Arginine deprivation by arginine deiminase ofStreptococcus pyogenescontrols primary glioblastoma growthin vitroandin vivo
| Autor: | Claudia Maletzki, Carl Friedrich Classen, Silvio Hering, Michael Linnebacher, Madlen Strauss, Bernd Kreikemeyer, Tomas Fiedler, Ulrike Redanz, Yvonne Rosche, Doreen William |
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| Rok vydání: | 2015 |
| Předmět: |
Male
Cancer Research Combination therapy Arginine Hydrolases Streptococcus pyogenes Argininosuccinate synthase Antineoplastic Agents Mice Inbred Strains Argininosuccinate Synthase Hydroxamic Acids In vivo Cell Line Tumor Antineoplastic Combined Chemotherapy Protocols Animals Humans Benzopyrans Arginine deiminase Cell Proliferation Pharmacology Vorinostat biology Reverse Transcriptase Polymerase Chain Reaction Cell growth Chloroquine DNA Methylation Cell cycle Argininosuccinate Lyase Xenograft Model Antitumor Assays Molecular biology Argininosuccinate lyase Recombinant Proteins Tumor Burden Gene Expression Regulation Neoplastic Treatment Outcome Oncology biology.protein Cancer research Molecular Medicine Glioblastoma Research Paper |
| Zdroj: | Cancer Biology & Therapy. 16:1047-1055 |
| ISSN: | 1555-8576 1538-4047 |
| DOI: | 10.1080/15384047.2015.1026478 |
| Popis: | Arginine auxotrophy constitutes a weak point of several tumors, among them glioblastoma multiforme (GBM). Hence, those tumors are supposed to be sensitive for arginine-depleting substances, such as arginine deiminase (ADI). Here we elucidated the sensitivity of patient-individual GBM cell lines toward Streptococcus pyogenes-derived ADI. To improve therapy, ADI was combined with currently established and pre-clinical cytostatic drugs. Additionally, effectiveness of local ADI therapy was determined in xenopatients. Half of the GBM cell lines tested responded well toward ADI monotherapy. In those cell lines, viability decreased significantly (up to 50 %). Responding cell lines were subjected to combination therapy experiments to test if any additive or even synergistic effects may be achieved. Such promising results were obtained in 2/3 cases. In cell lines HROG02, HROG05 and HROG10, ADI and Palomid 529 combinations were most effective yielding more than 70 % killing after 2 rounds of treatment. Comparable boosted antitumoral effects were observed after adding chloroquine to ADI (>60% killing). Apoptosis, as well as cell cycle dysregulation were found to play a minor role. In some, but clearly not all cases, (epi-) genetic silencing of arginine synthesis pathway genes (argininosuccinate synthetase 1 and argininosuccinate lyase) explained obtained results. In vivo, ADI as well as the combination of ADI and SAHA efficiently controlled HROG05 xenograft growth, whereas adding Palomid 529 to ADI did not further increase the strong antitumoral effect of ADI. The cumulative in vitro and in vivo results proved ADI as a very promising candidate therapeutic, especially for development of adjuvant GBM combination treatments. |
| Databáze: | OpenAIRE |
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