title: Arginine deprivation by arginine deiminase of Streptococcus pyogenes controls primary glioblastoma growth in vitro and in vivo.
abstract: 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.
authors.affiliation: a Institute for Medical Microbiology, Virology, and Hygiene; Rostock University Medical Centre ; Rostock , Germany.
authors.forename: Tomas
authors.initials: T
authors.lastname: Fiedler
authors.forename: Madlen
authors.initials: M
authors.lastname: Strauss
authors.forename: Silvio
authors.initials: S
authors.lastname: Hering
authors.forename: Ulrike
authors.initials: U
authors.lastname: Redanz
authors.forename: Doreen
authors.initials: D
authors.lastname: William
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Rosche
authors.forename: Carl Friedrich
authors.initials: CF
authors.lastname: Classen
authors.forename: Bernd
authors.initials: B
authors.lastname: Kreikemeyer
authors.forename: Michael
authors.initials: M
authors.lastname: Linnebacher
authors.forename: Claudia
authors.initials: C
authors.lastname: Maletzki
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001120:Arginine / Q000378:metabolism*; D001123:Argininosuccinate Lyase / Q000235:genetics; D001124:Argininosuccinate Synthase / Q000235:genetics; D001578:Benzopyrans / Q000008:administration & dosage; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D002738:Chloroquine / Q000008:administration & dosage; D019175:DNA Methylation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006867:Hydrolases / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D006877:Hydroxamic Acids / Q000008:administration & dosage; D008297:Male; D008815:Mice, Inbred Strains; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013297:Streptococcus pyogenes / Q000201:enzymology; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics; D000077337:Vorinostat; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001578:Benzopyrans; D006877:Hydroxamic Acids; D011994:Recombinant Proteins; D000077337:Vorinostat; D002738:Chloroquine; D001120:Arginine; D006867:Hydrolases; C019723:arginine deiminase; D001123:Argininosuccinate Lyase; D001124:Argininosuccinate Synthase; C533469:palomid 529
keywords: ADI, arginine deiminase; ASL, argininosuccinate lyase; Arg, L-Arginine; GBM, Glioblastoma multiforme, ASS1, argininosuccinate synthetase 1; SAHA, suberoylanilide hydroxamic acid; arginine-catabolizing enzymes; cellular metabolism; combination therapy; patient-derived GBM cell lines; xenopatient