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)

Sanguinarine, a benzophenanthridine alkaloid, has anticancer potential through induction of cell death. We previously demonstrated that sanguinarine treatment at a low level induced apoptosis or programmed cell death (PCD) in the Bcl-2 low-expressing K562 human erythroleukemia cells, and that a high level induced blister cell death (BCD); whereas Bcl-2 overexpressing, sanguinarine-treated JM1 pre-B lymphoblastic cells displayed neither apoptosis nor BCD morphologies. Here, we report that sanguinarine-treated K562 cells, when analyzed by western blot, showed significant increase in expression of the pro-apoptotic Bax protein in apoptosis, but not in BCD. cDNA expression array of PCD in K562 cells failed to reveal the presence of Bax at the gene transcript level, which suggests that this cell death process does not require de novo protein synthesis. Treated JM1 cells, on the other hand, showed an increase in the expression of Bcl-2 protein in both forms of cell death, but failed to show Bax expression. The role of other members of the Bcl-2 family remained negligible. Caspase-3 activation was observed in apoptosis of K562 cells but not in BCD or in sanguinarine-treated JM1 cells. These results suggest that sanguinarine in K562 cells induces apoptosis through increasing Bax and activating caspase-3, whereas sanguinarine-induced BCD involves neither. These results also suggest that in JM1 cells, Bcl-2 may play a role in susceptibility of cells to induction of apoptosis and BCD.
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PMID:Role of Bcl-2 family proteins and caspase-3 in sanguinarine-induced bimodal cell death. 1178 59

Sanguinarine, a benzophenanthrine alkaloid, is potentially antineoplastic through induction of cell death pathways. The development of multidrug resistance (MDR) is a major obstacle to the success of chemotherapeutic agents. The aim of this study was to investigate whether sanguinarine is effective against uterine cervical MDR and, if so, by which mechanism. The effects of treatment with sanguinarine on human papillomavirus (HPV) type 16-immortalized endocervical cells and their MDR counterpart cells were compared. Trypan blue exclusion assays and clonogenic survival assays demonstrated that MDR human cervical cells are as sensitive as their drug-sensitive parental cells to death induced by sanguinarine. Upon treatment of both types of cells with sanguinarine, two distinct concentration-dependent modes of cell death were observed. Treatment with 2.12 or 4.24 microM sanguinarine induced death in most cells that was characterized as apoptosis using the criteria of cell surface blebbing, as determined by light and scanning electron microscopy, and proteolytic activation of caspase-3 and cleavage of the caspase-3 substrate poly(ADP-ribose) polymerase (PARP), as detected by Western blot analysis. However, 8.48 and 16.96 microM sanguinarine caused a second mode of cell death, oncosis, distinguished by cell surface blistering, and neither caspase-3 activation nor PARP cleavage. This study provides the first evidence that sanguinarine is effective against MDR in cervical cells via bimodal cell death, which displays alternative mechanisms involving different morphologies and caspase-3 activation status.
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PMID:The alkaloid sanguinarine is effective against multidrug resistance in human cervical cells via bimodal cell death. 1199 82

Sanguinarine, derived from the root of Sanguinaria canadensis and other poppy fumaria species, possesses strong antimicrobial, anti-inflammatory, and antioxidant properties. We earlier showed that sanguinarine kills human epidermoid carcinoma A431 cells via an induction of apoptosis [N. Ahmad et al., Clin. Cancer Res., 6: 1524-1528, 2000]. In this study, using immortalized human keratinocytes (HaCaT cells), we provide information about mechanism of the antiproliferative effect of sanguinarine. Sanguinarine [0.1 (M-2 (M)] treatment to HaCaT cells was found to inhibit in a dose-dependent manner the cell proliferation and induce apoptosis, as measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and ELISA, respectively. Sanguinarine treatment also resulted in a significant cleavage of poly(ADP-ribose) polymerase in HaCaT cells. Because mitochondrial pathway is critical for the regulation of apoptosis, we studied the involvement and regulation of mitochondrial events in sanguinarine-mediated apoptosis of HaCaT cells. As shown by the immunoblot analysis, our data clearly demonstrated that sanguinarine treatment to HaCaT cells resulted in a dose-dependent (a) increase in the level of Bax with a concomitant decrease in Bcl-2 levels and (b) increase in Bax/Bcl-2 ratio. Sanguinarine also resulted in significant increases in the proapoptotic members of Bcl-2 family proteins, i.e., Bak and Bid. This was accompanied by increase in (a) protein expression of cytochrome c and apoptotic protease-activating factor-1 and (b) activity and protein expression of caspase-3, caspase-7, caspase-8, and caspase-9. Taken together, our data showed the involvement of mitochondrial pathway and Bcl-2 family proteins during sanguinarine-mediated apoptosis of immortalized keratinocytes. We suggest that sanguinarine could be developed as a drug for the management of hyperproliferative skin disorders, including skin cancer.
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PMID:Activation of prodeath Bcl-2 family proteins and mitochondrial apoptosis pathway by sanguinarine in immortalized human HaCaT keratinocytes. 1291 70

Expression of cyclooxygenase-2 (Cox-2), an inducible enzyme responsible for the production of prostaglandins from arachidonic acid, is elevated in human prostate tumor samples. The aim of this study was to investigate whether expression of Cox-2 is effective against prostate cancer cell apoptosis triggered by sanguinarine, the quaternary benzophenanthridine alkaloid with antineoplastic properties. Sanguinarine effectively induced apoptosis in LNCaP human prostate cancer epithelial cells as assessed by caspase-3 activation assay, Annexin V staining assay, or by visual analysis for the apoptotic morphology changes. Sanguinarine-mediated apoptosis was associated with the increase of nitric oxide (NO) formation in prostate cancer cells as assessed by measurements of nitrites with Sievers nitric oxide analyzer as well as flow cytometry analysis using NO fluorescent sensor. Activation of NO synthase (NOS) activity was crucial for sanguinarine-induced cell death because NOS inhibitor L-NMMA efficiently protected cells from apoptosis. Adenovirus-mediated transfer of Cox-2 into LNCaP cells inhibited sanguinarine-induced apoptosis and prevented an increase in NO production. Surprisingly, NO donors failed to induce apoptosis in LNCaP cells, suggesting that constitutive NO generation is not sufficient for triggering apoptosis in these cells. Besides NO generation, NOS is also capable of producing superoxide radicals. Sanguinarine-induced production of superoxide radicals, and the addition of MnTBAP, a scavenger of superoxide radicals, efficiently inhibited sanguinarine-mediated apoptosis. These results suggest that Cox-2 expression rescues prostate cancer cells from sanguinarine-induced apoptosis by a mechanism involving inhibition of NOS activity, and that coadministration of Cox-2 inhibitors with sanguinarine may be developed as a strategy for the management of prostate cancer.
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PMID:Cyclooxygenase 2 rescues LNCaP prostate cancer cells from sanguinarine-induced apoptosis by a mechanism involving inhibition of nitric oxide synthase activity. 1658 99

Primary effusion lymphoma (PEL) is an incurable, aggressive B-cell malignancy that develops rapid resistance to conventional chemotherapy. In efforts to identify novel approaches to block proliferation of PEL cells, we found that sanguinarine, a natural compound isolated from the root plant Sanguinaria canadendid, inhibits cell proliferation and induces apoptosis in a dose-dependent manner in several PEL cell lines. Our data show that sanguinarine treatment of PEL cells results in up-regulation of death receptor 5 (DR5) expression via generation of reactive oxygen species (ROS) and causes activation of caspase-8 and truncation of Bid (tBid). Subsequently, tBid translocates to the mitochondria causing conformational changes in Bax, leading to loss of mitochondrial membrane potential and release of cytochrome c to the cytosol. Sanguinarine-induced release of cytochrome c results in activation of caspase-9 and caspase-3 and poly(ADP-ribose) polymerase (PARP) cleavage, leading to induction of caspase-dependent apoptosis. In addition, we show that pretreatment of PEL cells with carbobenzoxy-Val-Ala-Asp-fluoromethylketone, a universal inhibitor of caspases, abrogates caspase and PARP activation and prevents cell death induced by sanguinarine. Moreover, treatment of PEL cells with sanguinarine down-regulates expression of inhibitor of apoptosis proteins (IAP). Finally, N-acetylcysteine, an inhibitor of ROS, inhibits sanguinarine-induced generation of ROS, up-regulation of DR5, Bax conformational changes, activation of caspase-3, and down-regulation of IAPs. Taken together, our findings suggest that sanguinarine is a potent inducer of apoptosis of PEL cells via up-regulation of DR5 and raise the possibility that this agent may be of value in the development of novel therapeutic approaches for the treatment of PEL.
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PMID:Sanguinarine-dependent induction of apoptosis in primary effusion lymphoma cells. 1744 Jan 3

Sanguinarine is a benzophenanthridine alkaloid that is derived from the root of Sanguinaria canadensis and other poppy fumaria species, and is known to have antimicrobial, antiinflammatory and antioxidant properties. This study investigated the possible mechanisms through which sanguinarine exerts its antiproliferative action in cultured C6 rat glioblastoma cells. The exposure of C6 cells to sanguinarine resulted in growth inhibition and the induction of apoptosis in a dose-dependent manner, as measured by the MTT assay, fluorescence microscopy, agarose gel electrophoresis and annexin-V-based assay. The sanguinarine treatment induced the proteolytic activation of caspases and ICAD/DFF45, which was associated with the modulation of the Bcl-2 family, concomitant degradation of poly(ADP ribose) polymerase and phospholipase C-gamma1 protein, and DNA fragmentation. z-DEVD-fmk, a caspase-3-specific inhibitor, blocked poly(ADP ribose) polymerase degradation, DNA fragmentation and increased the survival rate of sanguinarine-treated C6 cells. Moreover, the activity of extracellular signal-regulated kinase and Akt was downregulated in sanguinarine-treated cells, and PD98059, a specific extracellular signal-regulated kinase inhibitor, and phosphatidylinositol 3'-kinase/Akt inhibitors, LY294002 and wortmanin, sensitized the cells to sanguinarine-induced apoptosis, indicating that the downregulation of the extracellular signal-regulated kinase and Akt signaling pathway may play a key role in sanguinarine-induced apoptosis in C6 cells.
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PMID:Induction of apoptosis by sanguinarine in C6 rat glioblastoma cells is associated with the modulation of the Bcl-2 family and activation of caspases through downregulation of extracellular signal-regulated kinase and Akt. 1766 97

Sanguinarine is a benzophenanthridine alkaloid derived from the root of Sanguinaria canadensis and other poppy-fumaria species, possessing potent antibacterial, antifungal, and anti-inflammatory activities. In this study, we investigated the underling mechanisms by which sanguinarine induce apoptosis in human breast cancer MDA-231 cells. Treatment of MDA-231 cells with sanguinarine induced remarkable apoptosis accompanying the generation of ROS. Consistently, sanguinarine-induced apoptosis was mediated by the increased reproductive cell death. Pretreatment with NAC or GSH attenuated sanguinarine-induced apoptosis, suggesting the involvement of ROS in this cell death. During sanguinarin-induced apoptosis, protein levels of pro-caspase-3, Bcl-2, cIAP2, XIAP, and c-FLIPs were reduced. Sanguinarine-mediated apoptosis was substantially blocked by ectopic expression of Bcl-2 and cFLIPs. Additionally, we found that sub-lethal doses of sanguinarine remarkably sensitized breast cancer cells to TRAIL-mediated apoptosis, but the cell death induced by sanguinarine and TRAIL in combination was not blocked by overexpression of Bcl-2 or Akt. Therefore, combinatory treatment of sanguinarine and TRAIL may overcome the resistance of breast cancer cells due to overexpression of Akt or Bcl-2.
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PMID:Sanguinarine-induced apoptosis: generation of ROS, down-regulation of Bcl-2, c-FLIP, and synergy with TRAIL. 1818 68

Sanguinarine, chelerythrine and chelidonine possess prominent apoptotic effects towards cancer cells. In this study, we found that sanguinarine and chelerythrine induce apoptosis in human CEM T-leukemia cells, and that is accompanied by an early increase in cytosolic cytochrome c that precedes caspases-8, -9 and -3 processing. During apoptosis induction by sanguinarine and chelerythrine, reactive oxygen species (ROS) was rapidly generated and DeltaPsi(mt) dissipated, while Bax, Bcl-2 and Bcl-X((L/S)) proteins' content in the mitochondrial fraction did not change significantly. Caspase-3 activation and DNA fragmentation were considerably inhibited by N-acetyl-cysteine (NAC). Chelidonine induced only a slight release of cytochrome c (12h), parallel to caspase-3 activation. Effect of sanguinarine or chelerythrine towards mitochondria was confirmed by marked changes in morphology of this organelle (3h), while chelidonine did not affect mitochondria intactness. Sanguinarine or chelerythrine also caused an intensive DNA damage in cells in 1h, however a massive increase in number of such impaired cells occurred in 6h, while chelidonine induced intensive DNA damage in 15-20% cells only in 24h. Thus, our results demonstrated that rapid cytochrome c release in CEM T-leukemia cells exposed to sanguinarine or chelerythrine was not accompanied by changes in Bax, Bcl-2 and Bcl-X((L/S)) proteins in the mitochondrial fraction, and preceded activation of the initiator caspase-8.
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PMID:A decisive role of mitochondria in defining rate and intensity of apoptosis induction by different alkaloids. 1832 96

Sanguinarine is a benzophenanthridine alkaloid, derived from the root of Sanguinaria canadensis and other poppy Fumaria species, which is known to have antimicrobial, antiinflammatory and antioxidant properties. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is known to induce apoptosis in cancer cells but spare most normal cells. However, its effects are limited in some types of cancer cells, including AGS human gastric adenocarcinoma cells. In the present study, we showed that treatment with TRAIL in combination with subtoxic concentrations of sanguinarine sensitized TRAIL-mediated apoptosis in AGS cells. Combined treatment with sanguinarine and TRAIL effectively induced Bid cleavage and loss of mitochondrial membrane potential, leading to the activation of caspases, and cleavage of poly(ADP-ribose) polymerase and beta-catenin. The cytotoxic effects of the combined treatment were significantly inhibited by z-DEVD-fmk, a caspase-3 inhibitor, which demonstrates the important role of caspase-3 in the observed cytotoxic effect. In addition, the levels of Akt protein were markedly reduced in cells co-treated with sanguinarine and TRAIL. Apoptosis induced by the combined treatment was markedly increased by the phosphatidylinositol-3'-kinase inhibitor, LY294002 (Akt-upstream inhibitor), through the mitochondrial amplification step and caspase activation, suggesting that interactions of the synergistic effect were at least partially mediated through the Akt-dependent pathway.
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PMID:Sanguinarine sensitizes human gastric adenocarcinoma AGS cells to TRAIL-mediated apoptosis via down-regulation of AKT and activation of caspase-3. 2003 92

Sanguinarine, a plant alkaloid, was identified as a potent and specific protein phosphatase (PP) 2C inhibitor. It inhibited PP2C competitively with respect to alpha-casein (Ki=0.68 microM) and showed selectivity for PP2C as compared with PP1, PP2A, and PP2B in vitro. In vivo, sanguinarine showed cytotoxicity toward human promyelocytic leukemia cell line HL60, with an IC(50) value of 0.37 microM, and induced apoptosis through a caspase-3/7-dependent mechanism involving the phosphorylation of p38, a PP2Calpha substrate. The apoptosis activity induced by sanguinarine was partially inhibited by a p38 inhibitor, SB203580, and was involved in the phospho-p38 protein in HL60 cells.
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PMID:Sanguinarine as a potent and specific inhibitor of protein phosphatase 2C in vitro and induces apoptosis via phosphorylation of p38 in HL60 cells. 2020 61


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