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

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.

Keywords: Fanconi anemia; ovarian cancer; tumor prevention.

Figure 1:. Atorvastatin/celecoxib administration delayed tumor onset in Fancd2^−/−Trp53^+/− mice.

A). Kaplan-Meier survival curves of the Fancd2^−/−Trp53^+/− mice. The data represent 31 mice for placebo treatment and 29 mice for atorvastatin/celecoxib treatment. B). Kaplan-Meier survival curves of the Fancd2^+/+Trp53^+/− mice. The data represent 30 mice for placebo treatment and 30 mice for atorvastatin/celecoxib treatment. Tumor and selected tissues were fixed in 10% phosphate-buffered formalin and stained with hematoxylin and eosin before being examined under a microscope. The Kaplan-Meier survival curves were generated by Prism 7.0 Software and P values were calculated using the Log-rank (Mantel-Cox) test. NS, ATO, and CEL denote not significant, atorvastatin, and celecoxib, respectively.

Figure 2:. Atorvastatin/celecoxib administration delayed the onset of ovarian tumors in Fancd2^−/−Trp53^+/− mice.

A). Kaplan-Meier ovarian tumor-free survival curves of the Fancd2^−/−Trp53^+/− mice. The data represent 31 mice for placebo treatment and 29 mice for atorvastatin/celecoxib treatment. B). Kaplan-Meier ovarian tumor-free survival curves of the Fancd2^+/+Trp53^+/− mice. The data represent 30 mice for placebo treatment and 30 mice for atorvastatin/celecoxib treatment. NS denotes not significant. NS, ATO, and CEL denote not significant, atorvastatin, and celecoxib, respectively.

Figure 3:. Atorvastatin/celecoxib administration generated no beneficial or detrimental effects on hematopoiesis in Fancd2^−/− mice.

A). Representative flow cytometric profiles of CD34^-KSL cell frequencies in bone marrow after 12-months of atorvastatin/celecoxib administration. The cells were gated on PI^-Lin^- first. B). Quantification of the CD34^-KSL cell frequencies. Data represent 5 mice for each group. PI, NS, ATO, and CEL denote propidium iodide, not significant, atorvastatin, and celecoxib, respectively.