Phenylbutyrate, a histone deacetylase inhibitor, protects against Adriamycin-induced cardiac injury.
Cardiac injury is a major complication for oxidative-stress-generating anticancer agents exemplified by Adriamycin (ADR). Recently, several histone deacetylase inhibitors (HDACIs) including phenylbutyrate (PBA) have shown promise in the treatment of cancer with little known toxicity to normal tissues. PBA has been shown to protect against oxidative stress in normal tissues. Here, we examined whether PBA might protect heart against ADR toxicity in a mouse model. The mice were i.p. injected with ADR (20 mg/kg). PBA (400 mg/kg/day) was i.p. injected 1 day before and daily after the ADR injection for 2 days. We found that PBA significantly decreased the ADR-associated elevation of serum lactate dehydrogenase and creatine kinase activities and diminished ADR-induced ultrastructural damages of cardiac tissue by more than 70%. Importantly, PBA completely rescued ADR-caused reduction of cardiac functions exemplified by ejection fraction and fraction shortening, and increased cardiac manganese superoxide dismutase (MnSOD) protein and activity. Our results reveal a previously unrecognized role of HDACIs in protecting against ADR-induced cardiac injury and suggest that PBA may exert its cardioprotective effect, in part, by the increase of MnSOD. Thus, combining HDACIs with ADR could add a new mechanism to fight cancer while simultaneously decrease ADR-induced cardiotoxicity.
Daosukho
Chotiros
C
Graduate Center for Toxicology, University of Kentucky, Lexington, KY 40506, USA.
Chen
Yumin
Y
Noel
Teresa
T
Sompol
Pradoldej
P
Nithipongvanitch
Ramaneeya
R
Velez
Joyce M
JM
Oberley
Terry D
TD
St Clair
Daret K
DK
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D015153:Blotting, Western; D002316:Cardiotonic Agents / Q000627:therapeutic use*; D003402:Creatine Kinase / Q000378:metabolism; D004317:Doxorubicin / Q000633:toxicity*; D004452:Echocardiography; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D056572:Histone Deacetylase Inhibitors; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000187:drug effects; D010654:Phenylbutyrates / Q000627:therapeutic use*; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D002316:Cardiotonic Agents; D056572:Histone Deacetylase Inhibitors; D010654:Phenylbutyrates; C075773:4-phenylbutyric acid; D004317:Doxorubicin; D007770:L-Lactate Dehydrogenase; D013482:Superoxide Dismutase; D003402:Creatine Kinase