Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The clinical use of doxorubicin, a highly active anticancer drug, is limited by its severe cardiotoxic side effects. Increased oxidative stress and apoptosis have been implicated in the cardiotoxicity of doxorubicin. Carvedilol is an adrenergic blocking agent with potent anti-oxidant activity. In this study we investigated whether carvedilol has protective effects against doxorubicin-induced free radical production and apoptosis in cultured cardiac muscle cells, and we compared the effects of carvedilol to atenolol, a beta-blocker with no anti-oxidant activity. Reactive oxygen species (ROS) generation in cultured cardiac muscle cells (H9c2 cells) was evaluated by flow cytometry using dichlorofluorescein (DCF) and hydroethidine (HE). Apoptosis was assessed by measuring annexin V-FITC/propidium iodide double staining, DNA laddering, levels of expression of the pro-apoptotic protein Bax-alpha and the anti-apoptotic protein Bcl-2, and caspase-3 activity. Pre-treatment with carvedilol significantly attenuated the doxorubicin-induced increases in DCF (P < 0.001 compared to cells not pre-treated with carvedilol) and HE (P < 0.01) fluorescence. Doxorubicin increased the fraction of annexin V-FITC-positive fluorescent cells, while pre-treatment with carvedilol reduced the number of positive fluorescent cells (P < 0.01). Doxorubicin-induced DNA fragmentation to a clear ladder pattern, while carvedilol prevented DNA fragmentation. Doxorubicin-induced a fall in mRNA expression of the anti-apoptotic Bcl-2 and an increase in the expression of the pro-apoptotic Bax-alpha. Carvedilol pre-treatment blunted both the decrease of Bcl-2 (P < 0.01) and the increase of Bax-alpha mRNA expression (P < 0.01). Caspase-3 activity significantly increased after the addition of doxorubicin. Concurrently, carvedilol partially inhibited the doxorubicin-induced activation of caspase-3 (P < 0.01). Atenolol did not produce any effect in preventing doxorubicin-induced ROS generation and cardiac apoptosis. Our results suggest that carvedilol is potentially protective against doxorubicin cardiotoxicity by decreasing free radical release and apoptosis in cardiomyocytes.
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PMID:Carvedilol prevents doxorubicin-induced free radical release and apoptosis in cardiomyocytes in vitro. 1538 Jun 72

Apoptosis is associated with early changes in cell volume through a mechanism called apoptotic volume decrease (AVD). As volume-sensitive chloride channels (I(Cl,vol)) are known to play a key role in the regulation of cell volume, this study investigated the role of I(Cl,vol) and AVD in doxorubicin-induced apoptotic cell death in adult rabbit ventricular cardiomyocytes. Exposure of cardiomyocytes to 1 microm doxorubicin induced a rapid and significant reduction in cell volume of cardiomyocytes (average of 15%), i.e. AVD as well as increases in the early markers of apoptosis, annexin V labeling and caspase-3 activity. Doxorubicin also induced the activation of a current characterized as I(Cl,vol) on the basis of the external chloride sensitivity and pharmacological properties with the patch clamp technique. Doxorubicin-induced AVD and apoptosis were both abolished when cardiomyocytes were exposed to the I(Cl,vol) inhibitors 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB) (0.1 mM) or indanyloxyacetic acid 94 (IAA-94) (10 microM). The crucial role of I(Cl,vol) during AVD and apoptosis was confirmed using C(2)-ceramide, another pro-apoptotic compound. These results demonstrate that activation of I(Cl,vol) plays a major role in the mechanism leading to cell shrinkage and apoptosis-induced AVD by agents such as doxorubicin or C(2)-ceramide in adult cardiomyocytes.
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PMID:Volume-sensitive chloride channels (ICl,vol) mediate doxorubicin-induced apoptosis through apoptotic volume decrease in cardiomyocytes. 1548 74

We investigated in vivo the chemotherapeutic anthracycline agents doxorubicin and its ability to activate mitochondrial-mediated, receptor-mediated and endoplasmic/sarcoplasmic reticulum-mediated apoptosis transduction pathways in cardiac tissue from male and female rats. We administered a single low dose of doxorubicin (10 mg/kg of body weight, i.p.) and then isolated mitochondrial and cytosolic proteins one and four days later from the heart. Caspase-3 protein content and caspase-3 activity were significantly increased after day four of doxorubicin treatment in both male and female rats. However, while males had DNA fragmentation at day one but not day four following doxorubicin administration, females showed no significant increase in DNA fragmentation at either time. Caspase-12, localized in the SR, is considered a central caspase, and its activation by cleavage via calpain indicates activation of the SR-mediated pathway of apoptosis. Cleaved caspase-12 content and calpain activity significantly increased after day four of doxorubicin treatment in both sexes. In the mitochondrial-mediated pathway, there were no significant treatment effects observed in cytosolic cytochrome c and cleaved (active) caspase-9 in either sex. In control rats (saline injection), glutathione peroxidase (GPX) activity and hydrogen peroxide (H2O2) production were lower in females compared to males. Doxorubicin treatment did not significantly affect H2O2, GPX activity or ATP production in isolated mitochondria in either sex. Female rats produced significantly lower levels of H2O2 production one day after doxorubicin treatment, whereas male rats produced significantly less mitochondrial H2O2 four days after doxorubicin treatment. The receptor-mediated pathway (caspase-8 and c-FLIP) showed no evidence of being significantly activated by doxorubicin treatment. Hence, doxorubicin-induced apoptosis in vivo is mediated by the SR to a greater extent than other apoptotic pathways and should therefore be considered for targeted therapeutic interventions. Moreover, no major sex differences exist in apoptosis signaling transduction cascade due to doxorubicin treatment.
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PMID:Doxorubicin treatment in vivo activates caspase-12 mediated cardiac apoptosis in both male and female rats. 1555 33

Doxorubicin (Dox) is a highly effective antineoplastic antibiotic associated with a dose-limiting cardiotoxicity that may result in irreversible cardiomyopathy and heart failure. The purpose of this study was to examine the effects of low-intensity exercise training (LIET) during the course of Dox treatment on cardiac function, myosin heavy chain expression, oxidative stress, and apoptosis activation following treatment. Male Sprague-Dawley rats either remained sedentary or were exercise trained on a motorized treadmill at 15 m/min, 20 min/day, 5 days/wk (Monday through Friday) for 2 wk. During the same 2-wk period, Dox (2.5 mg/kg) or saline was administered intraperitoneally to sedentary and exercised rats 3 days/wk (Monday, Wednesday, Friday) 1-2 h following the exercise training sessions (cumulative Dox dose: 15 mg/kg). Five days following the final injections, hearts were isolated for determination of left ventricular (LV) function, lipid peroxidation, antioxidant enzyme protein expression, 72-kDa heat shock protein expression, caspase-3 activity, and myosin heavy chain isoform expression. Dox treatment significantly impaired LV function and increased caspase-3 activity in sedentary animals (P < 0.05). LIET attenuated the LV dysfunction and apoptotic signal activation induced by Dox treatment and increased glutathione peroxidase expression, but it had no significant effect on lipid peroxidation, protein expression of myosin heavy chain isoforms, 72-kDa heat shock protein, or superoxide dismutase isoforms. In conclusion, our data suggest that LIET applied during chronic Dox treatment protects against cardiac dysfunction following treatment, possibly by enhancing antioxidant defenses and inhibiting apoptosis.
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PMID:Low-intensity exercise training during doxorubicin treatment protects against cardiotoxicity. 1621 Apr 42

The effects of tocotrienols on murine liver cell viability and their apoptotic events were studied over a dose range of 0-32 microg mL(-1). Normal murine liver cells (BNL CL.2) and murine liver cancer cells (BNL 1ME A.7R.1) were treated with tocotrienols (T(3)), alpha tocopherol (alpha-T) and the chemo drug, Doxorubicin (Doxo, as a positive control). Cell viability assay showed that T(3) significantly (P < or = 0.05) lowered the percentage of BNL 1ME A.7R.1 cell viability in a dose-responsive manner (8-16 microg mL(-1)), whereas T did not show any significant (P>0.05) inhibition in cell viability with increasing treatment doses of 0-16 microg mL(-1). The IC(50) for tocotrienols were 9.8, 8.9, 8.1, 9.7, 8.1 and 9.3 microg mL(-1) at 12, 24, 36, 48, 60 and 72 hours respectively. Early apoptosis was detected 6 hours following T(3) treatment of BNL 1ME A.7R.1 liver cancer cells, using Annexin V-FITC fluorescence microscopy assay for apoptosis, but none were observed for the non-treated liver cancer cells at the average IC(50) of 8.98 microg mL(-1) tocotrienols for liver cancer cells. Several apoptotic bodies were detected in BNL 1ME A.7R.1 liver cancer cells at 6 hours post-treatment with tocotrienols (8.98 microg mL(-1)) using Acridine Orange/Propidium Iodide fluorescence assay. However, only a couple of apoptotic bodies were seen in the non-treated liver cancer cells and the BNL CL.2 normal liver cells. Some mitotic bodies were also observed in the T(3)-treated BNL 1ME A.7R.1 liver cancer cells but were not seen in the untreated BNL 1ME A.7R.1 cells and the BNL CL.2 liver cells. Following T(3)-treatment (8.98 microg mL(-1)) of the BNL 1ME A.7R.1 liver cancer cells, 24.62%, 25.53% and 44.90% of the cells showed elevated active caspase 3 activity at 9, 12 and 24 hours treatment period, respectively. DNA laddering studies indicated DNA fragmentation occurred in the T(3)-treated liver cancer cells, BNL 1ME A.7R.1 but not in non-treated liver cancer cells and the T(3)-treated and non-treated normal liver cells. These results suggest that tocotrienols were able to reduce the cell viability in the murine liver cancer cells at a dose of 8-32 microg mL(-1) and that this decrease in percentage cell viability may be due to apoptosis.
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PMID:Effects of tocotrienols on cell viability and apoptosis in normal murine liver cells (BNL CL.2) and liver cancer cells (BNL 1ME A.7R.1), in vitro. 1632 44

Doxorubicin (DOX), a potent antineoplastic agent, poses limitations for its therapeutic use due to the associated risk of developing cardiomyopathy and congestive heart failure. The cardiotoxicity of doxorubicin is associated with oxidative stress and apoptosis. We have recently shown that Spirulina, a blue-green alga with potent antioxidant properties, offered significant protection against doxorubicin-induced cardiotoxicity in mice. The aim of the present study was to establish the possible protective role of C-phycocyanin, one of the active ingredients of Spirulina, against doxorubicin-induced oxidative stress and apoptosis. The study was carried out using cardiomyocytes isolated from adult rat hearts. Doxorubicin significantly enhanced the formation of reactive oxygen species (ROS) in cells as measured by the 2',7'-dichlorodihydrofluorescein diacetate and dihydroethidium fluorescence. The doxorubicin-induced reactive oxygen species formation was significantly attenuated in cells pretreated with C-phycocyanin. It was further observed that the doxorubicin-induced DNA fragmentation and apoptosis, as assayed by TUNEL assay and flow cytometry coupled with BrdU-FITC/propidium iodide staining, were markedly attenuated by C-phycocyanin. C-phycocyanin also significantly attenuated the doxorubicin-induced increase in the expression of Bax protein, release of cytochrome c, and increase in the activity of caspase-3 in cells. In summary, C-phycocyanin ameliorated doxorubicin-induced oxidative stress and apoptosis in cardiomyocytes. This study further supports the crucial role of the antioxidant nature of C-phycocyanin in its cardioprotection against doxorubicin-induced oxidative stress and apoptosis.
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PMID:C-phycocyanin ameliorates doxorubicin-induced oxidative stress and apoptosis in adult rat cardiomyocytes. 1642 80

Doxorubicin (DOX) is widely used to treat patients suffering from cancer, but the usage for patients is limited because of the dose-dependent cardiotoxicity. We hypothesized that DOX induces apoptosis through caspase activation in cardiomyocytes, and we examined this hypothesis using both rat primary cultured cardiomyocytes and rat hearts from an animal model. Cardiomyocytes were treated with DOX for 24 h. The activity of caspase-3 was significantly increased by DOX treatment. In rats with DOX injected intravenously once a week for 5 weeks, left ventricular fractional shortening evaluated by echocardiography was significantly decreased at age 14 weeks, 2 weeks after the end of DOX-administration. At 16 weeks of age, endothelin-1 mRNA and atrial natriuretic peptide mRNA were also significantly increased, likewise, and TUNEL positive cells were significantly increased in the ventricles of DOX-treated rats. The activity of caspase-3 in the ventricles was also significantly increased compared to that of untreated rats at 16 weeks. However, the activity of caspase-8 and the expression level of Fas-ligand mRNA were comparable with those of the untreated rats. In conclusion, DOX induces apoptosis through the activation of caspase-3, suggesting that apoptosis has an important role in the progression of cardiomyopathy due to DOX.
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PMID:Doxorubicin induces apoptosis by activation of caspase-3 in cultured cardiomyocytes in vitro and rat cardiac ventricles in vivo. 1676 56

Doxorubicin is the anthracycline with the widest spectrum of antitumor activity, and it has been shown that the antitumor activity is mediated in vivo by selective triggering of apoptosis in proliferating endothelial cells. We studied cultured human endothelial cells and observed that doxorubicin-induced apoptosis was mediated by p38 mitogen-activated protein kinase (MAPK). Doxorubicin-provoked apoptosis was significantly inhibited by expression of dominant negative p38 MAPK or pharmacological inhibition with SB203580. Furthermore, blocking phosphatidylinositol-3-kinase/Akt signaling significantly increased doxorubicin-induced caspase-3 activity and cell death, indicating that Akt is a survival factor in this system. Notably, we also found that doxorubicin-provoked apoptosis included p38 MAPK-mediated inhibition of Akt and Bad phosphorylation. Furthermore, doxorubicin-stimulated phosphorylation of Bad in cells expressing dominant negative p38 MAPK was impeded by the inhibition of PI3-K. In addition to the impact on Bad phosphorylation, doxorubicin-treatment caused p38 MAPK-dependent downregulation of Bcl-xL protein.
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PMID:p38 MAPK downregulates phosphorylation of Bad in doxorubicin-induced endothelial apoptosis. 1684 35

Doxorubicin (DOX)-induced apoptosis is suppressed by p21 (waf1/cip1/sdi1), a cyclin dependent kinase (CDK) inhibitor. Here we show that exogenous expression of p21 before, but not after, the DOX-treatment protected p21-deficient human colorectal cancer cell line DLD1 from DOX-induced apoptosis. In previous work, we demonstrated that p21 inhibits DOX-induced apoptosis via its CDK-binding and CDK-inhibitory activity. Here we report that pre-existing p21 can associate with pro-caspase-3 and inhibit caspase-3 activation in the cells, which was at least in part responsible for enhancing survival of DOX-treated cells. Furthermore, the N-terminal domain of p21 was found to interact with pro-caspase-3 in DLD1 cells. Thus, we propose that pre-existing p21 is required to prevent DOX-induced apoptosis.
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PMID:Requirement for pre-existing of p21 to prevent doxorubicin-induced apoptosis through inhibition of caspase-3 activation. 1690 8

Four diterpenoids, ferruginol, salvipisone, aethiopinone and 1-oxoaethiopinone, were isolated from transformed roots of Salvia sclarea. Salvipisone and aethiopinone showed relatively high cytotoxicity against HL-60 and NALM-6 leukemia cells (IC50 range 0.6-7.7 microg/ mL which is equal to 2.0-24.7 microM), whereas 1-oxoaethiopinone and ferruginol were less active in this regard. Moreover, we have found that all four diterpenoids of S. sclarea had equal cytotoxic activity against parental HL-60 and multidrug-resistant HL-60 ADR cells, what indicates that they are poor substrates for transport by multidrug resistance-associated protein (MRP1). Caspase-3 activity determinations showed that salvipisone and aethiopinone were able to induce apoptosis in a time- and concentration-dependent manner. The results obtained in this study show that S. sclarea diterpenoids aethiopinone and salvipisone may be useful in the treatment of human cancers, especially in the case of drug resistance.
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PMID:Cytotoxic and proapoptotic activity of diterpenoids from in vitro cultivated Salvia sclarea roots. Studies on the leukemia cell lines. 1698 6


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