Combination therapy with atorvastatin and celecoxib delays tumor formation in a Fanconi anemia mouse model

Qing-Shuo Zhang, Matthew Deater, Ngoc Phan, Andrea Marcogliese, Angela Major, Eva C. Guinan, Markus Grompe

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Background: Fanconi anemia is an inherited bone marrow failure disorder associated with a high incidence of leukemia and solid tumors. Currently, no interventions to prevent or delay the formation of solid tumors are available. Procedure: Two of the most important hallmarks of Fanconi anemia are inflammation and oxidative stress. In this study, we administrated the antioxidant atorvastatin and the anti-inflammatory drug celecoxib to cohorts of Fancd2−/−/Trp53+/− mice, a model of Fanconi anemia. Treatment started at weaning and continued until the mice developed a palpable mass or suffered from >20% weight loss. Tumor samples and selected tissues were subjected to histopathological examination. χ2 test was performed to analyze tumor incidence, and Kaplan–Meier survival curves were evaluated with log-rank test. In addition, a small cohort of mice was monitored for the safety of the drugs. Results: The combined oral administration of both drugs significantly delayed tumor onset in Fancd2−/−/Trp53+/− mice. Specifically, the treatment delayed the onset of ovarian tumors in Fancd2−/−/Trp53+/− mice and increased the mean ovarian tumor-free survival time by 17%, whereas this combinatorial drug regimen did not have a significant effect on other tumor types. In addition, no detrimental effects on hematopoiesis from the drug treatment were observed during a 12-month safety monitoring. Conclusions: The data presented here suggest that a combination of atorvastatin and celecoxib may be a good candidate for chemoprevention in Fanconi anemia.

Original languageEnglish (US)
JournalPediatric Blood and Cancer
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Celecoxib
Fanconi Anemia
Neoplasms
Therapeutics
Pharmaceutical Preparations
Safety
Atorvastatin Calcium
Incidence
Hematopoiesis
Chemoprevention
Weaning

Keywords

  • Fanconi anemia
  • ovarian cancer
  • tumor prevention

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Hematology
  • Oncology

Cite this

Combination therapy with atorvastatin and celecoxib delays tumor formation in a Fanconi anemia mouse model. / Zhang, Qing-Shuo; Deater, Matthew; Phan, Ngoc; Marcogliese, Andrea; Major, Angela; Guinan, Eva C.; Grompe, Markus.

In: Pediatric Blood and Cancer, 01.01.2018.

Research output: Contribution to journalArticle

Zhang, Qing-Shuo ; Deater, Matthew ; Phan, Ngoc ; Marcogliese, Andrea ; Major, Angela ; Guinan, Eva C. ; Grompe, Markus. / Combination therapy with atorvastatin and celecoxib delays tumor formation in a Fanconi anemia mouse model. In: Pediatric Blood and Cancer. 2018.
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abstract = "Background: Fanconi anemia is an inherited bone marrow failure disorder associated with a high incidence of leukemia and solid tumors. Currently, no interventions to prevent or delay the formation of solid tumors are available. Procedure: Two of the most important hallmarks of Fanconi anemia are inflammation and oxidative stress. In this study, we administrated the antioxidant atorvastatin and the anti-inflammatory drug celecoxib to cohorts of Fancd2−/−/Trp53+/− mice, a model of Fanconi anemia. Treatment started at weaning and continued until the mice developed a palpable mass or suffered from >20{\%} weight loss. Tumor samples and selected tissues were subjected to histopathological examination. χ2 test was performed to analyze tumor incidence, and Kaplan–Meier survival curves were evaluated with log-rank test. In addition, a small cohort of mice was monitored for the safety of the drugs. Results: The combined oral administration of both drugs significantly delayed tumor onset in Fancd2−/−/Trp53+/− mice. Specifically, the treatment delayed the onset of ovarian tumors in Fancd2−/−/Trp53+/− mice and increased the mean ovarian tumor-free survival time by 17{\%}, whereas this combinatorial drug regimen did not have a significant effect on other tumor types. In addition, no detrimental effects on hematopoiesis from the drug treatment were observed during a 12-month safety monitoring. Conclusions: The data presented here suggest that a combination of atorvastatin and celecoxib may be a good candidate for chemoprevention in Fanconi anemia.",
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