| Autor: |
Chintalgattu V; Metabolic Disorders, Amgen Inc., Research, South San Francisco, CA, USA. vishnuc@amgen.com, Rees ML, Culver JC, Goel A, Jiffar T, Zhang J, Dunner K Jr, Pati S, Bankson JA, Pasqualini R, Arap W, Bryan NS, Taegtmeyer H, Langley RR, Yao H, Kupferman ME, Entman ML, Dickinson ME, Khakoo AY |
| Jazyk: |
angličtina |
| Zdroj: |
Science translational medicine [Sci Transl Med] 2013 May 29; Vol. 5 (187), pp. 187ra69. |
| DOI: |
10.1126/scitranslmed.3005066 |
| Abstrakt: |
Sunitinib malate is a multitargeted receptor tyrosine kinase inhibitor used in the treatment of human malignancies. A substantial number of sunitinib-treated patients develop cardiac dysfunction, but the mechanism of sunitinib-induced cardiotoxicity is poorly understood. We show that mice treated with sunitinib develop cardiac and coronary microvascular dysfunction and exhibit an impaired cardiac response to stress. The physiological changes caused by treatment with sunitinib are accompanied by a substantial depletion of coronary microvascular pericytes. Pericytes are a cell type that is dependent on intact platelet-derived growth factor receptor (PDGFR) signaling but whose role in the heart is poorly defined. Sunitinib-induced pericyte depletion and coronary microvascular dysfunction are recapitulated by CP-673451, a structurally distinct PDGFR inhibitor, confirming the role of PDGFR in pericyte survival. Thalidomide, an anticancer agent that is known to exert beneficial effects on pericyte survival and function, prevents sunitinib-induced pericyte cell death in vitro and prevents sunitinib-induced cardiotoxicity in vivo in a mouse model. Our findings suggest that pericytes are the primary cellular target of sunitinib-induced cardiotoxicity and reveal the pericyte as a cell type of concern in the regulation of coronary microvascular function. Furthermore, our data provide preliminary evidence that thalidomide may prevent cardiotoxicity in sunitinib-treated cancer patients. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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