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 (DCm) 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.

Targeted overexpression of mitochondrial catalase protects against cancer chemotherapy-induced skeletal muscle dysfunction

“…The chemotherapeutic agent doxorubicin alone caused the mice to lose weight following exposure, as shown previously (11)(12)(13)32). Whole body fat and lean mass were significantly decreased, a phenomenon that occurs in the clinic.…”

The histone deacetylase inhibitor butyroyloxymethyl diethylphosphate (AN-7) protects normal cells against toxicity of anticancer agents while augmenting their anticancer activity

“…Since we have shown that AN-7 protected cardiomyocytes against Dox toxicity [10], in this study we address the question of whether the combinations of AN-7 and Dox as well as AN-7 and anti-HER2, will display reduced toxicity in normal cells as well as increased anticancer activity against cancer cells. Moreover, we aimed to characterize some of the specific biological changes associated with the response to the treatments in the different cell types.…”

“…At doses of 25-50 mg/kg, it inhibited tumor growth, angiogenesis and metastasis in various mouse cancer models [6][7][8]. Importantly, while AN-7 interacted synergistically with doxorubicin (Dox) in killing cancer cells, as was demonstrated by Median Effect Analysis (MEA) [9], it also protected neonatal rat cardiomyocytes and adult mice against Dox toxicity [10,11].…”

Histone deacetylase inhibitors: the anticancer, antimetastatic and antiangiogenic activities of AN-7 are superior to those of the clinically tested AN-9 (Pivanex)

“…The formaldehyde-releasing prodrugs induce cell death in a variety of cancer cell lines while exhibiting significantly lower toxicity toward human cells including mononuclear, astrocytes and cardiomyocytes [5,6,13]. The observation that AN-7 displays contrasting biological roles toward cancer versus normal myocardial cells, demonstrates a diversity of activity and specificity tailored to particular cell types that is most desirable for an antineoplastic agent.…”

“…We have described the synergistic interaction between AN-7 or AN-9 and Doxorubicin (Dox) [5,8], and the protection provided by the AN-7 against the cardiotoxicity of Dox, where the formaldehyde released intracellularly from the prodrug was shown to be a dominant factor in the cardioprotective activity and in killing cancer cells [13]. The formaldehyde-releasing prodrugs induce cell death in a variety of cancer cell lines while exhibiting significantly lower toxicity toward human cells including mononuclear, astrocytes and cardiomyocytes [5,6,13].…”