Cardiac fibroblast growth factor‐16 increases efflux drug (ABC) transporter production and resistance to doxorubicin‐induced cardiomyocyte death
Notice bibliographique
Résumé
Doxorubicin (DOX) is a cytotoxic anthracycline antibiotic that is widely used in cancer treatment. However, its cardiotoxic side effects can be fatal, and have long been an issue for cancer patients both in the short and longer term. Strategies are needed to protect the heart. Fibroblast growth factor (FGF) 16 plays an important role in embryonic mouse heart development. After birth, FGF‐16 is predominantly expressed in the myocardium, and is linked to both anti‐fibrotic and anti‐hypertrophic activities. Supplementation with FGF‐16 increases resistance to DOX‐induced loss of ventricular function in an isolated mouse heart model. However, there is no report on the effects of DOX on endogenous FGF‐16 levels or the mechanism(s) for cardioprotection by FGF‐16. ATP‐binding cassette (ABC) transporters are a family of ATP‐dependent membrane proteins that play an important role in drug distribution and excretion. ABC transporters work as pumps effluxing drugs out of the cell immediately after drug entry thereby reducing cellular drug concentration. Drug concentration positively determines the ABC transporter levels. Previously we showed that FGF‐16 can compete with FGF‐2 binding to the same FGF receptors (FGFRs). Unlike FGF‐16, FGF‐2 is not cardiac‐specific but is cardioprotective and known to induce p‐glycoprotein (MDRs) and multidrug resistance‐associated protein (MRPs) expression in neonatal rat cardiomyocytes. Our hypothesis is that FGF‐16 protects cardiomyocytes from DOX‐induced cell death by increasing the levels of ABC drug transporters. Our results show that 1 μM DOX induces a time‐dependent decrease in endogenous FGF‐16 RNA levels with a rapid 80% reduction by 2 hours in neonatal rat cardiomyocytes. Knockdown of endogenous FGF‐16 levels using siRNA results in a significant increase in apoptotic (Annexin‐V positive) and necrotic (LDH release) cells; this is consistent with endogenous FGF‐16 serving as a cardiac maintenance/survival factor. Overexpression of FGF‐16 using adenoviral delivery significantly and specifically increases efflux drug transporter Mdr1a levels in a dose‐dependent manner. Significant decrease in calcein fluorescence intensity in a functional analysis using calcein AM as a substrate for the efflux drug transporters was consistent with the increased levels of drug transporters RNA post FGF‐16 overexpression. In addition, FGF‐16 adenovirus overexpression in cardiomyocytes treated with 1μM DOX significantly decreased the intracellular DOX concentration as measured by DOX autofluorescence. This was associated with a significant reduction in the apoptotic and necrotic cell population, consistent with a decrease in DOX cytotoxicity. Furthermore, inhibition of FGFR signaling using 20 μM SU5402 blocked the increased efflux effect of the ABC transporters. In conclusion , FGF‐16 increases resistance to DOX‐induced injury by increasing efflux drug transporters via binding to the FGFRs. Understanding the effect of FGF‐16 on drug transporter production and function may offer a further target for intervention in the context of DOX and cardiotoxicity. Support or Funding Information Funded by the Canadian Institutes of Health Research and Research Manitoba.
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Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».