FGF-2 protects cardiomyocytes from doxorubicin damage via protein kinase C-dependent effects on efflux transporters.

Abstract

AIMS:

The anti-cancer anthracycline doxorubicin (DOX) increases the risk of cardiac damage, indicating a need to protect the heart and still allow the benefits of drug treatment. Fibroblast growth factor-2 (FGF-2) is cardioprotective against ischaemia-reperfusion injury. Our aim is to investigate: (i) the ability of FGF-2 to protect against DOX-induced cardiomyocyte damage and (ii) the contribution of efflux drug transport to any increase in injury-resistance.

METHODS AND RESULTS:

Neonatal rat cardiomyocyte damage was assessed by measuring cell death markers and lactate dehydrogenase (LDH) activity in the culture medium. LDH activity was increased significantly after incubation with 0.5 μM DOX for 24 h in the absence but not presence of 10 nM FGF-2; this beneficial effect of FGF-2 was blocked by tyrosine kinase (FGF) receptor inhibition. An increase in efflux drug transporter RNA levels was also detected after FGF-2 treatment in the presence of DOX. The beneficial effect of FGF-2 against cell damage and increased transporter RNA levels were blunted with protein kinase C (PKC) inhibition. Finally, FGF-2 stimulated efflux transport of calcein and DOX, and treatment with efflux transporter inhibitors significantly attenuated the protective effect of FGF-2 from DOX-induced injury.

CONCLUSION:

Administered FGF-2 increases resistance to DOX-induced cardiomyocyte damage, by a mechanism dependent on PKC as well as regulation of efflux transporter production and/or function.

• Authors: Jie Wang, Mark W Nachtigal, Elissavet Kardami, Peter A Cattini
• Journal: Cardiovascular research (Cardiovasc Res) Vol. 98 Issue 1 Pg. 56-63 (Apr 01 2013) ISSN: 1755-3245 [Electronic] England
• PMID: 23341575 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• ATP-Binding Cassette Transporters
• Abcc2 protein, rat
• Antibiotics, Antineoplastic
• Membrane Transport Proteins
• Multidrug Resistance-Associated Proteins
• Fibroblast Growth Factor 2
• Doxorubicin
• Cyclosporine
• L-Lactate Dehydrogenase
• Protein Kinase C
• multidrug resistance-associated protein 1

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (genetics, physiology)
• ATP-Binding Cassette Transporters (genetics, physiology)
• Animals
• Antibiotics, Antineoplastic (toxicity)
• Cyclosporine (pharmacology)
• Doxorubicin (toxicity)
• Fibroblast Growth Factor 2 (pharmacology)
• L-Lactate Dehydrogenase (metabolism)
• Membrane Transport Proteins (physiology)
• Multidrug Resistance-Associated Proteins (genetics, physiology)
• Myocytes, Cardiac (drug effects)
• Protein Kinase C (antagonists & inhibitors, physiology)
• Rats
• Rats, Sprague-Dawley