A Key Role for Caspase-2 and Caspase-3 in the Apoptosis Induced by 2-Chloro-2′-deoxy-adenosine (Cladribine) and 2-Chloro-adenosine in Human Astrocytoma Cells

Ceruti, Stefania; Beltrami, Elena; Matarrese, Paola; Mazzola, Alessia; Cattabeni, Flaminio; Malorni, Walter; Abbracchio, Maria P.

doi:10.1124/mol.63.6.1437

Cited by 42 publications

(48 citation statements)

References 35 publications

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“…However, temporal ordering of caspase activation, particularly with respect to cytochrome c release, was not examined and may not have been possible in this whole animal model. Blockade of early caspase-2 activation (by zVDVAD-fmk) has been shown to be more protective than caspase-3 inhibition in a number of cellular models (6,7,46), including one examining staurosporine-induced apoptosis of chick cardiomyocytes (31). The release of cytochrome c from mitochondria on reperfusion of ischemic cells, however, has not been previously associated with caspase-2-like activity.…”

Section: Discussionmentioning

confidence: 98%

“…However, this cellular system is one of the few that exhibits several important qualities, including reperfusion-induced oxidant generation, synchronous contractile function, and preconditioning protection (38 -40). Furthermore, we believe that the well-documented conservation of apoptotic molecules and mechanisms (1,7,43) make this model a useful one in dissecting some of these mechanisms.…”

Section: Discussionmentioning

confidence: 99%

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Caspase-dependent cytochrome c release and cell death in chick cardiomyocytes after simulated ischemia-reperfusion

Qin¹,

Hoek²,

Wojcik³

et al. 2004

American Journal of Physiology-Heart and Circulatory Physiology

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. Caspase-dependent cytochrome c release and cell death in chick cardiomyocytes after simulated ischemia-reperfusion. Am J Physiol Heart Circ Physiol 286: H2280 -H2286, 2004. First published February 19, 2004 10.1152/ajpheart.01063.2003We recently demonstrated that reperfusion rapidly induces the mitochondrial pathway of apoptosis in chick cardiomyocytes after 1 h of simulated ischemia. Here we tested whether ischemia-reperfusion (I/R)-induced apoptosis could be initiated by caspase-dependent cytochrome c release in this model of cardiomyocyte injury. Fluorometric assays of caspase activity showed little, if any, activation of caspases above baseline levels induced by 1 h of ischemia alone. However, these assays revealed rapid activation of caspase-2, yielding a 2.95 Ϯ 0.52-fold increase (over ischemia only) within the 1st h of reperfusion, whereas activities of caspases-3, -8, and -9 increased only slightly from their baseline levels. The rapid and prominent activation of caspase-2 suggested that it could be an important initiator caspase in this model, and using specific caspase inhibitors given only at the point of reperfusion, we tested this hypothesis. The caspase-2 inhibitor benzyloxycarbonyl-Val-Asp(Ome)-Val-Ala-Asp(Ome)-CH2F was the only caspase inhibitor that significantly inhibited cytochrome c release from mitochondria. This inhibitor also completely blocked activation of caspases-3, -8, and -9. The caspase-3/7 inhibitor transiently and only partially blocked caspase-2 activity and was less effective in blocking the activities of caspases-8 and -9. The caspase-8 inhibitor failed to significantly block caspase-2 or -3, and the caspase-9 inhibitor blocked only caspase-9. Furthermore, the caspase-2 inhibitor protected against I/Rinduced cell death, but the caspase-8 inhibitor failed to do so. These data suggest that active caspase-2 initiates cytochrome c release after reperfusion and that it is critical for the I/R-induced apoptosis in this model. caspase activation; caspase inhibitor ISCHEMIA-REPERFUSION (I/R) can induce apoptosis in cardiomyocytes, and several studies have implicated the "intrinsic" or mitochondrial pathway in the cell injury in models of myocardial infarction and cardiomyocyte death (see Ref. 4 for a recent review). Caspases (cysteinyl aspartate-specific proteases) play critical roles in the initiation and execution of apoptotic pathways, including those induced by I/R (10,18,21,26,38,44). Several caspases have been described in vertebrates. Among these, important initiator functions have been documented for caspase-8 in death receptor-induced apoptosis and for caspase-9 in mitochondrial pathways (reviewed in Ref. 12). A large volume of literature also supports a role for caspase-3 as a central "executioner" or "downstream" caspase, and, for a number of years after its discovery in 1994 (22, 43), caspase-2 was thought to be primarily a downstream effector caspase as well (34). Across animal species, caspase-2 is one of the most conserved caspases (reviewed in Ref. 37) and, interesti...

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Caspase-dependent cytochrome c release and cell death in chick cardiomyocytes after simulated ischemia-reperfusion

Qin¹,

Hoek²,

Wojcik³

et al. 2004

American Journal of Physiology-Heart and Circulatory Physiology

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“…Caspase-3, a member of the caspase family, was shown to play an essential role in apoptosis induced by a variety of stimuli (13)(14)(15). Finally, we examined whether caspase-3 activity was increased during pitavastatin-induced apoptosis in HepG 2 cells.…”

Section: Induction Of Capase-3 Activity By Pitavastatin In Hepg 2 Cellsmentioning

confidence: 99%

Downregulation of survivin expression and elevation of caspase-3 activity involved in pitavastatin-induced HepG 2 cell apoptosis

Wang¹,

Xu²,

Zhang³

2007

Oncol Rep

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Abstract. The aim of the present study was to research the apoptosis of human hepatocellular carcinoma cell line HepG 2 induced by pitavastatin. HepG 2 cells were treated with increasing doses of pitavastatin or with mevalonic acid for 48 h. The proliferation of cells was detected with WST-8. The morphology of the nucleus was observed under a microscope by Hoechst 33258 staining. The apoptosis peaks were examined by flow cytometry. The expression of survivin mRNA was examined with RT-PCR. The caspase-3 activity was detected with caspase-3 colorimetric protease assay. We found that growth inhibitory effects were observed for treatment with pitavastatin at 10-50 μM. Pitavastatin at 10 μM induced granular apoptotic bodies of HepG 2 cells. Furthermore, pitavastatin at 10 μM increased the appearance of sub-G1 population of HepG 2 cells. Finally, pitavastatin at 10 μM downregulated the expression of survivin mRNA and upregulated the caspase-3 activity, which was clearly related to the HMG-CoA reductase activity. These results suggest that pitavastatin at 10 μM induces apoptosis of HepG 2 cells, which is associated with the decreased expression of survivin mRNA and increased caspase-3 activity of HepG 2 cells.

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“…Whether that will involve a caspase other than caspase-8 or caspase-9 (e.g., caspase-2; ref. 21), molecules in the intrinsic apoptotic pathway (e.g., Bcl-2 family protein), mitochondrial activity, or molecules in the other pathways (e.g., cathepsin L; ref. 22) will need detailed analysis.…”

Section: P53-r273h and Drug Resistancementioning

confidence: 99%

p53-R273H gains new function in induction of drug resistance through down-regulation of procaspase-3

Wong

Tsang

Chau

et al. 2007

Molecular Cancer Therapeutics

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Development of drug resistance is one of the major obstacles in cancer chemotherapy. The molecular mechanism leading to drug resistance is still not fully understood. A10A cells, a doxorubicin-resistant subline of human squamous cell carcinoma A431 cells, showed cross-resistance to methotrexate and also resistance to the drug-induced apoptosis. The cells also showed overexpression of a mutated form of p53, p53-R273H (Arg to His at codon 273), and down-regulation of procaspase-3. Knockdown of p53-R273H by p53 small interfering RNA in A431 cells increased procaspase-3 level and sensitized the cells to drug-induced apoptosis. On the other hand, transfection of p53-R273H into p53 null human osteosarcoma Saos-2 cells down-regulated procaspase-3 level and induced resistance to the drug toxicity and drug-induced apoptosis. The results support the idea that p53-R273H may gain new functions in induction of drug resistance and impairment in drug-induced apoptosis through downregulation of procaspase-3 level. The study sheds new light on the understanding of the gain of function and drug resistance mechanisms associated with mutant p53. [Mol Cancer Ther 2007;6(3):1054 -61]

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A Key Role for Caspase-2 and Caspase-3 in the Apoptosis Induced by 2-Chloro-2′-deoxy-adenosine (Cladribine) and 2-Chloro-adenosine in Human Astrocytoma Cells

Cited by 42 publications

References 35 publications

Caspase-dependent cytochrome c release and cell death in chick cardiomyocytes after simulated ischemia-reperfusion

Caspase-dependent cytochrome c release and cell death in chick cardiomyocytes after simulated ischemia-reperfusion

Downregulation of survivin expression and elevation of caspase-3 activity involved in pitavastatin-induced HepG 2 cell apoptosis

p53-R273H gains new function in induction of drug resistance through down-regulation of procaspase-3

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