Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Ukrain is a reaction product of different alkaloids from Chelidonium majus L. (celandine) conjugated with thiophosphoric acid. It has immunoregulatory effects on T lymphocyte subsets and cytotoxic and cytostatic effects on various malignant cells. Although Ukrain has been reported to induce alterations in the cell cycle and tubulin polymerization, the specific cellular target has not been described. Since antineoplasic agents induce NF-kappaB and their effects are regulated by this transcription factor, we investigated its possible participation in the apoptotic effects of Ukrain. Ukrain induced apoptosis in a panel of cancer cell lines by activating the intrinsic cell death pathway, as demonstrated by the cleavage of caspase 9 and the upregulation and cleavage of caspase 3. The effect was reversible, since long exposures (24 hours or more) were needed, as verified by clonogenic assays. Gene reporter assays showed that Ukrain activated NF-kappa B. Nevertheless, this activation was not required for, and did not modulate, the Ukrain effect: neither blockage of activation by a dominant negative version of Ikappa-B alpha or a Bcl-3 siRNA, nor activation of the pathway by overexpression of IKK2, changed the response to the drug. In conclusion, Ukrain induced apoptosis in HeLa cervical cancer cells by activating the intrinsic pathway. In contrast to other antineoplasic drugs, the effects of Ukrain were not regulated by NF-kappa B.
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PMID:NF-kappaB does not influence the induction of apoptosis by Ukrain. 1672 Oct 42

Phthalocyanine-nanoparticle conjugates have been designed and synthesised for the delivery of hydrophobic photosensitizers for photodynamic therapy (PDT) of cancer. The phthalocyanine photosensitizer stabilized gold nanoparticles have an average diameter of 2-4 nm. The synthetic strategy interdigitates a phase transfer reagent between phthalocyanine molecules on the particle surface that solubilises the hydrophobic photosensitizer in polar solvents enabling delivery of the nanoparticle conjugates to cells. The phthalocyanine is present in the monomeric form on the nanoparticle surface, absorbs radiation maximally at 695 nm and catalytically produces the cytotoxic species singlet oxygen with high efficiency. These properties suggest that the phthalocyanine-nanoparticle conjugates are ideally suited for PDT. In a process that can be considered as cancer therapy using a 'Trojan horse', when the nanoparticle conjugates are incubated with HeLa cells (a cervical cancer cell line), they are taken up thus delivering the phthalocyanine photosensitizer directly into the cell interior. Irradiation of the nanoparticle conjugates within the HeLa cells induced substantial cell mortality through the photodynamic production of singlet oxygen. The PDT efficiency of the nanoparticle conjugates, determined using colorimetric assay, was twice that obtained using the free phthalocyanine derivative. Following PDT with the nanoparticle conjugates, morphological changes to the HeLa cellular structure were indicative of cell mortality via apoptosis. Further evidence of apoptosis was provided through the bioluminescent assay detection of caspase 3/7. Our results suggest that gold nanoparticle conjugates are an excellent vehicle for the delivery of surface bound hydrophobic photosensitizers for efficacious photodynamic therapy of cultured tumour cells.
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PMID:Intracellular photodynamic therapy with photosensitizer-nanoparticle conjugates: cancer therapy using a 'Trojan horse'. 1688 87

The chemical structure of ursolic acid is very similar to that of dexamethasone, a synthetic glucocorticoid. Herein, we investigated the antiproliferative and antiviral effects of ursolic acid and dexamethasone in human papillomavirus (HPV)-associated cervical cancer cells. We performed 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazonium bromide assay to measure antiproliferative activity, and also characterized apoptosis by DNA fragmentation, 4'-6-diamidino-2-phenylindole (DAPI) staining, and flow cytometry (FACS) analysis. We investigated apoptosis-related proteins using western blots. After in vitro treatment, we used reverse transcription-polymerase chain reaction for the expression of the HPV E6/E7 gene to observe the antiviral effects. Ursolic acid suppressed the growth of HPV-positive cervical carcinoma cells (HeLa, CaSki, and SiHa) in a dose- and time-dependent manner, but not the HPV-negative cervical cancer cell line (C33A). Ursolic acid-treated HeLa cells showed typical apoptosis characteristics in DNA fragmentation, DAPI staining, and FACS analysis. The expression of Fas protein was induced, and caspase-8, caspase-3, and poly ADP-ribose polymerase (PARP) proteins were cleaved after ursolic acid treatment. HPV-18 E6/E7 gene expression decreased after ursolic acid treatment in HeLa cells, but the levels of p53 and Rb proteins did not change. In contrast, dexamethasone, which has a similar structure, did not inhibit proliferation. Our findings may offer new insight into the mechanism of antiproliferative and antiviral effect of ursolic acid. Also, these results suggest that ursolic acid might be a useful anticancer drug in treatment of HPV-associated cervical neoplasia.
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PMID:Antiproliferative and antiviral mechanisms of ursolic acid and dexamethasone in cervical carcinoma cell lines. 1717 41

The saponin ginsenoside Rd (1), isolated from Panax notoginseng, is used for the treatment of cardiovascular diseases, inflammation, different body pains, trauma, and internal and external bleeding due to injury. In this study, we report that 1 inhibits the cell growth of human cervical cancer (HeLa) cells in a concentration- and time-dependent manner, with an IC(50) value of 150.5+/-0.8 mcirog/ml after 48 h of incubation. The drug-treated cells displayed features of apoptosis, including typical morphological characteristics and formation of DNA ladders, as evident from agarose-gel electrophoresis. Flow-cytometric analysis showed that the cell-cycle distribution of HeLa cells exposed to 1 is characterized by a decrease of the G(0)/G(1)-phase and an increase of the S-phase cells, respectively, in a dose-dependent manner. The apoptotic rate of HeLa cells treated for 48 h with 210 microg/ml of 1 was 35.8%. Further, 1 was found to increase the expression of Bax and to decrease the expression of Bcl-2 proteins, respectively, and to lower the mitochondrial transmembrane potential of HeLa cells. The caspase-3 inhibitor DEVD-CHO (at 2 microM) increased the viability of HeLa cells treated with 1. Taken together, our study suggests that ginsenoside Rd (1) significantly inhibits HeLa cell proliferation, and induces cell apoptosis through down-regulating Bcl-2 expression, up-regulating Bax expression, lowering the mitochondrial transmembrane potential, and activating the caspase-3 pathway. Thus, 1 could serve as a lead to develop novel chemotherapeutic or chemopreventive agents against human cervical cancer.
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PMID:Ginsenoside Rd from Panax notoginseng is cytotoxic towards HeLa cancer cells and induces apoptosis. 1719 57

Retinoid-inducible gene 1 encodes RIG1 is a growth regulator, which inhibits the pathways of the RAS/mitogen-activated protein kinases by suppressing the activation of RAS. Confocal microscopic analysis demonstrated that RIG1 is localized in the endoplasmic reticulum (ER) and Golgi apparatus in HtTA cervical cancer cells. Carboxyterminal-deleted RIG1 targeted to the Golgi or ER was constructed and validated. The activation of HRAS was inhibited by 25.1% or 81.4% in cells cotransfected with wild-type or Golgi-targeted RIG1, respectively. Expression of wild-type or Golgi-targeted RIG1 for 24 h induced cellular apoptosis in HtTA cells, as assessed by MTT assay, the release of lactate dehydrogenase, and chromatin condensation. In contrast, ER-targeted RIG1 and carboxyterminal-deleted RIG1 (RIG1DeltaC) exhibited no activity. Caspase-2, -3, and -9 were activated following the expression of wild-type and Golgi-targeted RIG1. Although the caspase-3 inhibitor Z-DEVD-FMK partially or completely reversed the cell death induced by wild-type or Golgi-targeted RIG1, it did not prevent the anti-RAS effect of RIG1. In conclusion, the proapoptotic and anti-RAS activities of RIG1 are primarily associated with the Golgi localization of the protein. The proapoptotic activities of RIG1 are mediated through the activation of caspase-2 and -3 and are independent of its effect on RAS.
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PMID:RIG1 suppresses Ras activation and induces cellular apoptosis at the Golgi apparatus. 1719 92

Apoptosis induced by rhein, an active component of senna, has been reported in various human cancer cells, however, its molecular mechanisms are not precisely known. In this study, the mechanisms of apoptosis by which rhein acts on human cervical cancer Ca Ski cells were examined. Flow cytometric analysis demonstrated that rhein induced the abrogation of mitochondrial membrane potential (MMP) and cleavage of Bid protein. Rhein also induced an increase in the levels of Fas, p53, p21 and Bar, but a decrease in the level of Bcl-2. The activities of both caspase-8 and -9 were enhanced by rhein, promoting caspase-3 activation, leading to DNA fragmentation, thus, indicating that rhein-induced apoptosis is caspase-dependent. In addition, rhein induced an increase in the level of cytoplasmic Ca2+, which was inhibited by BAPTA (a calcium chelator). BAPTA attenuated the MMP abrogation and significantly dinimished the occurrence of rhein-induced apoptosis in Ca Ski cells. In conclusion, our data demonstrate that rhein-induced apoptosis occurs via a caspase-dependent and mitochondria-dependent pathway which is closely related to the level of cytoplasmic Ca2+ in Ca Ski cells.
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PMID:The role of Ca+2 on rhein-induced apoptosis in human cervical cancer Ca Ski cells. 1735 57

Arsenic trioxide (As2O3) induces apoptosis in certain types of cancer cells. But the detailed mechanisms of As2O3 efficacy are not completely known. Here we demonstrate that As2O3 has a therapeutic effect on cervical cancer in vitro and in vivo. We investigated the As2O3-induced apoptosis in various cervical cancer cells. The apoptosis was triggered by mitochondrial pathway and associated with dissociation of Bcl-2 from Bax and VDAC, then the release of cytochrome c from Bax and VDAC channel, resulting in the activation of caspase-9 and caspase-3. The overexpression of Bcl-2 counteracted the As2O3-mediated apoptosis. The As2O3 treatment also resulted in an increased M phase cell cycle distribution by inducing microtubule polymerization. Two independent death-signaling pathways in cervical cancer cells were activated, one dominated by JNK/p38/GADD45 and one by p53 signals. Further investigation involving assessment of As2O3 on tumor cell growth in mice indicated that As203 also inhibited in vivo tumor growth. As2O3 as an inhibitor of cervical cancer proliferation both in vitro and in vivo suggests a potential clinical application in cervical cancer therapies.
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PMID:Therapeutic effect of arsenic trioxide (As2O3) on cervical cancer in vitro and in vivo through apoptosis induction. 1737 90

Persistent infection with oncogenic human papillomaviruses (HPVs) is the most important factor in the induction of uterine cervical cancer, a leading cause of cancer mortality in women worldwide. Upon cell transformation, continual expression of the viral oncogenes is required to maintain the transformed phenotype. The viral E6 protein forms a ternary complex with the cellular E6-AP protein and p53 protein which promotes the rapid degradation of p53. Recent studies have revealed that lignans from the creosote bush (3'-O-methyl-nordihydroguaiaretic acid) can repress the viral promoter responsible for E6 gene expression. Work reported here shows that the lignan can subvert viral oncogene function resulting in stabilized p53 protein within treated HPV-containing tumor cells. The stabilized p53 is transcriptionally active as demonstrated by a luciferase reporter vector and induction of genes for Bax and PUMA proteins. Apoptosis is detected by annexin V binding to treated cells as analyzed by flow cytometry. Programmed cell death is confirmed by the induction of active caspases and TUNEL assay. Initiator caspase-9 is activated first, followed later by the effector caspase-3 enzyme. The stabilization and induced apoptosis are not observed within treated HPV-negative cervical tumor cells. Quantitative real time RT-PCR analysis of endogenous E6 gene transcription from the integrated HPV 16 promoter shows at least a fivefold repression of expression as compared to untreated cells. These results indicate that the loss of E6 protein in treated cells could be, in part, responsible for the stabilization of p53 within the lignan treated cells.
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PMID:A plant lignan, 3'-O-methyl-nordihydroguaiaretic acid, suppresses papillomavirus E6 protein function, stabilizes p53 protein, and induces apoptosis in cervical tumor cells. 1739 35

The cytotoxic effects of a new compound, ethyl 2-[N-p-chlorobenzyl-(2'-methyl)] aniline-4-oxo-4,5-dihydrofuran-3-carboxylate (JOT01007) have been tested in mouse leukemia WEHI-3 cells. In this study, the mechanisms by which JOT01007 acts on a human cervical cancer cell line (Ca Ski) to bring about an increase in the ratio of Bax/Bcl-2, reduction of the mitochondrial membrane potential (MMP), increase in the levels of cytoplasmic Ca2+, activation of caspases and fragmentation of DNA, and apoptosis were investigated. Flow cytometric analysis demonstrated that JOT01007 induced a decrease of MMP in Ca Ski cells. JOT01007 induced an increase in the level of cytoplasmic Ca2+, which was inhibited by BAPTA (calcium chelator), and BAPTA accelerated the MMP reduction, and significantly blocked JOT01007-induced apoptosis. Western blotting demonstrated that JOT01007 induced an increase in the levels of p53, p2I, cytochrome-c, caspase-3 and Bax, but decreased the level of Bcl-2. In conclusion, our data demonstrate that JOT01007-induced apoptosis occurs via a mitochondria-dependent pathway closely related to the level of cytoplasmic Ca2+ in Ca Ski cells.
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PMID:Ethyl 2- [N-p-chlorobenzyl- (2'-methyl)] anilino-4-oxo-4,5-dihydrofuran-3-carboxylate (JOT01007)induces apoptosis in human cervical cancer Ca Ski cells. 1743 94

The effect of celecoxib, a cyclooxygenase-2 selective inhibitor, on a human cervical cancer cell line, HeLa cells, was examined. We found that celecoxib increased DNA ladder formation and the activity of caspase-3, indicating that celecoxib induced apoptosis in HeLa cells. Celecoxib suppressed the expression of an anti-apoptotic protein, survivin, in both protein and mRNA levels. The overexpression of survivin overrode caspase-3 activation induced by celecoxib. Subsequently, we performed luciferase reporter assay with the reporter vector containing human survivin promoter region and electrophoretic mobility shift assay and found that the -75 to -66 bp region relative to the initiating codon played an important role in celecoxib action to suppress survivin promoter activity. Our findings might provide a new insight into the anti-cancer effects of celecoxib.
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PMID:Celecoxib induces apoptosis by inhibiting the expression of survivin in HeLa cells. 1746 71


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