Low-dose dasatinib rescues cardiac function in Noonan syndrome

Yi, Jae-Sung; Huang, Yan; Kwaczala, Andrea T.; Kuo, Ivana Y.; Ehrlich, Barbara E.; Campbell, Stuart G.; Giordano, Frank J.; Bennett, Anton M.

doi:10.1172/jci.insight.90220

Cited by 33 publications

(46 citation statements)

References 59 publications

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“…As an alternative to the genetic approach and one potentially applicable to humans, we have exploited the dependence of senescent cells on specific pro-survival pathways and identified a combination of “senolytics” – dasatinib (D; an FDA-approved tyrosine kinase inhibitor 28 ) and quercetin (Q; a flavanol present in many fruits and vegetables 29 ) – that specifically kill senescent cells without affecting proliferating or quiescent, differentiated cells 5 , 6 . To test this approach, 20-month-old male C57BL/6 mice were randomized to either vehicle or D+Q treatment once monthly for 4 months ( Fig.…”

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confidence: 99%

Targeting cellular senescence prevents age-related bone loss in mice

Farr

Weivoda

et al. 2017

Nat Med

808

862

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Aging is associated with increased cellular senescence, which is hypothesized to drive the eventual development of multiple co-morbidities1. Here, we investigate a role for senescent cells in age-related bone loss by multiple approaches. In particular, we used either genetic (i.e., the INK-ATTAC “suicide” transgene encoding an inducible caspase 8 expressed specifically in senescent cells2–4) or pharmacological (i.e., “senolytic” compounds5,6) means to eliminate senescent cells. We also inhibited the production of the pro-inflammatory secretome of senescent cells using a JAK inhibitor (JAKi)3,7. In old (20–22-months) mice with established bone loss, activation of the INK-ATTAC caspase 8 in senescent cells or treatment with senolytics or the JAKi for 2–4 months resulted in higher bone mass and strength and better bone microarchitecture compared to vehicle-treated mice. The beneficial effects of targeting senescent cells were due to lower bone resorption with either maintained (trabecular bone) or higher (cortical bone) bone formation as compared to vehicle-treated mice. In vitro studies demonstrated that senescent cell-conditioned medium impaired osteoblast mineralization and enhanced osteoclast progenitor survival, leading to increased osteoclastogenesis. Collectively, these data establish a causal role for senescent cells in bone loss with aging and demonstrate that targeting these cells has both anti-resorptive and anabolic effects on bone. As eliminating senescent cells and/or inhibiting their pro-inflammatory secretome also improves cardiovascular function4, enhances insulin sensitivity3, and reduces frailty7, targeting this fundamental mechanism to prevent age-related bone loss suggests a novel treatment strategy not only for osteoporosis but also for multiple age-related co-morbidities.

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confidence: 99%

Targeting cellular senescence prevents age-related bone loss in mice

Farr

Weivoda

et al. 2017

Nat Med

808

862

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“…One of the proposed repositioning candidates for LS was dasatinib, a BCR-ABL inhibitor, that was originally designed for treating chronic myelogenous leukemia (CML) and acute lymphoblastic leukemia (ALL). It was reported that a low dose of dasatinib reversed the expression levels of molecular markers of cardiomyopathy and reduced cardiac fibrosis in NS and LS mice with the PTPN11 mutation (Yi et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Drug Repositioning for Noonan and LEOPARD Syndromes by Integrating Transcriptomics With a Structure-Based Approach

et al. 2020

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“…Yi et al . described that, in a murine model of Noonan syndrome and Noonan syndrome with lentigines, the administration of low-dose dasatinib (tyrosine kinase inhibitor) improves cardiomyocyte contractility, reduces fibrosis, and—if administered in utero —rescues HCM phenotype 89 .…”

Section: Detection Of Abnormal Structure and Functionmentioning

confidence: 99%

Recent Advances in Understanding and Managing Cardiomyopathy

Álvarez

Tang

2017

F1000Res

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Cardiomyopathy is a disease of the heart muscle leading to abnormal structure or function in the absence of coronary artery disease, hypertension, or valvular or congenital heart disease. Currently, cardiomyopathy is the leading diagnosis of heart transplant patients worldwide. Incorporation of next-generation sequencing strategies will likely revolutionize genetic testing in cardiomyopathy. The use of patient-specific pluripotent stem cell-derived cardiomyocytes for disease modeling and therapeutic testing has opened a new avenue for precision medicine in cardiomyopathy. Stem cell therapy, gene therapy, interfering RNA, and small molecules are actively being evaluated in clinical trials.

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Low-dose dasatinib rescues cardiac function in Noonan syndrome

Cited by 33 publications

References 59 publications

Targeting cellular senescence prevents age-related bone loss in mice

Targeting cellular senescence prevents age-related bone loss in mice

Drug Repositioning for Noonan and LEOPARD Syndromes by Integrating Transcriptomics With a Structure-Based Approach

Recent Advances in Understanding and Managing Cardiomyopathy

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