TY - JOUR
T1 - Phenylbutyrate, a histone deacetylase inhibitor, protects against Adriamycin-induced cardiac injury
AU - Daosukho, Chotiros
AU - Chen, Yumin
AU - Noel, Teresa
AU - Sompol, Pradoldej
AU - Nithipongvanitch, Ramaneeya
AU - Velez, Joyce M.
AU - Oberley, Terry D.
AU - St. Clair, Daret K.
N1 - Funding Information:
This work was supported by NIH Grants CA 59797 and CA 94853.
PY - 2007/6/15
Y1 - 2007/6/15
N2 - 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 ultrastructual 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.
AB - 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 ultrastructual 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.
KW - Adriamycin
KW - Antioxidant
KW - Heart
KW - Histone deacetylase inhibitor
KW - Mitochondria
KW - Oxidative stress
KW - Sodium phenylbutyrate
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U2 - 10.1016/j.freeradbiomed.2007.03.007
DO - 10.1016/j.freeradbiomed.2007.03.007
M3 - Article
C2 - 17512461
AN - SCOPUS:34248591511
SN - 0891-5849
VL - 42
SP - 1818
EP - 1825
JO - Free Radical Biology and Medicine
JF - Free Radical Biology and Medicine
IS - 12
ER -