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: 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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Authors | Alexander J Neuwelt, Tam Nguyen, Y Jeffrey Wu, Andrew M Donson, Rajeev Vibhakar, Sujatha Venkatamaran, Vladimir Amani, Edward A Neuwelt, Louis B Rapkin, Nicholas K Foreman |
Journal | Pediatric blood & cancer
(Pediatr Blood Cancer)
Vol. 61
Issue 1
Pg. 120-7
(Jan 2014)
ISSN: 1545-5017 [Electronic] United States |
PMID | 23956023
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | © 2013 Wiley Periodicals, Inc. |
Chemical References |
- Acetaminophen
- Glutathione
- Cisplatin
- Acetylcysteine
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Topics |
- Acetaminophen
(administration & dosage)
- Acetylcysteine
(administration & dosage)
- Antineoplastic Combined Chemotherapy Protocols
(pharmacology)
- Apoptosis
(drug effects)
- Blotting, Western
- Cell Line, Tumor
- Cisplatin
(administration & dosage)
- Drug Evaluation, Preclinical
- Glutathione
(metabolism)
- Humans
- Membrane Potential, Mitochondrial
(drug effects)
- Rhabdoid Tumor
(metabolism, pathology)
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