Ranolazine Attenuates Trastuzumab-Induced Heart Dysfunction by Modulating ROS Production

Area of Science:

• Cardiology
• Oncology
• Pharmacology

Background:

• Trastuzumab, an ErbB2 blocker, enhances cancer patient survival but poses a risk of cardiotoxicity.
• Ranolazine, a late Na+ current inhibitor, mitigates experimental heart failure and doxorubicin-induced cardiotoxicity by reducing reactive oxygen species (ROS).
• ErbB2 signaling pathways may influence ROS, suggesting a potential link to trastuzumab cardiotoxicity.

Purpose of the Study:

• To investigate if ranolazine can prevent trastuzumab-induced cardiotoxicity.
• To explore the role of redox-mediated mechanisms in this protective effect.
• To determine if ranolazine's action involves the inhibition of the late Na+ current (I_Na).

Main Methods:

• Co-administration of trastuzumab and ranolazine in a mouse model.
• Assessment of cardiac function (fractional shortening, ejection fraction).
• Measurement of natriuretic peptides and matrix metalloproteinase 2 (MMP2) mRNA levels.
• Evaluation of caspase-3 cleavage as an indicator of apoptosis.
• In vitro studies using Neonatal Rat Ventricular Myocytes (NRVMs) subjected to oxidative stress.

Main Results:

• Ranolazine prevented the decrease in fractional shortening and ejection fraction caused by trastuzumab.
• Trastuzumab-induced elevations in natriuretic peptides and MMP2 mRNA were abolished by ranolazine.
• Ranolazine inhibited trastuzumab-induced caspase-3 cleavage, indicating reduced apoptosis.
• In NRVMs, ranolazine blunted oxidative stress induced by trastuzumab and isoproterenol.

Conclusions:

• Ranolazine effectively prevents trastuzumab-mediated cardiotoxicity in mice.
• The protective mechanism involves the regulation of redox balance and inhibition of apoptosis.
• These findings suggest that ranolazine may be a viable co-treatment to mitigate cardiotoxicity in patients receiving trastuzumab.