A comparison of cardiomyocyte cytotoxic mechanisms for 5-fluorouracil and its pro-drug capecitabine

Abstract

1. 5-Fluorouracil (5-FU) and its prodrug capecitabine are key chemotherapeutic agents in the treatment of many gastrointestinal tract adenocarcinomas. In addition to their beneficial antitumor effects, they also possess undesired cardiac toxicity. In the present study, we investigated the cytotoxic mechanisms of 5-FU and capecitabine in freshly isolated rat cardiomyocytes.

2. 5-FU and capecitabine cytotoxicities were associated with reactive oxygen species (ROS) formation, lipid peroxidation and rapid glutathione depletion. Increased intracellular ROS could target mitochondria, and our findings confirmed that the cardiomyocytes mitochondrial membrane potential (ΔΨm) was rapidly decreased by 5-FU and capecitabine. Mitochondrial dysfunction subsequently initiates downstream events that trigger caspase-3 activation, and our results showed that 5-FU and capecitabine activated caspase-3 which leads to apoptosis or necrosis. However, 5-FU acted much more powerful than capecitabine at inducing several cytotoxicity markers in heart cardiomyocytes. In addition, 5-FU but not capecitabine caused lysosomal membrane leakiness when it was incubated with cardiomyocytes. All cytotoxicity markers were prevented by antioxidants, ROS scavengers, mitochondrial permeability transition (MPT) pore sealing agents and lysosomotropic agents.

3. Our findings showed that the cytotoxic action of 5-FU and capecitabine on cardiomyocytes are mediated by oxidative stress and subsequent mitochondrial dysfunction which causes caspase-3 activation and cell death.

• 5-Fluorouracil
• capecitabine
• cardiotoxicity
• caspase-3
• lysosomes
• mitochondria
• oxidative stress

Acknowledgements

The results presented in this paper were partly extracted from thesis of Dr. Faezeh Moghaddam (Pharm.D. graduate of Faculty of Pharmacy, Shahid Beheshti University of Medical Sciences) who performed her thesis under supervision of Professor Jalal Pourahmad. The investigation was carried out in Professor J. Pourahmad's laboratory at the Faculty of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Declaration of interest

The authors declare no conflicts of interest.

This study was supported by a grant from Shahid Beheshti University of Medical Sciences, Deputy of Research (89-01-94-7031, 2010).