Abstract / Summary
Clinical usefulness of trastuzumab (TZ) is restrained owing to its cardiotoxic effect. This investigation was initiated to evaluate the potential protective impact of carnitine (CARN) against TZ-related cardiac influence; and to uncover the underlining mechanism. Cytotoxic effect of TZ, CARN and their combination was assessed in cardiac H9c2 cells. Carnitine pamlitoyltransferase-1B (CPT1B) and adenosine monophosphate activated protein kinase-α2 (AMPK-α2) expression were investigated using quantitative real-time Polymerase Chain Reaction (RT-PCR). Troponin I, creatine kinase-MB (CK-MB), Adenosine triphosphate (ATP), malonyl-CoA, acetyl-CoA carboxylase-2 (ACC2) and autophagy protein 5 (ATG-5) were investigated using Enzyme-linked immunosorbent assay (ELISA). Challenging cardiac cell with TZ resulted in concentration-dependent decrease in cell viability with inhibitory concentration 50 (IC 50 ) of (1.21 uM). Combining TZ’s IC 50 and CARN (5 mM) resulted in the most profound drop of cardiac cellular toxicity. Trastuzumab elevated Troponin I, CK-MB, ACC-2 and Malonyl-CoA, while CARN counteracted this elevation. TZ decreased mRNA expression of AMPK-α2 and CPT1B; as well as ATP and ATG-5 levels, but combination of TZ and CARN counteracted this reduction. TZ disorders AMPK-α2 downstream signaling with the consequent decrease of ATP production and disturbs autophagy. Carnitine tempers TZ-related cardiotoxicity and acts as guard against TZ-related cardiac impact. The current findings are preliminary and highlight the need for additional studies to answer this current research question.