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 work described here involved the synthesis and biological evaluation of new heteroaryldiamides and heteroaryldiamines. A new general model in which the structures can be adjusted has been applied in this study. Three different structural units can be distinguished: a central nucleus and two symmetric terminal units. The central element is either an aliphatic chain of varying length and flexibility, piperazine, or a polyamine nucleus. However, the terminal units are pyridine, quinoline, indole, benzene or pyrido[2,3-d]pyrimidine with different substituents. The antitumoural activities of the compounds were evaluated in vitro by examining their cytotoxic effects against human breast, colon, and bladder cancer cell lines. Compounds that showed cytotoxic activity were subjected to both apoptosis and caspase-3 assays. With regard to selectivity, the cytotoxicity was also determined in cell cultures of two nontumoural lines. The most promising compounds are 4c, 5c and 7, which are amino-pyridinium, quinolyl-N-oxide, and pyridyl derivatives, respectively, and these reveal a significant in vitro cytotoxicity in at least two of the three cell lines tested. These compounds induced apoptosis and also produced a rapid dose-dependent increase in the caspase-3 level in HT-29 cells. Other encouraging profiles were found, such as those presented by 1k and 8d, which are cytotoxic and apoptotic but do not provoke an increase in the level of caspase-3, or those presented by 2f, 3c and 4a, which are slightly cytotoxic but do not show any other significant activity. The different types of behaviour of each compound are not necessarily parallel in the three cell lines tested.
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PMID:Synthesis and biological evaluation of heteroaryldiamides and heteroaryldiamines as cytotoxic agents, apoptosis inducers and caspase-3 activators. 1657 81

In the search of new symmetrical derivatives with anticancer activity, we have looked for novel compounds able to induce a selective proapoptotic mechanism in cancer cells. The potential antitumoral activity of several quinazoline derivatives was evaluated in vitro examining their cytotoxic effects against human breast, colon and bladder cancer cell lines. The IC(50) value of the compounds that showed cytotoxic activity was calculated. These compounds were tested for their ability to induce caspase-3 activation and nuclear chromatin degradation. Non-tumoral human cell lines were used to test the selectivity of the cytotoxic compounds against cancer cells. Several compounds showed no cytotoxicity in these cell lines. Finally, JRF12 (2,4-dibenzylaminoquinazoline) was chosen as the best candidate and its mechanism of action was studied in more detail. A time dependent evaluation of apoptosis was performed in the three cancer cell lines, followed by an evaluation of the cell cycle regulation involvement that showed a decrease of cells in G(1) phase and increase of cells in G(2) phase before cell death. 2,4-dibenzylaminoquinazoline treatment produces few changes in the expression of genes as evaluated by using oligonucleotide microarrays and Q-RT-PCR assays. In conclusion, 2,4-dibenzylaminoquinazoline is a promising anticancer drug showing cytostatic and apoptotic effects mainly in a transcription independent manner.
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PMID:New symmetrical quinazoline derivatives selectively induce apoptosis in human cancer cells. 1676 Jun 48

Human beta-defensin-1 (hBD-1) is a candidate tumor suppressor gene located on chromosome 8p23. Previously, we showed that cancer-specific loss of hBD-1 was found in 90% of renal clear cell carcinomas and in 82% of prostate cancers. To investigate the possible mechanisms of decreased gene expression and determine the function of hBD-1 protein in urological cancers, we sequenced hBD-1 gene coding regions in prostatic and renal cancer samples. We then analyzed the frequency distribution of promoter polymorphisms and determined the effect of these base changes on transcriptional activity of the hBD-1 promoter. A polymorphism at -688 bases upstream of the ATG start codon affects hBD-1 promoter activity, leading to a rate of reporter gene transcription that is 40% to 50% lower than the wild-type sequence when tested in either DU145 or TSU-Pr1 cell lines. In addition, a polymorphism at -44 bases was shown to enhance transcription up to 2.3 times more than the wild-type sequence in the same cell lines. In addition, three novel hBD-1 promoter mutations were found in renal and prostate cancer clinical samples. An iso-5-aza-2'-deoxycytidine treatment was effective in transcription up-regulation in DU145, suggesting a possible upstream methylation-dependent effect. Synthetic hBD-1 peptide inhibited bladder cancer cell TSU-Pr1 proliferation. Overexpression of the hBD-1 gene in renal cancer cells SW156 resulted in caspase-3-mediated apoptosis. These data support the hypothesis that hBD-1 is a potential tumor suppressor gene for urological cancers. Promoter point mutations may be responsible for cancer-specific loss of hDB-1 expression.
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PMID:Human beta-defensin-1, a potential chromosome 8p tumor suppressor: control of transcription and induction of apoptosis in renal cell carcinoma. 1757 71

Tumor cells express HYAL1 hyaluronidase, which degrades hyaluronic acid. HYAL1 expression in bladder cancer cells promotes tumor growth, invasion, and angiogenesis. We previously described five alternatively spliced variants of HYAL1 that encode enzymatically inactive proteins. The HYAL1-v1 variant lacks a 30-amino acid sequence that is present in HYAL1. In this study, we examined whether HYAL1-v1 expression affects bladder cancer growth and invasion by stably transfecting HT1376 bladder cancer cells with a HYAL1-v1 cDNA construct. Although HYAL1-v1 transfectants expressed equivalent levels of enzymatically active HYAL1 protein when compared with vector transfectants, their conditioned medium had 4-fold less hyaluronidase activity due to a noncovalent complex formed between HYAL1 and HYAL1-v1 proteins. HYAL1-v1 transfectants grew 3- to 4-fold slower due to cell cycle arrest in the G(2)-M phase and increased apoptosis. In HYAL1-v1 transfectants, cyclin B1, cdc2/p34, and cdc25c levels were > or =2-fold lower than those in vector transfectants. The increased apoptosis in HYAL1-v1 transfectants was due to the extrinsic pathway involving Fas and Fas-associated death domain up-regulation, caspase-8 activation, and BID cleavage, leading to caspase-9 and caspase-3 activation and poly(ADP-ribose) polymerase cleavage. When implanted in athymic mice, HYAL1-v1-expressing tumors grew 3- to 4-fold slower and tumor weights at day 35 were 3- to 6-fold less than the vector tumors (P < 0.001). Whereas vector tumors were infiltrating and had high mitoses and microvessel density, HYAL1-v1 tumors were necrotic, infiltrated with neutrophils, and showed low mitoses and microvessel density. Therefore, HYAL-v1 expression may negatively regulate bladder tumor growth, infiltration, and angiogenesis.
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PMID:HYAL1-v1, an alternatively spliced variant of HYAL1 hyaluronidase: a negative regulator of bladder cancer. 1714 67

Recent data suggest that new treatment options for superficial bladder cancer are necessary, owing to the high recurrence rate after conventional treatment, especially in T1G3 and Bacillus Calmette-Guerin-refractory patients. Phase I and II studies have demonstrated that gemcitabine may represent a candidate for intravesical therapy in superficial bladder cancer. Despite clinical trials, the in-vitro cytotoxic and proapoptotic effects of gemcitabine have been poorly investigated. In the present study, we investigated how gemcitabine affects apoptosis in bladder cancer cell line 5637, which has the same molecular features of high-risk superficial bladder cancer. Apoptosis was evaluated by DNA fragmentation, flow cytometry and caspase activation. bcl-2, bcl-X, bax, survivin and fas gene expression were also evaluated by reverse-transcriptase polymerase chain reaction. Nuclear factor-kappa B activation was assessed by immunofluorescence. Gemcitabine induced apoptosis in 5637 cells in a time-dependent manner, with activation of caspase-3, -8 and -9. Expression of bcl-2, bax, survivin and bcl-X was not affected by treatment, whereas fas strongly increased after 24 h of treatment. After treatment, we failed to find any nuclear localization of nuclear factor-kappa B. As gemcitabine-induced apoptosis involves fas upregulation, these results may encourage the investigation of intravesical gemcitabine in fas-negative bladder tumors. Furthermore, as nuclear factor-kappa B activation by cisplatin, doxorubicin and adriamycin may result in enhanced proliferation, migration, immortality and inhibition of apoptosis, the observation that gemcitabine does not activate nuclear factor-kappa B may have implications in intravesical therapy of high-risk superficial bladder cancer.
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PMID:Gemcitabine-induced apoptosis in 5637 cell line: an in-vitro model for high-risk superficial bladder cancer. 1715 4

Clinical studies have shown gallium nitrate to have significant antitumor activity against non-Hodgkin's lymphoma and bladder cancer, thus indicating that gallium-based drugs have potential for further development as antineoplastic agents. In this study, we compared the cytotoxicity of gallium maltolate, a novel gallium compound, with gallium nitrate in lymphoma cell lines, including p53 variant and unique gallium nitrate-resistant cells. We found that gallium maltolate inhibited cell proliferation and induced apoptosis through the mitochondrial pathway at lower concentrations and more rapidly than gallium nitrate. Gallium maltolate produced an increase in intracellular reactive oxygen species (ROS) within 2 h of incubation with cells; this effect could be blocked by mitoquinone, a mitochondria-targeted antioxidant. The role of the transferrin receptor (TfR) in gallium maltolate's action was examined using monoclonal antibody (MoAb) 42/6 to block TfR function. However, although MoAb 42/6 reduced gallium maltolate-induced caspase-3 activity, it had only a minor effect on cell growth inhibition. Importantly, gallium maltolate induced apoptosis in cells resistant to gallium nitrate, and, unlike gallium nitrate, its cytotoxicity was not affected by cellular p53 status. Cellular gallium uptake was greater with gallium maltolate than with gallium nitrate. We conclude that gallium maltolate inhibits cell proliferation and induces apoptosis more efficiently than gallium nitrate. Gallium maltolate is incorporated into lymphoma cells to a greater extent than gallium nitrate via both TfR-independent and -dependent pathways; it has significant activity against gallium nitrate-resistant cells and acts independently of p53. Further studies to evaluate its antineoplastic activity in vivo are warranted.
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PMID:Development of gallium compounds for treatment of lymphoma: gallium maltolate, a novel hydroxypyrone gallium compound, induces apoptosis and circumvents lymphoma cell resistance to gallium nitrate. 1760 Jan 39

Recently, we reported prognostic significance of thromboxane synthase (TXAS) gene expression in invasive bladder cancer. The positive correlation between elevated TXAS expression and shorter patient survival supports a potential role for TXAS-regulated pathways in tumor metastases. In this study, using immunohistochemical analysis, we found an increased expression of TXAS protein in bladder cancer. Treatment of T24 and transitional cell carcinoma TCC-SUP bladder cancer cells with the TXAS inhibitors furegrelate or ozagrel induced an apoptotic effect measured as an increase in caspase-3 activation and cell death, and decreased survivin expression. Pharmacological inhibition of TXAS using the TXAS inhibitor furegrelate increased sensitivity to the chemotherapeutic agents cisplatin and paclitaxel. Molecular inhibition of TXAS expression by siRNA significantly decreased cell growth and migration. In concordance with the pharmacological data, siRNA-mediated reduction of TXAS expression increased sensitivity to cisplatin and paclitaxel in T24 and TCC-SUP cells. In summary, the data support a role for the thromboxane A(2) pathway in the pathogenesis of bladder cancer and the potential utility of modulation of this signaling pathway for cancer chemotherapy.
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PMID:Inhibition of thromboxane synthase activity modulates bladder cancer cell responses to chemotherapeutic agents. 1760 59

Chalcones (1,3-diphenyl-2-propenone) are cancer preventive food components found in a human diet rich in fruits and vegetables. In this study, we first report the chemopreventive effect of chalcone in two human bladder cancer cell lines: T24 and HT-1376. The results show that chalcone inhibits the proliferation of T24 and HT-1376 cells by inducing apoptosis and blocking cell cycle progression in the G2/M phase. Western blot assay showed that chalcone significantly increases the expression of p21 and p27 proteins, and decreases the levels of cyclin B1, cyclin A and Cdc2, thereby contributing to cell cycle arrest. In addition, chalcone increased the expression of Bax and Bak, but decreased the levels of Bcl-2 and Bcl-X(L) and subsequently triggered mitochondrial apoptotic pathway (release of cytochrome c and activation of caspase-9 and caspase-3). Our study suggests that the induction of mitochondrial pathway and inhibition of the nuclear factor kappa B survival system may play important roles in the antiproliferative activity of chalcone in T24 and HT-1376 cells.
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PMID:Chalcone arrests cell cycle progression and induces apoptosis through induction of mitochondrial pathway and inhibition of nuclear factor kappa B signalling in human bladder cancer cells. 1784 7

In the search for new derivatives with anticancer activity that are able to induce a selective pro-apoptotic mechanism in cancer cells, we have designed, synthesized, and evaluated a series of new 2-(alkylsulfanyl)-N-alkylpyrido[2,3-d]pyrimidine-4-amine derivatives as cytotoxic and apoptosis inducers. The potential antitumor activity of the compounds was evaluated in vitro by examining their cytotoxic effects against human breast, colon, and bladder cancer-cell lines. The IC(50)values of the compounds that showed cytotoxic activity were calculated. The cytotoxic compounds were then tested for their ability to induce caspase-3 activation and nuclear-chromatin degradation. Some compounds, such as 6c, 6d, 6e, 6j, 6o, and 6p, show significant in-vitro cytotoxicity in at least two of the three tested cell lines, induced apoptosis, and also produced a rapid dose-dependent increase in the caspase-3 level in some of the cell lines tested. In order to test the selectivity of the compounds, two non-tumoral human cell lines were used. Several compounds of the did not show cytotoxicity in these cell lines.
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PMID:Synthesis and biological evaluation of 2,4,6-functionalized derivatives of pyrido[2,3-d]pyrimidines as cytotoxic agents and apoptosis inducers. 1816 3

Apoptosis is a process that leads to programmed cell death and also a therapeutic target of cancer. In this study, potential apoptotic effects of shikonin on human bladder cancer cells (T24) in vitro were evaluated. Apoptosis induction, cell viability and morphological changes were investigated and caspase-3 and -9 activity was determined by flow cytometric assay and reverse transcription-polymerase chain reaction. The results showed marked differences in G0/G1 cell cycle arrest and cell death of the T24 cells between shikonin treated and untreated groups. Within 72 hours of treatment, shikonin influenced the cyclin dependent kinase (CDK) and cyclin activity by increasing p21 and decreasing cyclin E, CDK2 and CDK4 protein levels. A marked increase was found in apoptosis induction when the T24 cells were treated with shikonin compared to the untreated group, also confirmed by flow cytometry assay. Shikonin also promoted caspase-3 activity, which led to the induction of caspase-activated DNase (CAD) and cleavage poly(ADP-ribose)polymerase. Furthermore, the shikonin-induced apoptosis of the T24 cells was markedly blocked by the broad-spectrum caspase inhibitor, z-VAD-fmk. Shikonin may be a potential agent for the treatment of bladder transitional cell carcinoma since it induces apoptosis through the activation of caspase-3 activity in T24 human bladder cancer cells.
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PMID:Shikonin-induced apoptosis involves caspase-3 activity in a human bladder cancer cell line (T24). 1821 Jul 48


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