1682P - Anthracycline-induced cardiotoxicity in mice is prevented by late INA inhibition with ranolazine, with improvement in heart function, fibrosis and a...

Date 30 September 2012
Event ESMO Congress 2012
Session Poster presentation II
Topics Cancer Biology
Basic Scientific Principles
Presenter Nicola Maurea
Authors N. Maurea1, C. Coppola2, C. Quintavalle3, D. Rea4, A. Barbieri4, G. Piscopo5, R.V. Iaffaioli5, G. Condorelli3, C. Arra4, C.G. Tocchetti1
  • 1National Cancer Institute, Pascale Foundation, Naples/IT
  • 2Cardiology, National Cancer Institute, Pascale Foundation, Naples/IT
  • 3Biology And Cellular And Molecular Pathology, Federico II University, Naples/IT
  • 4Animal Experimental Research, National Cancer Institute, Pascale Foundation, Naples/IT
  • 5Colorectal Oncology, National Cancer Institute, Pascale Foundation, Naples/IT



Doxorubicin (DOX) produces a well-known cardiomyopathy through multiple mechanisms, which include, among many, Ca2+ overload due to reduced SERCA2a activity and inappropriate opening of the RyR2, and impaired myocardial energetics. DOX generates Reactive Oxygen and Nitrogen Species (ROS and RNS), posing the heart at increased demand for oxygen, setting the stage for metabolic ischemia that also activates late INa, target of ranolazine (RAN). Here, we aim at assessing whether RAN, diminishing intracellular Ca2+ through inhibition of late INa, and enhancing myocardial glucose utilization (and/or reverting impairment of glucose utilization caused by chemotherapy) prevents DOX cardiotoxicity.


We measured left ventricular (LV) function with fractional shortening (FS) by echocardiography in C57BL6 mice, 2-4 mo old, pretreated with RAN (370mg/kg/day, a dose comparable to the one used in humans) per os for 3 days. RAN was then administered for additional 7 days, alone and together with DOX (2.17mg/kg/day ip), according to our well established protocol. Hearts were then excised, mRNA expression was analyzed by qRT- PCR, interstitial fibrosis with picrosirius red staining. By Western blotting, we measured the activation of the apoptotic pathway.


After 7 days with DOX, FS decreased to 50 ± 2%, p = .002 vs 60 ± 1% (sham). RAN alone did not change FS (59 ± 2%). Interestingly, in mice treated with RAN + DOX, the reduction in FS was milder: 57 ± 1%, p = 0.01 vs DOX alone. DOX-cardiotoxicity was accompanied by significant elevations in ANP (1000 folds), BNP (500 folds), CTGF (26 folds) and MMP2 (81 folds) mRNAs, while co-treatment with RAN significantly lowered these same genes compared to DOX. The alterations in extracellular matrix remodeling were confirmed by an increase of interstitial collagen with DOX (3.66%), p = .004 vs 2.19% (sham), which was normal in hearts co-treated with RAN (2.02%, p = .0002 vs DOX). Finally, the levels of PARP and pro-Caspase 3 were significantly decreased in DOX (indicating activation of apoptosis) but not in RAN + DOX.


In mice, RAN prevents DOX cardiotoxic effects. We plan to test RAN as a cardioprotective agent with other antineoplastic cardiotoxic drugs in mice, and to better characterize the cardioprotective mechanisms of RAN in these settings.


All authors have declared no conflicts of interest.