tumor. Even with vigorous surgery, radiation and chemotherapy treatment, survival rates of GBM are very poor and predictive markers for prognosis are currently lacking. METHODS: We performed whole genome expression studies of 67 fresh frozen untreated GBM tumors and validated results by 210 GBM samples' expression data from The Cancer Genome Atlas. RESULTS AND DISCUSSION: Here we show that in GBM patients, high metallothionein (MT) expression is associated with poor survival whereas low MT levels correspond to good prognosis. Furthermore we show that in U87 GBM cell line, p53 is found to be in an inactive mutant-like conformation concurrently with more than 4 times higher MT3 expression level than normal astrocytes and U251GBM cell line. We then show that U87- p53 inactivity can be rescued by zinc (Zn). CONCLUSIONS: Taken together, these data suggest that MT expression may be a potential novel prognostic biomarker for GBM, and that U87 cells may be a good model for patients with non active WT p53 resulting from high levels of MTs.


Subject(s)
Gene Expression Regulation, Neoplastic , Glioblastoma/diagnosis , Glioblastoma/genetics , Metallothionein/genetics , Cell Line, Tumor , Female , Genomics , Glioblastoma/metabolism , Glioblastoma/pathology , Humans , Male , Middle Aged , Prognosis , Survival Rate , Tumor Suppressor Protein p53/metabolism
6.
Histol Histopathol ; 28(2): 211-26, 2013 02.
Article in English | MEDLINE | ID: mdl-23275304

ABSTRACT

Absence of, or loss-of-function mutations in the dysferlin gene (dysf) result in dysferlinopathy, characterized by increased muscle inflammation, collagen deposition and deterioration in muscle function. We evaluated halofuginone efficacy in improving muscle histopathology in mice with deleted dysf transmembrane domain. Quadriceps sublumbar and longissimus muscles of 9-month-old dysf-/- mice treated with halofuginone for 4 months exhibited a reduction in centrally-nucleated myofibers, inflammatory infiltrates and collagen content. Late onset of dysferlinopathy makes it ideal for evaluating the efficacy of early treatments on late outcome. The dysf-/- mice were treated with halofuginone for 3 to 4 months starting at 1, 5 or 9 months of age, and quadricep muscle histopathology was evaluated at 12 months. Collagen content and number of centrally nucleated myofibers decreased after early halofuginone treatment, administered when myofibers with central nuclei and inflammatory infiltrates are evident, but there was almost no fibrosis. When administered at the beginning of fibrosis it resulted in a further decrease in the number of centrally-nucleated myofibers with no additional decrease in collagen levels. Cardiac fibrosis was almost completely abolished following early halofuginone treatment. Halofuginone inhibited Smad3 phosphorylation and its translocation to the nucleus and increased the activity of matrix metalloproteinases 9 and 2 responsible for resolution of pre-existing collagen. Macrophage and myofibroblast invasion into the dystrophic muscle at the site of myofibers with central nuclei was inhibited by halofuginone. These results suggest that early halofuginone treatment can prevent the late outcome of dysferlinopathy and can cause resolution of the established fibrosis when administered at later stages.


Subject(s)
Membrane Proteins/deficiency , Muscle, Skeletal/pathology , Muscular Dystrophies, Limb-Girdle/drug therapy , Muscular Dystrophies, Limb-Girdle/pathology , Piperidines/therapeutic use , Protein Synthesis Inhibitors/therapeutic use , Quinazolinones/therapeutic use , Animals , Collagen/metabolism , Disease Models, Animal , Dysferlin , Fibrosis , Male , Matrix Metalloproteinase 2/metabolism , Matrix Metalloproteinase 9/metabolism , Membrane Proteins/genetics , Membrane Proteins/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Muscle, Skeletal/drug effects , Muscular Dystrophies, Limb-Girdle/metabolism , Phosphorylation/drug effects , Piperidines/pharmacology , Protein Synthesis Inhibitors/pharmacology , Quinazolinones/pharmacology , Smad3 Protein/antagonists & inhibitors , Treatment Outcome
7.
Muscle Nerve ; 42(2): 218-29, 2010 Aug.
Article in English | MEDLINE | ID: mdl-20589893

ABSTRACT

In muscular dystrophies (MD) the loss of muscle and its ability to function are associated with fibrosis. We evaluated the efficacy of halofuginone in reducing fibrosis in the dy(2J)/dy(2J) mouse model of congenital MD. Mice were injected intraperitoneally with 5 microg of halofuginone 3 times a week for 5 or 15 weeks, starting at the age of 3 weeks. Halofuginone caused a reduction in collagen synthesis in hindlimb muscles. This was associated with reductions in the degenerated area, in cell proliferation, in the number of myofibers with central nuclei, with increased myofiber diameter, and with enhanced motor coordination and balance. Halofuginone caused a reduction in infiltrating fibroblasts that were located close to centrally nucleated myofibers. Our results suggest that halofuginone reduced the deleterious effects of fibrosis, thus improving muscle integrity. Halofuginone meets the criteria for a novel antifibrotic therapy for MD patients.


Subject(s)
Laminin/genetics , Muscle, Skeletal/pathology , Muscular Dystrophy, Animal/pathology , Piperidines/pharmacology , Quinazolinones/pharmacology , Animals , Cell Count , Cell Proliferation/drug effects , Collagen/biosynthesis , Fibrosis/drug therapy , Fibrosis/pathology , Mice , Mice, Knockout , Muscle Strength/drug effects , Muscle, Skeletal/drug effects , Muscular Dystrophy, Animal/therapy , Piperidines/therapeutic use , Quinazolinones/therapeutic use , Rotarod Performance Test
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