Preclinical high-dose acetaminophen with N-acetylcysteine rescue enhances the efficacy of cisplatin chemotherapy in atypical teratoid rhabdoid tumors

Alexander J. Neuwelt, Tam Nguyen, Y. Jeffrey Wu, Andrew M. Donson, Rajeev Vibhakar, Sujatha Venkatamaran, Vladimir Amani, Edward Neuwelt, Louis B. Rapkin, Nicholas K. Foreman

Research output: Contribution to journalArticle

7 Citations (Scopus)

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. Procedure: BT16 (cisplatin-resistant) and BT12 (cisplatin-sensitive) AT-RT cell lines were treated with combinations of AAP, cisplatin, and the anti-oxidantN-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.

Original languageEnglish (US)
Pages (from-to)120-127
Number of pages8
JournalPediatric Blood and Cancer
Volume61
Issue number1
DOIs
StatePublished - 2014

Fingerprint

Acetylcysteine
Acetaminophen
Cisplatin
Drug Therapy
Peroxides
Atypical Teratoid Tumor
Typical Teratoid Rhabdoid Tumor
Central Nervous System Neoplasms
Poisons
Therapeutics
Tumor Cell Line
Glutathione
Cell Survival
Pediatrics
Apoptosis

Keywords

  • Acetaminophen
  • Cisplatin
  • N-acetylcysteine

ASJC Scopus subject areas

  • Oncology
  • Pediatrics, Perinatology, and Child Health
  • Hematology
  • Medicine(all)

Cite this

Preclinical high-dose acetaminophen with N-acetylcysteine rescue enhances the efficacy of cisplatin chemotherapy in atypical teratoid rhabdoid tumors. / Neuwelt, Alexander J.; Nguyen, Tam; Wu, Y. Jeffrey; Donson, Andrew M.; Vibhakar, Rajeev; Venkatamaran, Sujatha; Amani, Vladimir; Neuwelt, Edward; Rapkin, Louis B.; Foreman, Nicholas K.

In: Pediatric Blood and Cancer, Vol. 61, No. 1, 2014, p. 120-127.

Research output: Contribution to journalArticle

Neuwelt, AJ, Nguyen, T, Wu, YJ, Donson, AM, Vibhakar, R, Venkatamaran, S, Amani, V, Neuwelt, E, Rapkin, LB & Foreman, NK 2014, 'Preclinical high-dose acetaminophen with N-acetylcysteine rescue enhances the efficacy of cisplatin chemotherapy in atypical teratoid rhabdoid tumors', Pediatric Blood and Cancer, vol. 61, no. 1, pp. 120-127. https://doi.org/10.1002/pbc.24602
Neuwelt, Alexander J. ; Nguyen, Tam ; Wu, Y. Jeffrey ; Donson, Andrew M. ; Vibhakar, Rajeev ; Venkatamaran, Sujatha ; Amani, Vladimir ; Neuwelt, Edward ; Rapkin, Louis B. ; Foreman, Nicholas K. / Preclinical high-dose acetaminophen with N-acetylcysteine rescue enhances the efficacy of cisplatin chemotherapy in atypical teratoid rhabdoid tumors. In: Pediatric Blood and Cancer. 2014 ; Vol. 61, No. 1. pp. 120-127.
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AU - Donson, Andrew M.

AU - Vibhakar, Rajeev

AU - Venkatamaran, Sujatha

AU - Amani, Vladimir

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AU - Foreman, Nicholas K.

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AB - 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. Procedure: BT16 (cisplatin-resistant) and BT12 (cisplatin-sensitive) AT-RT cell lines were treated with combinations of AAP, cisplatin, and the anti-oxidantN-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.

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