Fibroblast growth factor-16 and acute doxorubicin cardiotoxicity: a target for early protection

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Wang, Jie
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Background: Doxorubicin is an anti-cancer drug that is widely used in chemotherapy. However, doxorubicin-induced cardiotoxicity is a major risk factor for cancer patients and survivors, and can lead to heart failure. Dexrazoxane is the only approved drug to offer protection against doxorubicin-induced cardiotoxicity, but its use is limited. Strategies are needed to protect the heart against doxorubicin-induced cardiotoxicity and still allow its effective treatment of cancer. Fibroblast growth factors (FGFs) are a family of 23 multifunctional proteins, with properties that include effects on cell growth, survival, efflux transport, and cytoprotection. FGF-16 is the only member of the family that is produced preferentially by postnatal cardiac myocytes. Production of cardiac-specific proteins, including α-actin, troponin I, and myosin light chain 2, are often targeted negatively by doxorubicin due to effects at the transcriptional level. In addition, evidence including from FGF-16 null mice that were stressed through chronic high blood pressure, suggests FGF-16 contributes to the maintenance of a healthy myocardium and may have cardioprotective properties. Hypothesis: FGF-16 synthesis (transcription) is an early target of doxorubicin, and decreased endogenous FGF-16 levels will decrease cardiac myocyte survival and, as a result, may contribute to a decreased resistance to heart damage. Thus, maintaining and/or increasing cardiac FGF-16 levels will increase resistance to doxorubicin-induced cardiotoxicity. This is due, at least in part, to a specific effect on efflux drug transport consistent with a decrease in intracellular doxorubicin concentration in cardiac myocytes. Approaches and Results: Using quantitative polymerase chain reaction, FGF-16 messenger RNA levels were significantly decreased within 6 hours of doxorubicin treatment in both 8-week-old rat hearts and neonatal rat cardiac myocytes. The latter was linked to decreased transcription factor Csx/Nkx2.5 association with the FGF-16 gene promoter, based on the results of transient gene transfer, protein binding, and RNA stability assays. Together with the relatively short FGF-16 mRNA half-life (~1.75 hours), FGF-16 is an early target of doxorubicin-induced cardiotoxicity. Furthermore, a decrease in FGF-16 production using FGF-16 siRNA “knockdown” was linked to reduced cardiac myocyte survival, while an increase in FGF-16 levels using adenoviral delivery was associated with resistance to doxorubicin-induced cardiac dysfunction and cardiac myocyte death; the latter corresponded to an increase in efflux transport of calcein AM and doxorubicin. Discussion: Observations made demonstrate that postnatal cardiac-specific FGF-16 synthesis is an early target of acute doxorubicin-induced cardiotoxicity due to a negative effect on the cardiac transcription factor Csx/Nkx2.5 and the relatively unstable FGF-16 transcripts. Endogenous FGF-16 helps maintain neonatal cardiac myocyte viability, while exogenous FGF-16 is protective by, at least in part, upregulation of efflux drug transporters. These observations are consistent with a cardioprotective role for FGF-16.
Fibroblast growth factor 16, doxorubicin, multidrug resistance protein 1, cardioprotection