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

43 Scopus citations

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

Bibliographical note

Funding Information:
Grant sponsor: Israel Ministry of Science, Art and Sports (AR, GK-I and AN); a grant 542/00-4 from Israel Science Foundation (AR and AN); a project grant from the Israel Cancer Research Fund; Israel Cancer Association; Fellowships from the Ministry of Absorption in Science (IT and NT), Australian Research Council (DRP and SC). SW-Y performed this work as part of the requirement for MSc of the Department of Cell Biology, Sackler School of Medicine, Tel-Aviv University.

Funding

Grant sponsor: Israel Ministry of Science, Art and Sports (AR, GK-I and AN); a grant 542/00-4 from Israel Science Foundation (AR and AN); a project grant from the Israel Cancer Research Fund; Israel Cancer Association; Fellowships from the Ministry of Absorption in Science (IT and NT), Australian Research Council (DRP and SC). SW-Y performed this work as part of the requirement for MSc of the Department of Cell Biology, Sackler School of Medicine, Tel-Aviv University.

FundersFunder number
Israel Ministry of Science, Art and Sports542/00-4
Ministry of Absorption in Science
Israel Cancer Research Fund
Australian Research Council
Israel Cancer Association
Israel Science Foundation

    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