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

作者：Wang Jie; Nachtigal Mark W; Kardami Elissavet; Cattini Peter A^*

来源：Cardiovascular Research, 2013, 98(1): 56-63.

DOI：10.1093/cvr/cvt011

• FGF-2
• Doxorubicin
• Cardiac myocytes
• Efflux transport
• Drug resistance

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 ischaemiareperfusion 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. %26lt;br%26gt;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 M 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. %26lt;br%26gt;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.

• 出版日期2013-4-1