Pifithrin-α protects against doxorubicin-induced apoptosis and acute cardiotoxicity in mice

Liu, Xuwan; Chua, Chu Chang; Gao, Jinping; Chen, Zhongyi; Landy, Cathy; Hamdy, Ronald C.; Chua, Balvin H.L.

doi:10.1152/ajpheart.00759.2003

Cited by 156 publications

(141 citation statements)

References 38 publications

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“…Promotion of p53 activity, already shown in other biological contexts, is prompted by nucleolar stress in an early cellular response preceding p53 activation and the induction of a suicide signal program (1,3,4,26,27). Although the importance of multiple pathways to explain DOX-mediated pathogenesis should not be underestimated, data presented herein implicate nucleolar stress as an important mechanism of DOX cardiotoxicity and corroborate reports that DOX cardiotoxic effects are ameliorated by p53 inhibition (37)(38)(39).…”

Section: Discussionsupporting

confidence: 86%

Nucleolar stress is an early response to myocardial damage involving nucleolar proteins nucleostemin and nucleophosmin

Avitabile

Bailey

Cottage

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Nucleolar stress, characterized by loss of nucleolar integrity, has not been described in the cardiac context. In addition to ribosome biogenesis, nucleoli are critical for control of cell proliferation and stress responses. Our group previously demonstrated induction of the nucleolar protein nucleostemin (NS) in response to cardiac pathological insult. NS interacts with nucleophosmin (NPM), a marker of nucleolar stress with cytoprotective properties. The dynamic behavior of NS and NPM reveal that nucleolar disruption is an early event associated with stress response in cardiac cells. Rapid translocation of NS and NPM to the nucleoplasm and suppression of new preribosomal RNA synthesis occurs in both neonatal rat cardiomyocytes (NRCM) and cardiac progenitor cells (CPC) upon exposure to doxorubicin or actinomycin D. Silencing of NS significantly increases cell death resulting from doxorubicin treatment in CPC, whereas NPM knockdown alone induces cell death. Overexpression of either NS or NPM significantly decreases caspase 8 activity in cultured cardiomyocytes challenged with doxorubicin. The presence of altered nucleolar structures resulting from myocardial infarction in mice supports the model of nucleolar stress as a general response to pathological injury. Collectively, these findings serve as the initial description of myocardial nucleolar stress and establish the postulate that nucleoli acts as sensors of stress, regulating the cellular response to pathological insults.nucleolus | rRNA | hypoxia | hypertrophy

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Section: Discussionsupporting

confidence: 86%

Nucleolar stress is an early response to myocardial damage involving nucleolar proteins nucleostemin and nucleophosmin

Avitabile

Bailey

Cottage

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…To verify the role of the PML-acetylated p53 complex in DOXtreated cardiomyocytes, we used pifithrin-α, an inhibitor of p53 expression (Liu et al, 2004), and resveratrol, an inhibitor of p53 acetylation (Howitz et al, 2003). In cardiomyocytes treated with DOX and pifithrin-α, the protein levels of both p53 and p21 cip1/waf1 were decreased (Fig.…”

Section: Altered Cell Cycle Regulatory Protein Expression In Aged Andmentioning

confidence: 99%

Induction of premature senescence in cardiomyocytes by doxorubicin as a novel mechanism of myocardial damage

Maejima¹,

Adachi²,

Ito³

et al. 2007

Aging Cell

182

150

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SummaryCellular senescence is an important phenomenon in decreased cellular function. Recently, it was shown that cellular senescence is induced in proliferating cells within a short period of time by oxidative stresses. This phenomenon is known as premature senescence. However, it is still unknown whether premature senescence can be also induced in cardiomyocytes. The aim of the present study was to investigate whether a senescence-like phenotype can be induced in cardiomyocytes by oxidative stress. In cardiomyocytes obtained from aged rats (24 months of age), the staining for senescence-associated β β β β -galactosidase increased significantly and the protein or RNA levels of cyclin-dependent kinase inhibitors increased compared to those of young rats. Decreased cardiac troponin I phosphorylation and telomerase activity were also observed in aged cardiomyocytes. Treatment of cultured neonatal rat cardiomyocytes with a low concentration of doxorubicin (DOX) (10 -7 mol L -1 ) did not induce apoptosis but did induce oxidative stress, which was confirmed by 2′ ′ ′ ′ ,7′ ′ ′ ′ -dichlorofluorescin diacetate staining. In DOX-treated neonatal cardiomyocytes, increased positive staining for senescence-associated β β β β -galactosidase, cdk-I expression, decreased cardiac troponin I phosphorylation, and decreased telomerase activity were observed, as aged cardiomyocytes. Alterations in mRNA expression typically seen in aged cells were observed in DOX-treated neonatal cardiomyocytes. We also found that promyelocytic leukemia protein and acetylated p53, key proteins involved in stressinduced premature senescence in proliferating cells, were associated with cellular alterations of senescence in DOX-treated cardiomyocytes. In conclusion, cardiomyocytes treated with DOX showed characteristic changes similar to cardiomyocytes of aged rats. promyelocytic leukemiarelated p53 acetylation may be an underlying mechanism of senescence-like alterations in cardiomyocytes. These findings indicate a novel mechanism of myocardial dysfunction induced by oxidative stress.

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“…Pifithrin-a, a p53 transactivation blocker, and doxorubicin were used to assess the effect of GA on cell survival (33). As shown in Fig.…”

Section: Ga Induced Apoptosis Partially Through Up-regulation Of P53mentioning

confidence: 99%

Gambogic acid mediates apoptosis as a p53 inducer through down-regulation of mdm2 in wild-type p53-expressing cancer cells

Wang

Rao

et al. 2008

Molecular Cancer Therapeutics

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Pifithrin-α protects against doxorubicin-induced apoptosis and acute cardiotoxicity in mice

Cited by 156 publications

References 38 publications

Nucleolar stress is an early response to myocardial damage involving nucleolar proteins nucleostemin and nucleophosmin

Nucleolar stress is an early response to myocardial damage involving nucleolar proteins nucleostemin and nucleophosmin

Induction of premature senescence in cardiomyocytes by doxorubicin as a novel mechanism of myocardial damage

Gambogic acid mediates apoptosis as a p53 inducer through down-regulation of mdm2 in wild-type p53-expressing cancer cells

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