Anticancer prodrugs of butyric acid and formaldehyde protect against doxorubicin-induced cardiotoxicity

A. Rephaeli, S. Waks-Yona, A. Nudelman, I. Tarasenko, N. Tarasenko, D. R. Phillips, S. M. Cutts, G. Kessler-Icekson

Research output: Contribution to journalArticlepeer-review

Abstract

Formaldehyde has been previously shown to play a dominant role in promoting synergy between doxorubicin (Dox) and formaldehyde-releasing butyric acid (BA) prodrugs in killing cancer cells. In this work, we report that these prodrugs also protect neonatal rat cardiomyocytes and adult mice against toxicity elicited by Dox. In cardiomyocytes treated with Dox, the formaldehyde releasing prodrugs butyroyloxymethyl diethylphosphate (AN-7) and butyroyloxymethyl butyrate (AN-1), but not the corresponding acetaldehyde-releasing butyroyloxydiethyl phosphate (AN-88) or butyroyloxyethyl butyrate (AN-11), reduced lactate dehydrogenase leakage, prevented loss of mitochondrial membrane potential (ΔΨm) and attenuated upregulation of the proapoptotic gene Bax. In Dox-treated mice, AN-7 but not AN-88 attenuated weight-loss and mortality, and increase in serum lactate dehydrogenase. These findings show that BA prodrugs that release formaldehyde and augment Dox anticancer activity also protect against Dox cardiotoxicity. Based on these observations, clinical applications of these prodrugs for patients treated with Dox warrant further investigation.

Original languageEnglish
Pages (from-to)1667-1674
Number of pages8
JournalBritish Journal of Cancer
Volume96
Issue number11
DOIs
StatePublished - 4 Jun 2007
Externally publishedYes

Keywords

  • Cardiomyocytes
  • Doxorubicin
  • Formaldehyde
  • Histone acetylation
  • Prodrugs

Fingerprint

Dive into the research topics of 'Anticancer prodrugs of butyric acid and formaldehyde protect against doxorubicin-induced cardiotoxicity'. Together they form a unique fingerprint.

Cite this