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)

This study examined the effect of Saeng-Ji-Hwang (SJH: Radix Rehmanniae) on cardiac muscle cells. Adriamycin-exposed H9C2 cardiac muscle cells were treated with a water extract of SJH. The adriamycin induced cell death and caspase-3 activation were significantly inhibited by SJH (2 mg/ml), which can be explained by the increase in Bcl-2 expression and the inhibition of Bax expression. Adriamycin reduced the Mn-SOD protein expression level in H9C2 cardiac muscle cells but a SJH treatment partially but significantly reversed this effect. Manganese (Mn)-TBAP or Mn-TMyM--mitochondria-specific SOD mimetic agent--reduced the adriamycin-induced cytotoxicity. It was also shown that SJH inhibits the release of H2O2 and prevents lipid peroxidation in the presence of adriamycin. This study examined the intracellular GSH level, which showed that adriamycin significantly decreased the intracellular GSH level but SJH increased it. BSO, a selective inhibitor of glutamyl cysteinyl ligase, which is a rate-limiting enzyme in GSH synthesis, did not affect the viability of the cardiac muscle cells. However, a combination of BSO with SJH in the presence of adriamycin reversed the SJH-induced protection. Overall, the results suggest that SJH-associated Mn-SOD and GSH are important factors in the mechanism of the SJH-induced protective mechanism in H9C2 cardiac muscle cells.
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PMID:Saeng-Ji-Hwang has a protective effect on adriamycin-induced cytotoxicity in cardiac muscle cells. 1582 71

Combined radiotherapy and chemotherapy have represented major advance in the therapeutic management of cancer therapy. Anthracycline antineoplastic agents are limited by a high incidence of severe and usually irreversible cardiac toxicity, the cause of which remains controversial. When the primary cardiomyocytes isolated from neonatal rats were preirradiated by gamma-ray, the cells were highly resistant to adriamycin-induced apoptosis. This study shows that irradiation inhibited apoptosis by enhancing Bcl-2, attenuating Bax induction, and preventing collapse of mitochondrial membrane potential (delta psi), cytochrome c release into cytoplasm and caspase-3, -6 and -9 activations. In addition, the preirradiation stimulated the activity of manganese-superoxide dismutase (Mn-SOD) and the expression of Mn-SOD mRNA and protein. Adriamycin decreased Mn-SOD activity but did not change the activity of copper/zinc (Cu/Zn)-SOD under either pre- or nonirradiated condition. Phosphothioate-linked antisense against Mn-SOD, which specifically knocked down the activity of Mn-SOD but not that of Cu/Zn-SOD, reversed irradiation-induced protective effect in adriamycin-exposed cardiomyocytes. These data suggest that the irradiation-induced expression of Mn-SOD plays an important role in irradiation-mediated protection in adriamycin-exposed rat ventricular cardiomyocytes.
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PMID:Radiation protects adriamycin-induced apoptosis. 1611 6

Adriamycin-induced nephrosis in rats is a commonly used experimental model for pharmacological studies of human chronic renal diseases. Adriamycin-induced apoptosis of renal tubular cells has been reported in adriamycin-treated rats. In addition, prostacyclin (PGI(2)) is known to have various protective effects on many kinds of cells. To investigate the protective effect of PGI(2) on cells undergoing adriamycin-induced apoptosis, this study selectively augmented PGI(2) production via adenovirus-mediated transfer of genes for cyclooxygenase-1 (COX-1) and prostacyclin synthase (PGIS) (two key enzymes of PGI(2) synthesis) to renal tubular cells. This PGI(2) overexpression protected rat renal tubular cells from adriamycin-induced apoptosis. Ad-COX-1/PGIS transfection was found to reduce the adriamycin-stimulated activities of caspase-3 and caspase-9, inhibit adriamycin-induced release of cytochrome c, elevate the expression of Bcl-x(L), and suppress the activation and translocation of nuclear factor-kappaB (NF-kappaB) in adriamycin-treated renal tubular cells. Our results reveal that selective augmentation of PGI(2) production can protect rat renal tubular cells from adriamycin-induced apoptosis via the NF-kappaB signaling pathway. This implies the therapeutic potential of combined COX-1 and PGIS gene transfer in gene therapy for chronic renal diseases.
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PMID:The protective effect of prostacyclin on adriamycin-induced apoptosis in rat renal tubular cells. 1634 80

Adriamycin is a potent antitumor drug that is known to cause severe cardiotoxicity. This study examined the protective effect of calceolarioside on adriamycin-induced cardiomyocyte toxicity. Calceolarioside significantly inhibited the adriamycin induced cell death and caspase-3 activation, which may be explained by the increase in Bcl-2 expression and the inhibition of Bax expression. Calceolarioside increased the expression of the antioxidant molecules and decreased the level of intracellular reactive oxygen species. Catalase, glutathione, N-acetylcysteine, Mannitol and Mn-TBAP (manganese (III) tetrakis-(4-benzoic acid) porphyrin) significantly inhibited the H9c2 cell death induced by adriamycin. Calceolarioside significantly inhibited H9c2 cell death, and was more effective than that observed with the other antioxidants, including probucol, ascorbic acid, and alpha-tocopherol. Overall, these results suggest that calceolarioside can inhibit adriamycin-induced apoptosis in H9c2 cardiomyocyte by inhibiting the generation of reactive oxygen species. Calceolarioside may be a potential candidate agent that inhibits cardiomyocyte-toxicity in adriamycin-exposed patients.
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PMID:Protective effect of calceolarioside on adriamycin-induced cardiomyocyte toxicity. 1678 Aug 32

Peroxisome proliferator-activated receptor-alpha (PPAR-alpha) is a transcription factor and has been reported to inhibit cisplatin-mediated proximal tubule cell death. In addition, doxorubicin (Adriamycin)-induced nephrosis in rats is a commonly used experimental model for pharmacological studies of human chronic renal diseases. In this study, we investigated the protective effect of PPAR-alpha on doxorubicin-induced apoptosis and its detailed mechanism in NRK-52E cells and animal models. The mRNA level of PPAR-alpha was found to be reduced by doxorubicin treatment in NRK-52E cells. PPAR-alpha overexpression in NRK-52E cells significantly inhibited doxorubicin-induced apoptosis and the quantity of cleaved caspase-3. Endogenous prostacyclin (PGI(2)) augmentation, which has been reported to protect NRK-52E cells from doxorubicin-induced apoptosis, induced the translocation and activation of PPAR-alpha. The transformation of PPAR-alpha short interfering RNA was applied to silence the PPAR-alpha gene, which abolished the protective effect of PGI(2) augmentation in doxorubicin-treated cells. To confirm the protective role of PPAR-alpha in vivo, PPAR-alpha activator docosahexaenoic acid (DHA) was administered to doxorubicin-treated mice, and it has been shown to significantly reduce the doxorubicin-induced apoptotic cells in renal cortex. However, this protective effect of DHA did not exist in PPAR-alpha-deficient mice. In NRK-52E cells, the overexpression of PPAR-alpha elevated the activity of catalase and superoxide dismutase and inhibited doxorubicin-induced reactive oxygen species (ROS). PPAR-alpha overexpression also inhibited the doxorubicin-induced activity of nuclear factor-kappaB (NF-kappaB), which was associated with the interaction between PPAR-alpha and NF-kappaB p65 subunit as revealed in immunoprecipitation assays. Therefore, PPAR-alpha is capable of inhibiting doxorubicin-induced ROS and NF-kappaB activity and protecting NRK-52E cells from doxorubicin-induced apoptosis.
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PMID:Peroxisomal proliferator-activated receptor-alpha protects renal tubular cells from doxorubicin-induced apoptosis. 1767 Oct 96

Although the primary response to Adriamycin (doxorubicin) in p53 mutant MDA-MB231 and p53 null MCF-7/E6 breast tumor cells is apoptotic cell death, the residual surviving population appears to be in a state of senescence, based on cell morphology, beta galactosidase staining, induction of p21(waf1/cip1) and down regulation of cdc2/cdk1. Suppression of apoptosis in MDA-MB231 and MCF-7/E6 cells treated with Adriamycin using the broad spectrum caspase inhibitor, zvad-Fmk, results in substantial induction of autophagy. Overall sensitivity to Adriamycin, measured by clonogenic survival, is not altered in the cells undergoing autophagy, consistent with autophagy contributing to cell death in response to Adriamycin. The free radical scavengers, glutathione and N-acetyl cysteine attenuate the accelerated senescence response to Adriamycin in MCF-7 cells as well as in MDA-MB231 and MCF-7/E6 cells, but protect primarily the MCF-7 cells, indicating that reactive oxygen is unlikely to be directly responsible for Adriamycin toxicity in breast tumor cells. Expression of caspase 3 or induced expression of c-myc in MCF-7 cells fails to abrogate accelerated senescence induced by Adriamycin. Taken together, these studies suggest that accelerated senescence induced by Adriamycin is similar in cells with wild type p53 and in cells lacking functional p53 with regard to the upregulation of p21(waf1/cip1), down regulation of cdc2 and the involvement of reactive oxygen species. Furthermore, accelerated senescence, autophagy and apoptosis all appear to be effective in suppressing self-renewal capacity in breast tumor cells exposed to Adriamycin.
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PMID:Apoptosis, autophagy, accelerated senescence and reactive oxygen in the response of human breast tumor cells to adriamycin. 1918 64

Given that arsenic trioxide (As(2)O(3)) has been successfully used as a chemotherapeutic agent for refractory malignant tumors, this study is aimed at investigating the effect of As(2)O(3) on human Adriamycin resistant osteosarcoma cell line Saos-2. The mechanism underlying multi drug resistance (MDR) in osteosarcoma cells and the anti-tumor effect of As(2)O(3) on Adriamycin resistant osteosarcoma cells were analyzed. In our experiment, we first selected Adriamycin resistant osteosarcoma cell line by growing the classic osteosarcoma cell line Saos-2 in the medium with increasing drug concentrations. Then, we compared the IC50s of the osteosarcoma cells treated with different anticancer drugs by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Subsequently, we assessed the expression of classic MDR related molecules, Pgp, multidrug resistance-associated protein (MRP) and glutathione (GSH) activity in the wild type and Adriamycin resistant Saos-2 cells. Furthermore, the apoptosis was assessed by concerning DNA fragment and flow cytometry with Annexin-V staining. To elucidate the underlying mechanism of the apoptosis, related proteins Bcl-2, Bcl-xL, Bax, Bak, cleaved Caspase-3 and cleaved Caspase-9 were analyzed by western blotting. The data showed that the resistance to Adriamycin affected the sensitivity of osteosarcoma cell to other chemotherapeutic agents. The IC50s of Saos-2/ADM cells for methotrexate (1.74-fold), Cisplatin (1.43-fold) and As(2)O(3) (1.21-fold) were increased compared with Saos-2 control cells. The expression of Pgp was upregulated comparing with the control cells. No significant difference was detected about the MRP and the glutathione-S-transferase activity and intracellular GSH concentration among different treated osteosarcoma cells. Apoptosis was observed and proved. The western blotting showed that the expression of Bcl-2 and Bcl-xL was downregulated. Meanwhile, the level of Bax, Bak, cleaved Caspase-3 and cleaved Caspase-9 was upregulated after treated with As(2)O(3). The study suggests that Adriamycin resistant osteosarcoma cells have good response to As(2)O(3)-based chemotherapy in vitro, probably via the pathway of inducing apoptosis. And As(2)O(3) might serve as an excellent alternative candidate for adjuvant chemotherapeutic agent on this incurable pediatric sarcoma.
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PMID:Arsenic trioxide inhibits the growth of adriamycin resistant osteosarcoma cells through inducing apoptosis. 1970 92

This study was designed to investigate the effect and molecular mechanisms of Haishengsu (HSS), a protein extract from a shellfish Tegillarca granosaL., on a drug resistant leukemia cell line. Cultured K562/Adriamycin (ADM) cells were treated with HSS at 10, 20 and 40 microg/mL, respectively. The apoptosis and expression of p-glycoprotein was evaluated by flow cytometry. Expressions of caspase-3 and Bcl-2 were also evaluated. There was a significant dose-dependent increase in the apoptosis in the HSS treated K562/ADM cells (P < 0.05 and 0.01, respectively). The p-glycoprotein expression in the 40 microg/mL HSS group (14.8%) was lower than in the control (16.9%, P < 0.05) and the 10 microg/mL HSS group (7.3%, P < 0.05), but it was similar to the HSS 20 microg/mL group (10.7%, P > 0.05). The expressions of apoptosis-stimulating protein caspase-3 protein were increased, whereas the expressions of apoptosis-suppressing Bcl-2 were decreased in the HSS groups, as compared with the levels in the control group (P < 0.05). We conclude that HSS induces apoptosis of the Adriamycin-resistant K562/ADM cells. The enhanced expressions in caspase-3 and the reduced expressions in Bcl-2 protein may have contributed to the apoptosis-stimulating effect of HSS. The inhibition of p-glycoprotein suggests that HSS may diminish the resistance to Adriamycin and potentially enhance the therapeutic effects.
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PMID:Tegillarca granosa extract Haishengsu inhibits the expression of P-glycoprotein and induces apoptosis in drug-resistant K562/ADM cells. 2064 95

Malignant gliomas are the most common and lethal primary central nervous system neoplasms. Several intriguing lines of evidence have recently emerged indicating that the cellular prion protein (PrPC) may exert neuro- and cyto-protective functions: PrPC overexpression protects cultured neurons and also tumor cell lines exposed to various pro-apoptotic stimuli while, on the contrary, PrPC silencing sensitizes Adriamycin-resistant human breast carcinoma cells to TRAIL-mediated cell death. In order to determine if PrPC is involved in the resistance of glial tumors to cell death, the effects of cellular prion protein downregulation by antisense approach were investigated in different human malignant glioma cell lines. PrPC downregulation induced profound morphological changes and significant cell death. In addition, a significant tumor volume reduction was noted after PrPC silencing in a EGFP-GL261 glioma murine model. Investigations of the molecular effects induced by PrPC silencing were carried out on T98G human glioma cells by analysing autophagic as well as typical apoptotic markers (nuclear morphology, caspase-3/7, p53 and PARP-1). The results indicated that apoptosis was not induced after PrPC downregulation while, on the contrary, electron microscopy analysis, and an accumulation of GFP-LC3-II in autophagosomal membranes of GFP-LC3 transfected cells, indicated a predominant activation of autophagy. PrPC silencing also led to induction of LC3-II, increase in Beclin-1 and a concomitant decrease in p62, Bcl-2 and in the phosphorylation of 4E-BP1, a target of mTOR autophagy signaling. In conclusion, our results show for the first time that interfering with the cellular prion protein expression could modulate autophagy-dependent cell death pathways in glial tumor cells.
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PMID:Silencing of cellular prion protein (PrPC) expression by DNA-antisense oligonucleotides induces autophagy-dependent cell death in glioma cells. 2147 78

Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cancer killer in the world. Adriamycin (ADM) is a widely used anti-cancer drug. However, the efficacy is low since high dose of ADM causes toxicity to normal tissues. Curcumin, derived from turmeric (Curcumin longa), has shown its therapeutic potential against HCC. Here, we aim to investigate the effects of curcumin combined with ADM on human liver-derived Hepatoma G2 (HepG2) cell death. We found that combination treatment of curcumin with ADM significantly decreased the number of viable cells as compared to single agent treatment. Hoechst staining demonstrated that apoptotic cell death occurred upon curcumin and ADM treatment. The decreased Bcl-2/Bax protein ratio and the activation of caspase-3 were also detected. In addition, curcumin plus ADM led to mitochondrial fragmentation, the reduction of mitochondrial membrane potential, as well as the activation of autophagy. These findings suggest the combined treatment of curcumin with ADM might be an optional chemotherapeutic method for HCC.
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PMID:Curcumin enhanced adriamycin-induced human liver-derived Hepatoma G2 cell death through activation of mitochondria-mediated apoptosis and autophagy. 2151 82


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