title: Anticancer prodrugs of butyric acid and formaldehyde protect against doxorubicin-induced cardiotoxicity.
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 (DeltaPsim) 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.
authors.affiliation: Sackler Faculty of Medicine, Felsenstein Medical Research Center, Tel-Aviv University, Beilinson Campus, Petach-Tikva, 49100, Israel. adarep@post.tau.ac.il
authors.forename: A
authors.initials: A
authors.lastname: Rephaeli
authors.forename: S
authors.initials: S
authors.lastname: Waks-Yona
authors.forename: A
authors.initials: A
authors.lastname: Nudelman
authors.forename: I
authors.initials: I
authors.lastname: Tarasenko
authors.forename: N
authors.initials: N
authors.lastname: Tarasenko
authors.forename: D R
authors.initials: DR
authors.lastname: Phillips
authors.forename: S M
authors.initials: SM
authors.lastname: Cutts
authors.forename: G
authors.initials: G
authors.lastname: Kessler-Icekson
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D002087:Butyrates; D020148:Butyric Acid / Q000378:metabolism / Q000494:pharmacology*; D002478:Cells, Cultured; D019610:Cytoprotection / Q000187:drug effects*; D004317:Doxorubicin / Q000633:toxicity*; D004353:Drug Evaluation, Preclinical; D005260:Female; D005557:Formaldehyde / Q000378:metabolism / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006655:Histone Deacetylases / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D010755:Organophosphates / Q000494:pharmacology*; D009943:Organophosphorus Compounds; D011355:Prodrugs / Q000494:pharmacology*; D051381:Rats
chemical_list: D000970:Antineoplastic Agents; D002087:Butyrates; D010755:Organophosphates; D009943:Organophosphorus Compounds; D011355:Prodrugs; C502471:diethoxyphosphoryloxymethyl butanoate; D020148:Butyric Acid; D005557:Formaldehyde; D004317:Doxorubicin; D006655:Histone Deacetylases