title: Preclinical high-dose acetaminophen with N-acetylcysteine rescue enhances the efficacy of cisplatin chemotherapy in atypical teratoid rhabdoid tumors.
abstract: BACKGROUND
  Atypical teratoid rhabdoid tumors (AT-RT) are pediatric tumors of the central nervous system with limited treatment options and poor survival rate. We investigated whether enhancing chemotherapy toxicity by depleting intracellular glutathione (GSH; a key molecule in cisplatin resistance) with high dose acetaminophen (AAP), may improve therapeutic efficacy in AT-RT in vitro.
  
  
  METHODS
  BT16 (cisplatin-resistant) and BT12 (cisplatin-sensitive) AT-RT cell lines were treated with combinations of AAP, cisplatin, and the anti-oxidant N-acetylcysteine (NAC). Cell viability, GSH and peroxide concentrations, mitochondrial damage, and apoptosis were evaluated in vitro.
  
  
  RESULTS
  AAP enhanced cisplatin cytotoxicity in cisplatin-resistant BT16 cells but not cisplatin-sensitive BT12 cells. Baseline GSH levels were elevated in BT16 cells compared to BT12 cells, and AAP decreased GSH to a greater magnitude in BT16 cells than BT12 cells. Unlike BT12 cells, BT16 cells did not have elevated peroxide levels upon treatment with cisplatin alone, but did have elevated levels when treated with AAP + cisplatin. Both cell lines had markedly increased mitochondrial injury when treated with AAP + cisplatin relative to either drug treatment alone. The enhanced toxic effects were partially reversed with concurrent administration of NAC.
  
  
  CONCLUSIONS
  Our results suggest that AAP could be used as a chemo-enhancement agent to potentiate cisplatin chemotherapeutic efficacy particularly in cisplatin-resistant AT-RT tumors with high GSH levels in clinical settings.
authors: University of Colorado, Aurora, Colorado.
authors: Alexander J
authors: AJ
authors: Neuwelt
authors: Tam
authors: T
authors: Nguyen
authors: Y Jeffrey
authors: YJ
authors: Wu
authors: Andrew M
authors: AM
authors: Donson
authors: Rajeev
authors: R
authors: Vibhakar
authors: Sujatha
authors: S
authors: Venkatamaran
authors: Vladimir
authors: V
authors: Amani
authors: Edward A
authors: EA
authors: Neuwelt
authors: Louis B
authors: LB
authors: Rapkin
authors: Nicholas K
authors: NK
authors: Foreman
mesh_terms: D000082:Acetaminophen / Q000008:administration & dosage*; D000111:Acetylcysteine / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage*; D004353:Drug Evaluation, Preclinical; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D018335:Rhabdoid Tumor / Q000378:metabolism / Q000473:pathology
chemical_list: D000082:Acetaminophen; D005978:Glutathione; D002945:Cisplatin; D000111:Acetylcysteine
keywords: N-acetylcysteine; acetaminophen; cisplatin
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