| 1. |
- Alao, John Patrick, 1973, et al.
(författare)
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Inhibition of type I histone deacetylase increases resistance of checkpoint-deficient cells to genotoxic agents through mitotic delay
- 2009
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Ingår i: Molecular Cancer Therapeutics. - 1535-7163 .- 1538-8514. ; 8, s. 2606-2615
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Tidskriftsartikel (refereegranskat)abstract
- Histone deacetylase (HDAC) inhibitors potently inhibit tumor growth and are currently being evaluated for their efficacy as chemosensitizers and radiosensitizers. This efficacy is likely to be limited by the fact that HDACinhibitors also induce cell cycle arrest. Deletion of the class I HDACRpd3 has been shown to specifically suppress the sensitivity of Saccharomyces cerevisiae DNA damage checkpoint mutants to UV and hydroxyurea. We show that in the fission yeast Schizosaccharomyces pombe, inhibition of the homologous class I HDACspe cifically suppresses the DNA damage sensitivity of checkpoint mutants. Importantly, the prototype HDACinhibitor Trichostatin A also suppressed the sensitivity of DNA damage checkpoint but not of DNA repair mutants to UV and HU. TSA suppressed DNA damage activity independently of the mitogen-activated protein kinase–dependent and spindle checkpoint pathways. We show that TSA delays progression into mitosis and propose that this is the main mechanism for suppression of the DNA damage sensitivity of S. pombe checkpoint mutants, partially compensating for the loss of the G2 checkpoint pathway. Our studies also show that the ability of HDACinhibitors to suppress DNA damage sensitivity is not species specific. Class I HDACs are the major target of HDAC inhibitors and cancer cells are often defective in checkpoint activation. Effective use of these agents as chemosensitizers and radiosensitizers may require specific treatment schedules that circumvent their inhibition of cell cycle progression.
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| 2. |
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| 3. |
- Cetinkaya, Cihan, et al.
(författare)
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Combined IFN-gamma and retinoic acid treatment targets the N-Myc/Max/Mad1 network resulting in repression of N-Myc target genes in MYCN-amplified neuroblastoma cells
- 2007
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Ingår i: Molecular Cancer Therapeutics. - 1535-7163 .- 1538-8514. ; 6:10, s. 2634-2641
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Tidskriftsartikel (refereegranskat)abstract
- The MYCN protooncogene is involved in the control of cell proliferation, differentiation, and survival of neuroblasts. Deregulation of MYCN by gene amplification contributes to neuroblastoma development and is strongly correlated to advanced disease and poor outcome, emphasizing the urge for new therapeutic strategies targeting MYCN function. The transcription factor N-Myc, encoded by MYCN, regulates numerous genes together with its partner Max, which also functions as a cofactor for the Mad/Mnt family of Myc antagonists/transcriptional repressors. We and others have previously reported that IFN-gamma synergistically potentiates retinoic acid (RA)induced sympathetic differentiation and growth inhibition in neuroblastoma cells. This study shows that combined treatment of MYCN-amplified neuroblastorna cells with RA+IFN-gamma down-regulates N-Myc protein expression through increased protein turnover, up-regulates Mad1 mRNA and protein, and reduces N-Myc/Max heteroclimerization. This results in a shift of occupancy at the ornithine decarboxylase N-Myc/Mad1 target promoter in vivo from N-Myc/Max to Madl/Max predominance, correlating with histone H4 deacetylation, indicative of a chromatin structure typical of a transcriptionally repressed state. This is further supported by data showing that RA + IFN-gamma treatment strongly represses expression of N-Myc/Mad1 target genes ornithine decarboxylase and hTERT. Our results suggest that combined IFN-gamma and RA signaling can form a basis for new therapeutic strategies targeting N-Myc function for patients with high-risk, MYCN-amplified neuroblastoma.
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| 4. |
- Hernlund, Emma, et al.
(författare)
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Ovarian carcinoma cells with low levels of beta-F1-ATPase are sensitive to combined platinum and 2-deoxy-D-glucose treatment.
- 2009
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Ingår i: Molecular Cancer Therapeutics. - : American Association for Cancer Research. - 1535-7163 .- 1538-8514. ; 8:7, s. 1916-1923
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Tidskriftsartikel (refereegranskat)abstract
- We have here examined chemopotentiating effects of glycolysis inhibitor 2-deoxy-d-glucose (DG) in two epithelial ovarian carcinoma (EOC) cell lines and 17 freshly isolated ascitic EOC cell samples, and we identify low expression of the beta-F1-ATPase involved in mitochondrial ATP production as a candidate marker for sensitivity to this strategy. Although in the majority of samples, DG per se did not induce apoptosis, cotreatment with DG potentiated apoptosis and total antiproliferative effects of cisplatin and, to a lesser degree, carboplatin. In the cell lines, combination treatment with DG and cisplatin or carboplatin at noninhibitory concentrations prevented posttreatment regrowth in drug-free medium over a total of 5 days. DG per se allowed complete recuperation in drug-free medium. The more platinum-resistant a cell line was, the more sensitive it was to potentiation by DG and showed higher glucose uptake, DG-sensitive lactate production, and lower beta-F1-ATPase levels. In the ascitic samples, DG reduced the median IC(50) for cisplatin by 68% and, in the most sensitive samples, up to 90%, and DG-mediated potentiation correlated with low expression of beta-F1-ATPase. By contrast, cisplatin sensitivity did not correlate with beta-F1-ATPase levels. The findings validate targeting cancer cell glucose metabolism for potentiating platinum chemotherapy in EOC and indicate that reduced beta-F1-ATPase/oxidative phosphorylation distinguishes cells that are amenable to this strategy.
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| 5. |
- Johansson, Gunnar, et al.
(författare)
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Effective in vivo targeting of the mammalian target of rapamycin pathway in malignant peripheral nerve sheath tumors.
- 2008
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Ingår i: Molecular Cancer Therapeutics. - 1535-7163 .- 1538-8514. ; 7:5, s. 1237-45
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Tidskriftsartikel (refereegranskat)abstract
- Malignant peripheral nerve sheath tumors (MPNST) are chemoresistant sarcomas with poor 5-year survival that arise in patients with neurofibromatosis type 1 (NF1) or sporadically. We tested three drugs for single and combinatorial effects on collected MPNST cell lines and in MPNST xenografts. The mammalian target of rapamycin complex 1 inhibitor RAD001 (Everolimus) decreased growth 19% to 60% after 4 days of treatment in NF1 and sporadic-derived MPNST cell lines. Treatment of subcutaneous sporadic MPNST cell xenografts with RAD001 significantly, but transiently, delayed tumor growth, and decreased vessel permeability within xenografts. RAD001 combined with the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib caused additional inhibitory effects on growth and apoptosis in vitro, and a small but significant additional inhibitory effect on MPNST growth in vivo that were larger than the effects of RAD001 with doxorubicin. RAD001 plus erlotinib, in vitro and in vivo, reduced phosphorylation of AKT and total AKT levels, possibly accounting for their additive effect. The results support the consideration of RAD001 therapy in NF1 patient and sporadic MPNST. The preclinical tests described allow rapid screening strata for drugs that block MPNST growth, prior to tests in more complex models, and should be useful to identify drugs that synergize with RAD001.
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| 6. |
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| 7. |
- Mani, Katrin, et al.
(författare)
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HIV-Tat protein transduction domain specifically attenuates growth of polyamine deprived tumor cells.
- 2007
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Ingår i: Molecular Cancer Therapeutics. - 1538-8514. ; 6:2, s. 782-788
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Tidskriftsartikel (refereegranskat)abstract
- Polyamines are essential for tumor cell growth, and the polyamine pathway represents an attractive target for cancer treatment. Several polyamine transport proteins have been cloned and characterized in bacteria and yeast cells; however, the mechanism of polyamine entry into mammalian cells remains poorly defined, although a role for proteoglycans has been suggested. Here, we show that the HIV-Tat transduction peptide, which is known to enter cells via a proteoglycan-dependent pathway, efficiently inhibits polyamine uptake. Polyamine uptake–deficient mutant cells with intact proteoglycan biosynthesis (CHO MGBG) displayed unperturbed HIV-Tat uptake activity compared with wild-type cells, supporting the notion that HIV-Tat peptide interferes with polyamine uptake via competition for proteoglycan binding sites rather than a putative downstream transporter. HIV-Tat specifically inhibited growth of human carcinoma cells made dependent on extracellular polyamines by treatment with the polyamine biosynthesis inhibitor {alpha}-difluoromethylornithine; accordingly, the Tat peptide prevented intracellular accumulation of exogenous polyamines. Moreover, combined treatment with {alpha}-difluoromethylornithine and HIV-Tat efficiently blocked tumor growth in an experimental mouse model. We conclude that HIV-Tat transduction domain and polyamines enter cells through a common pathway, which can be used to target polyamine-dependent tumor growth in the treatment of cancer.
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| 8. |
- Pettersson, Helen, et al.
(författare)
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Arsenic trioxide is highly cytotoxic to small cell lung carcinoma cells.
- 2009
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Ingår i: Molecular Cancer Therapeutics. - 1538-8514 .- 1535-7163. ; 8:1, s. 160-170
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Tidskriftsartikel (refereegranskat)abstract
- Small cell lung carcinoma (SCLC) is an extremely aggressive form of cancer and current treatment protocols are insufficient. SCLC have neuroendocrine characteristics and show phenotypical similarities to the childhood tumor neuroblastoma. As multidrug-resistant neuroblastoma cells are highly sensitive to arsenic trioxide (As2O3) in vitro and in vivo, we here studied the cytotoxic effects of As2O3 on SCLC cells. As2O3 induced pronounced cell death in SCLC cells at clinically relevant concentrations, and also at hypoxia. SCLC cells were more sensitive than non-SCLC cells to As2O3. Cell death was mainly due to necrosis, although apoptotic responses were also seen. A significant in vivo effect of As2O3 on SCLC growth was shown in a nude mice-xenograft model, although a fraction of the treated tumor-bearing animals did not respond. The nonresponding SCLC tumors differed in morphology and cell organization compared with treatment-responsive tumors, which in turn, showed decreased vascularization and higher expression of neuroendocrine markers compared with control tumors. Our results suggest a potential clinical application of As2O3 in SCLC therapy. In addition to cell death induction, antiangiogenic induction of differentiation may also be part of the in vivo effect of As2O3 on SCLC growth, as suggested by an increase in neuroendocrine markers in cultured cells.
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| 9. |
- Polischouk, Anya G., et al.
(författare)
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The antipsychotic drug trifluoperazine inhibits DNA repair and sensitizes non-small cell lung carcinoma cells to DNA double-strand break-induced cell death
- 2007
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Ingår i: Molecular Cancer Therapeutics. - 1535-7163 .- 1538-8514. ; 6:8, s. 2303-2309
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Tidskriftsartikel (refereegranskat)abstract
- Trifluoperazine (TFP), a member of the phenothiazine class of antipsychotic drugs, has been shown to augment the cytotoxicity of the DNA-damaging agent bleomycin. In the present study, we investigated the effect of trifluoperazine on (a) survival of bleomycin-treated human non-small cell lung carcinoma U1810 cells, (b) induction and repair of bleomycin-induced DNA strand breaks, and (c) nonhomologous end-joining (NHEJ), the major DNA double-strand break (DSB) repair pathway in mammalian cells. By using a clonogenic survival assay, we show here that concomitant administration of trifluoperazine at a subtoxic concentration enhances the cytotoxicity of bleomycin. Moreover, trifluoperazine also increases the longevity of bleomycin-induced DNA strand breaks in U1810 cells, as shown by both comet assay and fraction of activity released (FAR)-assay. This action seems to be related to suppression of cellular DNA DSB repair activities because NHEJ-mediated rejoining of DSBs occurs with significantly lower efficiency in the presence of trifluoperazine. We propose that TFP might be capable of inhibiting one or more elements of the DNA DSB repair machinery, thereby increasing the cytotoxicity of bleomycin in lung cancer cells.
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| 10. |
- Wickström, Malin, et al.
(författare)
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The novel melphalan prodrug J1 inhibits neuroblastoma growth in vitro and in vivo
- 2007
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Ingår i: Molecular Cancer Therapeutics. - 1535-7163 .- 1538-8514. ; 6:9, s. 2409-2417
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Tidskriftsartikel (refereegranskat)abstract
- Neuroblastoma is the most common extracranial solid tumor of childhood. The activity of J1 (l-melphalanyl-p-l-fluorophenylalanine ethyl ester), an enzymatically activated melphalan prodrug, was evaluated in neuroblastoma models in vitro and in vivo. Seven neuroblastoma cell lines with various levels of drug resistance were screened for cytotoxicity of J1 alone or in combination with standard cytotoxic drugs, using a fluorometric cytotoxicity assay. J1 displayed high cytotoxic activity in vitro against all neuroblastoma cell lines, with IC50 values in the submicromolar range, significantly more potent than melphalan. The cytotoxicity of J1, but not melphalan, could be significantly inhibited by the aminopeptidase inhibitor bestatin. J1 induced caspase-3 cleavage and apoptotic morphology, had additive effects in combination with doxorubicin, cyclophosphamide, carboplatin, and vincristine, and synergistically killed otherwise drug-resistant cells when combined with etoposide. Athymic rats and mice carrying neuroblastoma xenografts [SH-SY5Y, SK-N-BE(2)] were treated with equimolar doses of melphalan, J1, or no drug, and effects on tumor growth and tissue morphology were analyzed. Tumor growth in vivo was significantly inhibited by J1 compared with untreated controls. Compared with melphalan, J1 more effectively inhibited the growth of mice with SH-SY5Y xenografts, was associated with higher caspase-3 activation, fewer proliferating tumor cells, and significantly decreased mean vascular density. In conclusion, the melphalan prodrug J1 is highly active in models of neuroblastoma in vitro and in vivo, encouraging further clinical development in this patient group.
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