Linked Life Data

18310471

Source:http://linkedlifedata.com/resource/pubmed/id/18310471

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
3
pubmed:dateCreated
2008-5-16
pubmed:abstractText
Inhibitors of histone deacetylases, including suberoylanilide hydroxamic acid (SAHA) and Trichostatin A, are a new class of anticancer agents. With potent chemotherapy effects in cancers, these agents are not obviously toxic in normal nonmalignant cells or tissues. However, their toxicity in kidney cells has not been carefully evaluated. Here, we demonstrate a potent apoptosis-inducing activity of SAHA in cultured renal proximal tubular cells. SAHA induces apoptosis at low micromolar concentrations. At 5 muM, SAHA induces 30 to approximately 40% apoptosis in 18 h. The apoptosis is accompanied by notable caspase activation; however, the general caspase inhibitor VAD can only partially suppress SAHA-induced apoptosis, suggesting the involvement of both caspase-dependent and -independent mechanisms. SAHA treatment leads to cytochrome c release from mitochondria, which is suppressed by Bcl-2 but not by VAD. Bcl-2 consistently blocks SAHA-induced apoptosis. During SAHA treatment, Bcl-2 and Bcl-XL decrease, and Bid is proteolytically cleaved, whereas Bax and Bak expression remains constant. Bid cleavage, but not Bcl-2/Bcl-XL decrease, is completely suppressed by VAD. SAHA does not activate p53, and pifithrin-alpha (a pharmacological p53 inhibitor) does not attenuate SAHA-induced apoptosis, negating a role of p53 in SAHA-induced apoptosis. SAHA induces histone acetylation, which is not affected by VAD, Bcl-2, or pifithrin-alpha. Trichostatin A can also induce apoptosis and histone acetylation in renal tubular cells. Together, the results have shown evidence for renal toxicity of histone deacetylase inhibitors. The toxicity may be related to protein acetylation and decrease of antiapoptotic proteins including Bcl-2 and Bcl-XL.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jun
pubmed:issn
1521-0103
pubmed:author
pubmed:issnType
Electronic
pubmed:volume
325
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
978-84
pubmed:dateRevised
2009-11-19
pubmed:meshHeading
pubmed:year
2008
pubmed:articleTitle
Induction of apoptosis in renal tubular cells by histone deacetylase inhibitors, a family of anticancer agents.
pubmed:affiliation
Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta, GA 30912, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, N.I.H., Extramural