Induction of caspase-independent apoptosis in H9c2 cardiomyocytes by adriamycin treatment

Youn, Ho‐Joong; Kim, Ho‐Shik; Jeon, Mi-Hee; Lee, Jung‐Hee; Seo, Yun-Jee; Lee, Yong-Joon; Lee, Jeong-Hwa

doi:10.1007/s11010-005-2541-2

Cited by 43 publications

(34 citation statements)

References 39 publications

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“…In NeRCaMs, the observed caspase-9 activation seems to be merely a co-phenomenon of DOX-induced apoptosis. In line with that, Youn et al (2005) reported that DOX-induced death of the rat cardiac muscle cell line H9c2 was associated with p53 upregulation and caspase-independency. Altogether, this indicates the involvement of caspase-independent apoptotic routes in mediating death in cardiac myocytes by DOX.…”

Section: Discussionsupporting

confidence: 80%

“…Evidence for mitochondria-dependent activation of caspases was only obtained in HUVECs, in which DOX exposure resulted in the occurrence of a shorter form of BAX, which was suppressed by monoHER. This shorter form may be produced by cleavage of full-length Bax or may represent an alternatively spliced variant with mitochondria destabilising activity leading to the apoptosome-dependent activation of caspase-9 and the subsequent activation of apoptotic cell death (Youn et al, 2005). In A2780 cells the mitochondrial pathway seemed to be less involved in DOX-induced apoptosis because DOX did not show clear changes in BAX or pro-caspase-9 or -3 levels.…”

Section: Discussionmentioning

confidence: 96%

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Caspase-dependent and -independent suppression of apoptosis by monoHER in Doxorubicin treated cells

et al. 2007

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Doxorubicin (DOX) is an antitumour agent for different types of cancer, but the dose-related cardiotoxicity limits its clinical use. To prevent this side effect we have developed the flavonoid monohydroxyethylrutoside (monoHER), a promising protective agent, which did not interfere with the antitumour activity of DOX. To obtain more insight in the mechanism underlying the selective protective effects of monoHER, we investigated whether monoHER (1 mM) affects DOX-induced apoptosis in neonatal rat cardiac myocytes (NeRCaMs), human endothelial cells (HUVECs) and the ovarian cancer cell lines A2780 and OVCAR-3. DOX-induced cell death was effectively reduced by monoHER in heart, endothelial and A2780 cells. OVCAR-3 cells were highly resistant to DOXinduced apoptosis. Experiments with the caspase-inhibitor zVAD-fmk showed that DOX-induced apoptosis was caspase-dependent in HUVECs and A2780 cells, whereas caspase-independent mechanisms seem to be important in NeRCaMs. MonoHER suppressed DOX-dependent activation of the mitochondrial apoptotic pathway in normal and A2780 cells as illustrated by p53 accumulation and activation of caspase-9 and -3 cleavage. Thus, monoHER acts by suppressing the activation of molecular mechanisms that mediate either caspase-dependent or -independent cell death. In light of the current work and our previous studies, the use of clinically achievable concentrations of monoHER has no influence on the antitumour activity of DOX whereas higher concentrations as used in the present study could influence the antitumour activity of DOX.

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Section: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 96%

Caspase-dependent and -independent suppression of apoptosis by monoHER in Doxorubicin treated cells

et al. 2007

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“…28,33 However, depending on in vitro and in vivo analyses, the results were not always consistent. 34,35 In the present study, no sex difference in cell death was observed in vivo and in vitro after doxorubicin. These results match those of the gene expression analysis of cell death markers that did not change in both sexes after doxorubicin treatment.…”

Section: Discussioncontrasting

confidence: 59%

Sexual Dimorphism of Doxorubicin-Mediated Cardiotoxicity

Moulin

Piquereau

Matéo

et al. 2015

Circ: Heart Failure

114

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Background— Cardiovascular diseases are the major cause of mortality among both men and women with a lower incidence in women before menopause. The clinical use of doxorubicin, widely used as an antineoplastic agent, is markedly hampered by severe cardiotoxicity. Even if there is a significant sex difference in incidence of cardiovascular disease at the adult stage, it is not known whether a difference in doxorubicin-related cardiotoxicity between men and women also exists. The objective of this work was to explore the cardiac side effects of doxorubicin in adult rats and decipher whether signaling pathways involved in cardiac toxicity differ between sexes. Methods and Results— After 7 weeks of doxorubicin (2 mg/kg per week), males developed major signs of cardiomyopathy with cardiac atrophy, reduced left ventricular ejection fraction and 50% mortality. In contrast, no female died and their left ventricular ejection fraction was only moderately affected. Surprisingly, neither global oxidation levels nor the antioxidant response nor the apoptosis signaling pathways were altered by doxorubicin. However, the level of total adenosine monophosphate–activated protein kinase was severely decreased only in males. Moreover, markers of mitochondrial biogenesis and cardiolipin content were strongly reduced only in males. To analyze the onset of the pathology, maximal oxygen consumption rate of left ventricular permeabilized fibers after 4 weeks of treatment was reduced only in doxorubicin-treated males. Conclusions— Altogether, these results clearly evidence sex differences in doxorubicin toxicity. Cardiac mitochondrial dysfunction and adenosine monophosphate–activated protein kinase seem as critical sites of sex differences in cardiotoxicity as evidenced by significant statistical interactions between sex and treatment effects.

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“…Doxorubicin is a DNA-intercalating drug that induces both caspase-dependent and -independent cell death in various cell types (29), including cardiomyocytes (51). In response to doxorubicin injection, the percentage of cardiomyocytes undergoing apoptosis, as assessed with the TUNEL assay (see a representative example on the left-hand side of Fig.…”

Section: % Confidence Interval [Ci])mentioning

confidence: 99%

Caspase-3 Protects Stressed Organs against Cell Death

Khalil

Peltzer

Walicki

et al. 2012

Molecular and Cellular Biology

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The ability to generate appropriate defense responses is crucial for the survival of an organism exposed to pathogenesis-inducing insults. However, the mechanisms that allow tissues and organs to cope with such stresses are poorly understood. Here we show that caspase-3-knockout mice or caspase inhibitor-treated mice were defective in activating the antiapoptotic Akt kinase in response to various chemical and environmental stresses causing sunburns, cardiomyopathy, or colitis. Defective Akt activation in caspase-3-knockout mice was accompanied by increased cell death and impaired survival in some cases. Mice homozygous for a mutation in RasGAP that prevents its cleavage by caspase-3 exhibited a similar defect in Akt activation, leading to increased apoptosis in stressed organs, marked deterioration of their physiological functions, and stronger disease development. Our results provide evidence for the relevance of caspase-3 as a stress intensity sensor that controls cell fate by either initiating a RasGAP cleavage-dependent cell resistance program or a cell suicide response. Executioner caspases mediate cell death during apoptosis (45). Of these, caspase-3 has the ability to cleave the majority of the caspase substrates (43), and its activity is required for the induction of cell death in response to many apoptotic stimuli (1). While executioner caspases are indispensable for apoptosis, there are situations when their activation does not lead to death. For example, healthy dividing cells can weakly activate caspase-3 in response to mild stresses (47). Caspase-3 also participates, in an apoptosisindependent manner, in T and B cell homeostasis (35,46), in microglia activation (6), in long-term depression (26), and in muscle (17), monocyte (44), embryonic stem cell (18), and erythroid cell (13) differentiation. However, it remains unclear how activation of caspase-3 under these conditions does not eventually lead to cell death (1, 24). Cells could have an intrinsic ability to tolerate low caspase activity by constitutively expressing antiapoptotic molecules, such as members of the inhibitors of the apoptosis protein family, or may stimulate antiapoptotic pathways in parallel to caspase activation (24). Alternatively, the caspases themselves might activate prosurvival pathways, in particular, when they are mildly stimulated. Indeed, there is evidence in cultured cells that caspase-3 mediates neuroprotection after preconditioning (30) and that caspase-3 activity turns on the antiapoptotic Akt kinase following partial cleavage of the RasGAP protein (47). Other caspase substrates that could potentially induce protective signals once cleaved include p27 kip1 (14), Lyn (28), synphilin-1 (19), and Rb (42), yet the physiological importance of these cleaved substrates has not been evaluated to date.In the present study, we have investigated the role played by caspase-3 and its substrate p120 RasGAP in the induction of the antiapoptotic Akt kinase in stressed tissues in vivo. MATERIALS AND METHODS Caspase-3-KO mice. B6.129S1...

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Induction of caspase-independent apoptosis in H9c2 cardiomyocytes by adriamycin treatment

Cited by 43 publications

References 39 publications

Caspase-dependent and -independent suppression of apoptosis by monoHER in Doxorubicin treated cells

Caspase-dependent and -independent suppression of apoptosis by monoHER in Doxorubicin treated cells

Sexual Dimorphism of Doxorubicin-Mediated Cardiotoxicity

Caspase-3 Protects Stressed Organs against Cell Death

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