166P - Doxorubicin-cardiotoxicity is blunted if ranolazine is administered after doxorubicin treatment, in experimental models

Date 28 September 2014
Event ESMO 2014
Session Poster Display session
Topics Anti-Cancer Agents & Biologic Therapy
Complications of Treatment
Basic Science
Presenter Rosario Iaffaioli
Citation Annals of Oncology (2014) 25 (suppl_4): iv53-iv57. 10.1093/annonc/mdu325
Authors R.V. Iaffaioli1, C. Coppola2, G. Piscopo2, D. Rea3, F. Galletta2, C. Maurea2, C. Arra3, N. Maurea4
  • 1Dipartimento Di Oncologia Addominale, Istituto Nazionale Tumori – I.R.C.C.S - Fondazione Pascale, 80131 - Napoli/IT
  • 2Cardiology, National Cancer Institute, Pascale Foundation, Naples/IT
  • 3Animal Experimental Research, National Cancer Institute, Pascale Foundation, Naples/IT
  • 4Cardiology, INT Pascale Naples, 80131 - Naples/IT

Abstract

Aim

Anthracyclines are first line drugs against cancer, but produce a well-known cardiomyopathy through multiple mechanisms, which also include, among many, Ca2+ overload due to reduced SERCA2a activity and inappropriate opening of the RyR2, and impaired myocardial energetics. Anthracyclines generate Reactive Oxigen and Nitrogen Species (ROS and RNS), posing the heart at increased demand for oxygen, thus setting the stage for a metabolic ischemia that also activates late INa, the target of Ranolazine (RAN). Here, we aim at assessing whether RAN, diminishing intracellular Ca2+ through its inhibition of late INa blunts anthracyclines cardiotoxicity.

Methods

To evaluate cardiac function in vivo, fractional shortening (FS) and ejection fraction (EF) were measured by M/B mode echocardiography and radial and longitudinal strain (RS and LS) were measured using 2D speckle-tracking ecocardiography, in C57/BL6 mice, 2-4 mo old, at day 0, and after 2 and 7 days of daily administration of Doxorubicin (Doxo, 2.17 mg/kg/day, ip). These measurements were repeated after 5 days of RAN treatment (750 mg/kg/day, a dose comparable to the one used in humans) iniziated at the end of Doxo treatment.

Results

In our in vivo studies, after 7 days with Doxo, FS decreased to 50.5 ± 8.4%, p < 0.05 vs 61.5 ± 1% (sham), EF to 82.2 ± 8.1%, p < 0.05 vs 91.3 ± 0.5% (sham), RS to 14.3 ± 4.7%, p < 0.01 vs 40.5 ± 4.8% (sham), and LS to -16.6 ± 7.9%, p < 0.01 vs -38.8 ± 6% (sham). Interestingly, in mice treated with Ran after Doxo treatment, indices of cardiac function recovered: FS was 61.5 ± 1.1%, EF was 91.25 ± 1.1%, p < 0.01 vs mice treated with Doxo for 7 days; RS was 29.5 ± 3.4%, p < 0.05 vs mice treated with Doxo for 7 days; however persists after treatment with RAN, the alteration of LS (-25.5 ± 6.3%, p = 0.16).

Conclusions

RAN post-treatment blunts cardiotoxic effects due to anthracyclines, as demonstrated by the normalization of the values of FS, EF and RS. It remains to explain the persistent abnormality of the LS.

Disclosure

All authors have declared no conflicts of interest.