Evaluation of resveratrol and <i>N</i>‐acetylcysteine for cancer chemoprevention in a Fanconi anemia murine model

Zhang, Qing Shuo; Marquez-Loza, Laura; Sheehan, Andrea M.; Watanabe-Smith, Kevin; Eaton, Laura; Benedetti, Eric; Major, Angela; Schubert, Kathryn; Deater, Matthew; Joseph, Eric W.; Grompe, Markus

doi:10.1002/pbc.24780

Cited by 14 publications

(13 citation statements)

References 16 publications

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“…38 New therapeutic approaches that have the ability to treat or prevent bone marrow failure and cancer are thus clearly needed for FA. 8,9,20,37,42 Here we show that the widely used diabetes drug metformin improves hematopoiesis and delays tumor formation in Fancd2 2/2 mutant mice. Of note, metformin is the first compound to improve both of these FA phenotypes: oxymetholone, 9 resveratrol, 8 sirtuin activator, 20 and N-acetylcysteine 42 all improve hematopoiesis in Fancd2 2/2 mice, but none has been shown to diminish tumor incidence.…”

Section: Discussionmentioning

confidence: 70%

Metformin improves defective hematopoiesis and delays tumor formation in Fanconi anemia mice

Zhang

Tang

Deater

et al. 2016

Blood

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• The widely used diabetes drug metformin improves hematopoiesis and delays tumor formation in a preclinical murine model of FA.• Metformin reduces DNA damage in human FA patient-derived cells.Fanconi anemia (FA) is an inherited bone marrow failure disorder associated with a high incidence of leukemia and solid tumors. Bone marrow transplantation is currently the only curative therapy for the hematopoietic complications of this disorder. However, long-term morbidity and mortality remain very high, and new therapeutics are badly needed. Here we show that the widely used diabetes drug metformin improves hematopoiesis and delays tumor formation in Fancd2 2/2 mice. Metformin is the first compound reported to improve both of these FA phenotypes. Importantly, the beneficial effects are specific to FA mice and are not seen in the wild-type controls. In this preclinical model of FA, metformin outperformed the current standard of care, oxymetholone, by improving peripheral blood counts in Fancd2 2/2 mice significantly faster. Metformin increased the size of the hematopoietic stem cell compartment and enhanced quiescence in hematopoietic stem and progenitor cells. In tumor-prone Fancd2 2/2 Trp53 1/2 mice, metformin delayed the onset of tumors and significantly extended the tumor-free survival time. In addition, we found that metformin and the structurally related compound aminoguanidine reduced DNA damage and ameliorated spontaneous chromosome breakage and radials in human FA patient-derived cells. Our results also indicate that aldehyde detoxification might be one of the mechanisms by which metformin reduces DNA damage in FA cells. (Blood. 2016; 128(24):2774-2784

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Section: Discussionmentioning

confidence: 70%

Metformin improves defective hematopoiesis and delays tumor formation in Fanconi anemia mice

Zhang

Tang

Deater

et al. 2016

Blood

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“…Fancd2 and Trp53 ‐mutant mice were maintained on the 129S4 strain background as described before . Fancd2 +/− /Trp53/ +/− breeding pairs were crossed to generate female Fancd2 −/− /Trp53 +/− mice and littermate Fancd2 +/+ /Trp53 +/− controls.…”

Section: Methodsmentioning

confidence: 99%

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

Zhang

Deater

Phan

et al. 2018

Pediatric Blood & Cancer

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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. Tumors samples and selected tissues were subjected to histopathological examination. X2 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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“…Thus, a possible attempt to improve FA's clinical course by means of aldehyde detoxifying agents might not compensate the basic-and multi-faceted-pro-oxidant state featured in FA phenotype. A few studies tested some different antioxidants in FA knock-out mice reporting protective effects of some antioxidants (tempol and resveratrol, but not N-acetylcysteine) [74][75][76]. These findings might suggest an appropriate design of further animal studies, and possibly, of clinical trials.…”

Section: Oxidative Stress and Mitochondrial Dysfunction In Fa Phenotypementioning

confidence: 97%

“…A few studies tested some different antioxidants in FA knock‐out mice reporting protective effects of some antioxidants (tempol and resveratrol, but not N‐acetylcysteine) . These findings might suggest an appropriate design of further animal studies, and possibly, of clinical trials.…”

Section: Oxidative Stress and Mitochondrial Dysfunction In Fa Phenotypementioning

confidence: 98%

Fanconi anemia (FA) and crosslinker sensitivity: Re‐appraising the origins of FA definition

Pagano¹,

d’Ischia

Pallardó

2015

Pediatric Blood & Cancer

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The commonly accepted definition of Fanconi anemia (FA) relying on DNA repair deficiency is submitted to a critical review starting from the early reports pointing to mitomycin C bioactivation and to the toxicity mechanisms of diepoxybutane and a group of nitrogen mustards causing DNA crosslinks in FA cells. A critical analysis of the literature prompts revisiting the FA phenotype and crosslinker sensitivity in terms of an oxidative stress (OS) background, redox-related anomalies of FA (FANC) proteins, and mitochondrial dysfunction. This re-appraisal of FA basic defect might lead to innovative approaches both in elucidating FA phenotypes and in clinical management.

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Evaluation of resveratrol and N‐acetylcysteine for cancer chemoprevention in a Fanconi anemia murine model

Cited by 14 publications

References 16 publications

Metformin improves defective hematopoiesis and delays tumor formation in Fanconi anemia mice

Metformin improves defective hematopoiesis and delays tumor formation in Fanconi anemia mice

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

Fanconi anemia (FA) and crosslinker sensitivity: Re‐appraising the origins of FA definition

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