Phenylbutyrate, a histone deacetylase inhibitor, protects against Adriamycin-induced cardiac injury

Chotiros Daosukho, Yumin Chen, Teresa Noel, Pradoldej Sompol, Ramaneeya Nithipongvanitch, Joyce M. Velez, Terry D. Oberley, Daret K. St. Clair

Research output: Contribution to journalArticlepeer-review

90 Scopus citations


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.

Original languageEnglish
Pages (from-to)1818-1825
Number of pages8
JournalFree Radical Biology and Medicine
Issue number12
StatePublished - Jun 15 2007

Bibliographical note

Funding Information:
This work was supported by NIH Grants CA 59797 and CA 94853.


  • Adriamycin
  • Antioxidant
  • Heart
  • Histone deacetylase inhibitor
  • Mitochondria
  • Oxidative stress
  • Sodium phenylbutyrate

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)


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