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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. ?2 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.

SUBMITTER: Zhang QS

PROVIDER: S-EPMC6249055 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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

Zhang Qing-Shuo QS Deater Matthew M Phan Ngoc N Marcogliese Andrea A Major Angela A Guinan Eva C EC Grompe Markus M

Pediatric blood & cancer 20180925 1

<h4>Background</h4>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.<h4>Procedure</h4>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<sup>-/-</sup> /Trp53<sup>+/-</su ...[more]

PMID: 30255556

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Project description:BackgroundAbdominal aortic aneurysm (AAA) is a life-threatening vascular disease. It is controversial whether statin and calcium channel blockers (CCBs) has an inhibitory effect on the expansion of AAA. Some studies reported that CCBs have an inhibitory effect on Rho-kinase activity. Rho-kinase plays an important role in the pathogenesis of various cardiovascular diseases. However, there is no study reporting of the association between Rho-kinase and human AAAs.Methods and resultsExperimental AAA was induced in Apolipoprotein E-deficient (ApoE(-/-)) mice infused with angiotensin II (AngII) for 28 days. They were randomly divided into the following 5 groups; saline infusion alone (sham), AngII infusion alone, AngII infusion plus atorvastatin (10 mg/kg/day), AngII infusion plus amlodipine (1 mg/kg/day), and AngII infusion plus combination therapy with atorvastatin (10 mg/kg/day) and amlodipine (1 mg/kg/day). The combination therapy significantly suppressed AngII-induced increase in maximal aortic diameter as compared with sham, whereas each monotherapy had no inhibitory effects. The combination therapy significantly reduced AngII-induced apoptosis and elastin degradation at the AAA lesion, whereas each monotherapy did not. Moreover, Rho-kinase activity, as evaluated by the extent of phosphorylation of myosin-binding subunit (a substrate of Rho-kinase) and matrix metalloproteinase activity were significantly increased in the AngII-induced AAA lesion as compared with sham, both of which were again significantly suppressed by the combination therapy. In human aortic samples, immunohistochemistory revealed that the activity and expression of Rho-kinase was up-regulated in AAA lesion as compared with abdominal aorta from control subjects.ConclusionsRho-kinase is up-regulated in the aortic wall of human AAA. The combination therapy with amlodipine and Atorvastatin, but not each monotherapy, suppresses AngII-induced AAA formation in mice in vivo, for which Rho-kinase inhibition may be involved.

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

Publications

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

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