Anthracycline toxicity to cardiomyocytes or cancer cells is differently affected by iron chelation with salicylaldehyde isonicotinoyl hydrazone.

Abstract

BACKGROUND AND PURPOSE:

The clinical utility of anthracycline antineoplastic drugs is limited by the risk of cardiotoxicity, which has been traditionally attributed to iron-mediated production of reactive oxygen species (ROS).

EXPERIMENTAL APPROACH:

The aims of this study were to examine the strongly lipophilic iron chelator, salicylaldehyde isonicotinoyl hydrazone (SIH), for its ability to protect rat isolated cardiomyocytes against the toxicity of daunorubicin (DAU) and to investigate the effects of SIH on DAU-induced inhibition of proliferation in a leukaemic cell line. Cell toxicity was measured by release of lactate dehydrogenase and staining with Hoechst 33342 or propidium iodide and lipid peroxidation by malonaldehyde formation.

KEY RESULTS:

SIH fully protected cardiomyocytes against model oxidative injury induced by hydrogen peroxide exposure. SIH also significantly but only partially and with no apparent dose-dependency, reduced DAU-induced cardiomyocyte death. However, the observed protection was not accompanied by decreased lipid peroxidation. In the HL-60 acute promyelocytic leukaemia cell line, SIH did not blunt the antiproliferative efficacy of DAU. Instead, at concentrations that reduced DAU toxicity to cardiomyocytes, SIH enhanced the tumoricidal action of DAU.

CONCLUSIONS AND IMPLICATIONS:

This study demonstrates that iron is most likely involved in anthracycline cardiotoxicity and that iron chelation has protective potential, but apparently through mechanism(s) other than by inhibition of ROS-induced injury. In addition to cardioprotection, iron chelation may have considerable potential to improve the therapeutic action of anthracyclines by enhancing their anticancer efficiency and this potential warrants further investigation.

• Authors: T Simůnek, M Sterba, O Popelová, H Kaiserová, M Adamcová, M Hroch, P Hasková, P Ponka, V Gersl
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 155 Issue 1 Pg. 138-48 (Sep 2008) ISSN: 0007-1188 [Print] England
• PMID: 18536744 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Aldehydes
• Antibiotics, Antineoplastic
• Hydrazones
• Iron Chelating Agents
• salicylaldehyde isonicotinoyl hydrazone
• Malondialdehyde
• Daunorubicin

Topics

• Aldehydes (pharmacology)
• Animals
• Animals, Newborn
• Antibiotics, Antineoplastic (toxicity)
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Cytoprotection
• Daunorubicin (toxicity)
• Dose-Response Relationship, Drug
• HL-60 Cells
• Humans
• Hydrazones (pharmacology)
• Iron Chelating Agents (pharmacology)
• Leukemia, Promyelocytic, Acute (metabolism, pathology)
• Lipid Peroxidation (drug effects)
• Malondialdehyde (metabolism)
• Myocytes, Cardiac (drug effects, metabolism, pathology)
• Oxidative Stress (drug effects)
• Rats
• Rats, Wistar
• Time Factors