title: Asparagine depletion potentiates the cytotoxic effect of chemotherapy against brain tumors.
abstract: Targeting amino acid metabolism has therapeutic implications for aggressive brain tumors. Asparagine is an amino acid that is synthesized by normal cells. However, some cancer cells lack asparagine synthetase (ASNS), the key enzyme for asparagine synthesis. Asparaginase (ASNase) contributes to eradication of acute leukemia by decreasing asparagine levels in serum and cerebrospinal fluid. However, leukemic cells may become ASNase-resistant by upregulating ASNS. High expression of ASNS has also been associated with biologic aggressiveness of other cancers, including gliomas. Here, the impact of enzymatic depletion of asparagine on proliferation of brain tumor cells was determined. ASNase was used as monotherapy or in combination with conventional chemotherapeutic agents. Viability assays for ASNase-treated cells demonstrated significant growth reduction in multiple cell lines. This effect was reversed by glutamine in a dose-dependent manner--as expected, because glutamine is the main amino group donor for asparagine synthesis. ASNase treatment also reduced sphere formation by medulloblastoma and primary glioblastoma cells. ASNase-resistant glioblastoma cells exhibited elevated levels of ASNS mRNA. ASNase cotreatment significantly enhanced gemcitabine or etoposide cytotoxicity against glioblastoma cells. Xenograft tumors in vivo showed no significant response to ASNase monotherapy and little response to temozolomide alone. However, combinatorial therapy with ASNase and temozolomide resulted in significant growth suppression for an extended duration of time. Taken together, these findings indicate that amino acid depletion warrants further investigation as adjunctive therapy for brain tumors.
  
  
  CONCLUSIONS
  Findings have potential impact for providing adjuvant means to enhance brain tumor chemotherapy.
authors: Authors' Affiliations: Department of Pediatrics, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, Torrance; Departments of 2Psychiatry and Molecular and Medical Pharmacology and 3Pediatrics; and 4The Jonsson Comprehensive Cancer Center, University of California Los Angeles (UCLA), Los Angeles, California.
authors: Eduard H
authors: EH
authors: Panosyan
authors: Yuntao
authors: Y
authors: Wang
authors: Peng
authors: P
authors: Xia
authors: Wai-Nang Paul
authors: WN
authors: Lee
authors: Youngju
authors: Y
authors: Pak
authors: Dan R
authors: DR
authors: Laks
authors: Henry J
authors: HJ
authors: Lin
authors: Theodore B
authors: TB
authors: Moore
authors: Timothy F
authors: TF
authors: Cloughesy
authors: Harley I
authors: HI
authors: Kornblum
authors: Joseph L
authors: JL
authors: Lasky
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001215:Asparaginase / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D001216:Asparagine / Q000172:deficiency* / Q000378:metabolism; D001217:Aspartate-Ammonia Ligase / Q000378:metabolism; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D004249:DNA Damage; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D004357:Drug Synergism; D005909:Glioblastoma / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D005973:Glutamine / Q000494:pharmacology; D006801:Humans; D008297:Male; D008527:Medulloblastoma / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D000077204:Temozolomide; D023041:Xenograft Model Antitumor Assays
chemical_list: D005973:Glutamine; D001216:Asparagine; D003606:Dacarbazine; D001215:Asparaginase; D001217:Aspartate-Ammonia Ligase; D000077204:Temozolomide