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 investigates the apoptotic activity of the cyclooxygenase-2 (COX-2) inhibitor celecoxib in prostate carcinoma cells. COX-2 is constitutively expressed in androgen-responsive LNCaP and androgen-nonresponsive PC-3 cells. Exposure of these cells to celecoxib induces characteristic features of apoptosis, including morphological changes, DNA laddering, and caspase-3 activation, whereas piroxicam, a COX-1-specific inhibitor, displays no appreciable effect on either cancer cell line even after prolonged exposure. Moreover, the potency of celecoxib in apoptosis induction is significantly higher than that of other COX-2 inhibitors examined despite the observation that these inhibitors exhibit similar IC(50) in COX-2 inhibition. It is noteworthy that normal human prostate epithelial cells, expressing a marginally detectable level of COX-2, are insensitive to the induction of apoptosis by celecoxib. These data suggest a correlation between COX-2 expression and sensitivity to the apoptotic effect of the COX-2 inhibitor. In an effort to delineate the underlying mechanism, we examined the effect of celecoxib on the expression of Bcl-2 as well as the activation of the key anti-apoptotic kinase Akt. In contrast to an earlier report that attributed the apoptotic activity of NS398 in LNCaP cells to Bcl-2 down-regulation, we provide evidence that the induction of apoptosis by celecoxib in LNCaP and PC-3 cells is independent of Bcl-2. First, treatment with celecoxib does not alter the cellular Bcl-2 level in both cell lines. Second, enforced Bcl-2 expression in PC-3 cells does not confer protection against the induction of apoptosis by celecoxib. Our data show that celecoxib treatment blocks the phosphorylation of Akt. This correlation is supported by studies showing that overexpression of constitutively active Akt protects PC-3 cells from celecoxib-induced apoptosis. Nevertheless, how celecoxib down-regulates Akt is not clear because the drug does not adversely affect phosphoinositide 3-kinase activity in vivo and okadaic acid, a protein phosphatase 2A inhibitor, cannot rescue the inhibition. In summary, our data demonstrate that inhibition of Akt activation may play a crucial role in the induction of apoptosis by celecoxib.
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PMID:The cyclooxygenase-2 inhibitor celecoxib induces apoptosis by blocking Akt activation in human prostate cancer cells independently of Bcl-2. 1075 55

The synthetic retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437) induces apoptosis in several types of cancer cell. CD437 inhibited the growth of both androgen-dependent and -independent human prostate carcinoma (HPC) cells in a concentration-dependent manner by rapid induction of apoptosis. CD437 was more effective in killing androgen-independent HPC cells such as DU145 and PC-3 than the androgen-dependent LNCaP cells. The caspase inhibitors Z-VAD-FMK and Z-DEVD-FMK blocked apoptosis induced by CD437 in DU145 and LNCaP cells, in which increased caspase-3 activity and PARP cleavage were observed, but not in PC-3 cells, in which CD437 did not induce caspase-3 activation and PARP cleavage. Thus, CD437 can induce either caspase-dependent or caspase-independent apoptosis in HPC cells. CD437 increased the expression of c-Myc, c-Jun, c-Fos, and death receptors DR4, DR5 and Fas. CD437's potency in apoptosis induction in the different cell lines was correlated with its effects on the expression of oncogenes and death receptors, thus implicating these genes in CD437-induced apoptosis in HPC cells. However, the importance and contribution of each of these genes in different HPC cell lines may vary. Because CD437 induced the expression of DR4, DR5 and Fas, we examined the effects of combining CD437 and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and Fas ligand, respectively, in HPC cells. We found synergistic induction of apoptosis, highlighting the importance of the modulation of these death receptors in CD437-induced apoptosis in HPC cells. This result also suggests a potential strategy of using CD437 with TRAIL for treatment of HPC. Oncogene (2000) 19, 4513 - 4522.
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PMID:Implication of multiple mechanisms in apoptosis induced by the synthetic retinoid CD437 in human prostate carcinoma cells. 1100 24

The flavonoid baicalin (baicalein 7-D-beta-glucuronate), isolated from the dried root of Scutellaria baicalensis Georgi (Huang Qin), is widely used in the traditional Chinese herbal medicine for its anti-inflammatory, anti-pyretic and anti-hypersensitivity effects. In the present study, we investigated the in vitro effects of baicalin on the growth, viability, and induction of apoptosis in several human prostate cancer cell lines, including DU145, PC-3, LNCaP and CA-HPV-10. The cell viability after treating with baicalin for 2-4 days was quantified by a colorimetric 3-(4, 5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-s ulfophenyl)- 2H-tetrazolium (MTS) assay. The results showed that baicalin could inhibit the proliferation of prostate cancer cells. The responses to baicalin were different among different cell lines, with DU145 cells being the most sensitive and LNCaP cells the most resistant. Baicalin caused a 50% inhibition of DU145 cells at concentrations of 150 microM or above. The inhibition of proliferation of prostate cancer cells after a short period of exposure to baicalin was associated with induction by apoptosis, as evidenced by the typical nuclear fragmentation using Hoechst 33258 staining, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) labeling, DNA fragmentation, activation of caspase-3 and cleavage of poly-ADP-ribose polymerase (PARP). The results indicate that baicalin has direct anti-tumor effects on human prostate cancer cells.
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PMID:Induction of apoptosis in prostate cancer cell lines by a flavonoid, baicalin. 1105 52

Epidemiological and clinical data suggest that selenium may prevent prostate cancer, but the biological effects of selenium on normal or malignant prostate cells are not well known. We evaluated the effects of sodium selenite (Na2SeO3) or l-selenomethionine (SeMet) on monolayer and anchorage-independent growth in a series of normal primary prostate cultures (epithelial, stromal, and smooth muscle) and prostate cancer cell lines (LNCaP, PC-3, and DU145). We observed differential, dose-dependent growth inhibition and apoptosis within prostate cancer cells (compared with normal prostate cells) treated with 1-500 microM of Na2SeO3 or SeMet. Na2SeO3 more potently inhibited growth at any given concentration. The androgen-responsive LNCaP cells were the most sensitive to selenium growth suppression (IC50s at 72 h for Na2SeO3 and SeMet were 0.2 and 1.0 microM, respectively). Growth of the primary prostate cells virtually was not suppressed (IC50s at 72 h for Na2SeO3 and SeMet were 22-38 and >500 microM, respectively). We also observed that DNA condensation and DNA fragmentation (terminal deoxynucleotidyltransferase dUTP nick end labeling/fluorescence-activated cell sorting) were elevated in selenium-treated cells and that activated caspase-3 colocalized with terminal deoxynucleotidyltransferase dUTP nick end labeling-stained cells by immunofluorescence. Higher basal poly(ADP-ribose) polymerase (PARP) expression levels and PARP cleavage (a substrate for caspase-3) were observed during apoptosis in tumor cells, compared with normal cells. Selective tumor cell death was associated with an increase in sub-G0-G1 cells after propidium iodide staining and fluorescence-activated cell sorting analysis. SeMet caused an increase in arrest in the G2-M phase of the cell cycle selectively in cancer cells. Inhibition of cancer cell growth by SeMet was associated with phosphorylation of P-Tyr15-p34/cdc2, which caused growth arrest in the G2-M phase. Anchorage-independent growth of prostate cancer cells in soft agar was sensitive to selenium. Our results suggest that Na2SeO3 is the more potent inducer of apoptosis in normal and cancer prostate cells. Our SeMet results involving PARP and G2-M cell-cycle arrest (cited above) indicate that SeMet selectively induces apoptosis in cancer but not primary cells of the human prostate. Our overall findings are relevant to the molecular mechanisms of selenium actions on prostate carcinogenesis and help demonstrate the selective, dose-dependent effects of selenium (especially SeMet) on prostate cancer cell death and growth inhibition.
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PMID:Selenium effects on prostate cell growth. 1109 24

Fluorodeoxyuridine (5-FdUrd) is an antineoplastic agent with clinical activity against different types of solid tumours. To enhance the effectiveness of this drug, we have synthesised new heterodinucleoside phosphate dimers of 5-FdUrd. These dimers were compared to 5-FdUrd for their cytotoxic effect and the cell cycle dependence of cytotoxicity, as well as for their capacity to induce apoptosis and inhibit thymidylate synthetase (TS) in androgen-independent human PC-3 prostate tumour cells. Incubation of the cells with the dimers N(4)-palmitoyl-2'-deoxycytidylyl-(3'-->5')-5-fluoro-2'-deoxyuri din e (dCpam-5-FdUrd) and 2'-deoxy-5-flourouridylyl-(3'-->5')-2'-deoxy-5-fluoro-N(4)-octa decylc ytidine (5-FdUrd-5-FdC18) resulted in a marked cytotoxicity with IC(50) values of 4 microM, similar to 5-FdUrd. In contrast to 5-FdUrd, 100% toxicity was achieved with concentrations of 100-200 microM 5-FdUrd-5-FdC18. Flow cytometric analysis revealed an increase in the cell population in S-phase after treatment with 5-FdUrd, 5-FdUrd-5-FdC18, and dCpam-5-FdUrd from 36 to 63%, 50%, and 77%, respectively. dCpam-5-FdUrd was more potent than 5-FdUrd in arresting the cell cycle. Significant S-phase arrest was indicated by a decreased proportion of cells in G1- and G2/M-phases. Cell cycle arrest and inhibition of cell proliferation were followed by apoptosis, as shown by a 6- to 8-fold increased binding of Apo2.7 antibody, a 9- to 11-fold increase in caspase-3 activity, DNA fragmentation, and by cell morphology showing the appearance of apoptotic bodies. Importantly, 5-FdUrd-5-FdC18 increased the number of apoptotic cells to 160% compared to 5-FdUrd under the same conditions. As with 5-FdUrd, the two dimers also inhibited TS in a time- and concentration-dependent manner, although requiring 100-fold higher concentrations. In conclusion, dCpam-5-FdUrd and 5-FdUrd-5-FdC18 exert stronger cytotoxicity and induce more S-phase arrest and apoptosis than does 5-FdUrd in PC-3 cells, suggesting their potential role in the treatment of human prostate cancer.
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PMID:Induction of cell cycle-dependent cytotoxicity and apoptosis by new heterodinucleoside phosphate dimers of 5-fluorodeoxyuridine in PC-3 human prostate cancer cells. 1110 5

Using adenoviral technology, we overexpressed the proapoptotic molecules pro-caspase-3, pro-caspase-7, and Bax to induce therapeutic apoptosis of prostate cancer cell lines growing in vitro and in vivo. Because overexpressed pro-caspase-3 did not undergo autocatalytic activation in any of the five prostate cancer cell lines evaluated, this strategy was unable to engage any component of the apoptotic pathway. Overexpressed pro-caspase-7 was proteolytically cleaved in LNCaP and LnCaP-Bcl-2 cells but not in PC-3, DU-145, or TsuPr(1) cells. Cleavage was associated with engagement of many components of the apoptotic pathway, including DEVDase activity, cleavage of intracellular caspase targets such as the DNA fragmentation factor and the proapoptotic Bid, release of cytochrome c from the mitochondria to the cytoplasm, and terminal deoxynucleotidyl transferase-mediated nick end labeling. No apoptosis was observed in the cells where caspase-7 did not undergo autocatalytic activation. Searching for an approach that would more reliably induce therapeutic apoptosis of prostate cancer cell lines, we used a binary adenoviral system to overexpress the proapoptotic molecule Bax. Bax was dramatically overexpressed and caused apoptosis of every cell line infected by engaging the mitochondrial pathway, including proteolytic cleavage and catalytic activation of the caspases, cleavage of caspase substrates, release of cytochrome c from the mitochondria, and DNA fragmentation. Furthermore, three injections of the Bax overexpression system into PC-3 cell tumors in nude mice in vivo caused a 25% regression in tumor size corresponding to a 90% reduction relative to continued tumor growth in animals that received injections with the control binary system expressing Lac-Z. These experiments show that adenovirus-mediated Bax overexpression is capable of inducing therapeutic programmed cell death in vitro and in vivo by activating the mitochondrial pathway of apoptosis. On the basis of these studies, we conclude that manipulation of Bax expression is an attractive new gene therapy approach for the treatment of prostate cancer.
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PMID:Adenovirus-mediated Bax overexpression for the induction of therapeutic apoptosis in prostate cancer. 1119 58

We have demonstrated that Apo-2 ligand (Apo-2L)/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis of human prostate cancer PC-3, DU145, and LNCaP cells in a dose-dependent manner, with PC-3 cells displaying the greatest sensitivity to Apo-2L/TRAIL. Susceptibility of the prostate cancer cell types to Apo-2L/TRAIL-induced apoptosis did not appear to correlate with the levels of the Apo-2L/TRAIL receptors death receptor (DR) 4 (TRAIL receptor 1) or DR5 (TRAIL receptor 2), decoy receptor (DcR) 1 and DcR2, Flame-1, or the inhibitors of apoptosis proteins family of proteins. Apo-2L/TRAIL-induced apoptosis of PC-3 cells was associated with the processing of caspase-8, caspase-10, and the proapoptotic Bid protein, resulting in the cytosolic accumulation of cytochrome c as well as the processing of procaspase-9 and procaspase-3. Cotreatment with the caspase-8 inhibitor z-IETD-fmk or DR4:Fc significantly inhibited Apo-2L/TRAIL-induced apoptosis. Treatment with paclitaxel or taxotere increased DR4 and/or DR5 protein levels (up to 8-fold) without affecting the protein levels of DcR1 and DcR2, Apo-2L/TRAIL, Fas, or Fas ligand. Up-regulation of DR4 and DR5 was not preceded by the induction of their mRNA levels but was inhibited by cotreatment with cycloheximide. Importantly, sequential treatment of PC-3, DU145, and LNCaP cells with paclitaxel followed by Apo-2L/TRAIL induced significantly more apoptosis than Apo-2L/TRAIL treatment alone (P < 0.01). This was also associated with greater processing of procaspase-8 and Bid, as well as greater cytosolic accumulation of cytochrome c and the processing of caspase-3. These findings indicate that up-regulation of DR4 and DR5 protein levels by treatment with paclitaxel enhances subsequent Apo-2L/TRAIL-induced apoptosis of human prostate cancer cells.
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PMID:Pretreatment with paclitaxel enhances apo-2 ligand/tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis of prostate cancer cells by inducing death receptors 4 and 5 protein levels. 1121 79

Activation of the caspase cascade is involved in the execution of apoptosis in a variety of cellular systems. Recent studies demonstrated that caspase-1 activation was required for human prostate cancer cells to undergo apoptosis in response to transforming growth factor-beta (Y. Guo and N. Kyprianou, Cancer Res., 59: 1366-1371, 1999). In the present study, to identify the significance of caspases in prostate cancer progression, we examined the expression of three key caspases, caspase-1, caspase-3, and caspase-9, in normal and malignant human prostates. Caspase-1, -3, and -9 expression was examined at the mRNA and the protein level in a series of human normal and malignant prostate specimens. No significant differences were observed in the mRNA expression in prostatic tumors relative to the normal gland for any of the three caspases. Immunohistochemical analysis revealed that the pattern of protein expression and distribution was uniformly homogeneous in the normal prostate, with the epithelial cells exhibiting a diffuse cytoplasmic staining for caspase-1 and caspase-3. Significantly, the majority of primary prostate cancer specimens (80%) had total lack of caspase-1 immunoreactivity, whereas the remaining showed a significantly reduced expression compared with the normal prostate (P < 0.05). Caspase-3 expression was also reduced in moderately and poorly differentiated prostatic tumors compared with well-differentiated prostate adenocarcinomas and the normal prostate (P < 0.05). No significant correlation was found between the apoptotic index or Gleason grade and the pattern of caspase protein expression in the primary prostatic tumors analyzed. Western blot analysis revealed constitutive expression of the proenzyme forms of caspase-1, -3, and -9 in the human prostate cancer cell lines PC-3, DU-145, TSU-Pr1m and LNCaP, but caspase-1 expression was low in the less tumorigenic cell lines, DU-145 and LNCaP. These findings implicate the loss of caspase-1 protein as a potential step in the loss of apoptotic control during prostate tumorigenesis. This study suggests that the pattern of caspase-1 and -3 expression in prostatic tumors may have prognostic significance in disease progression.
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PMID:Loss of caspase-1 and caspase-3 protein expression in human prostate cancer. 1122 55

In patients with localized prostate cancer, radical prostatectomy and radiation therapy, although effective in controlling localized disease, are often associated with significant side effects attributable to injury of adjacent tissues. Moreover, patients with metastatic disease eventually fail systemic hormonal or chemotherapy because of the development of progressive, refractory disease. In this study, we evaluated the safety and efficacy of a novel suicide gene therapy that could potentially spare normal tissue while bypassing molecular mechanisms of apoptosis resistance by using chemically inducible effector caspases to trigger apoptosis in prostate cancer cells. Initially, we compared the ability of a panel of inducible Fas signaling intermediates to kill human and murine prostate cancer cell lines. On the basis of the superior killing by downstream caspase-1 and caspase-3, replication-deficient adenoviral vectors expressing conditional caspase-1 (Ad-G/iCasp1) or caspase-3 (Ad-G/iCasp3), regulated by nontoxic, lipid-permeable, chemical inducers of dimerization (CID), were constructed. Upon vector transduction followed by CID administration, aggregation and activation of these recombinant caspases occur, leading to rapid apoptosis. In vitro, both human (LNCaP and PC-3) and murine (TRAMP-C2 and TRAMP-C2G) prostate cancer cell lines were efficiently transduced and killed in a CID-dependent fashion. In vivo, direct injection of Ad-G/iCasp1 into s.c. TRAMP-C2 tumors caused focal but extensive apoptosis without evidence for a bystander effect at the maximal viral dose (i.e., 2.5 x 10(10) viral particles/25 microl) in host animals that also received CID compared with control animals. Treatment with Ad-G/iCasp1 plus CID resulted in a transient, yet significant, reduction both in tumor growth and volume compared with tumors treated with vector but not CID (P < 0.035) or vector-diluent plus CID (P < 0.022), both of which grew more rapidly. These results demonstrate that CID-regulated, caspase-based suicide gene therapy is safe and can inhibit the growth of experimental prostate cancer in vitro and in vivo through potent induction of apoptosis, providing a rationale for further development.
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PMID:Adenovirus-mediated transfer of inducible caspases: a novel "death switch" gene therapeutic approach to prostate cancer. 1128 32

Arsenic trioxide (As2O3) induces clinical remission of patients with acute promyelocytic leukemia. As a novel anticancer agent for treatment of solid cancers, As2O3 is promising, but no in vivo experimental investigations of its efficacy on solid cancers have been done at clinically obtained concentrations. In addition, the cell death mechanism of As2O3 has yet to be clarified, especially in solid cancers. In this study, human androgen-independent prostate cancer cell lines, PC-3, DU-145, and TSU-PR1 were examined as cellular models for As2O3 treatment, and As2O3-induced cell death and inhibition of cell growth and colony formation were evaluated. The involvement of p38, c-Jun NH2-terminal kinase (JNK), caspase-3, and reactive oxygen species (ROS) were investigated in As2O3-induced cell death. Finally, As2O3 was administered to severe combined immunodeficient mice inoculated orthotopically with PC-3 cells to estimate in vivo efficacy. In all three of the cell lines, at high concentrations, As2O3 induced apoptosis and, at low concentrations, growth inhibition. As2O3 activated p38, JNK, and caspase-3 dose dependently. Treatment with the p38 inhibitor and over-expression of dominant-negative JNK did not guard against As2O3-induced cell death. In contrast with partial protection by the caspase-3 inhibitor, the antioxidant N-acetyl-L-cysteine gave marked protection from As2O3-induced apoptosis and eliminated the activation of p38, JNK, and caspase-3, and the generation of ROS. The orthotopic murine metastasis model showed in vivo tumor growth inhibition in orthotopic and metastatic lesions with no signs of toxicity. This study establishes that As2O3 provides a novel, safe approach for treatment of androgen-independent prostate cancer. Generation of ROS as a therapeutic target for the potentiation of As2O3-induced apoptosis also was shown.
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PMID:Tumor growth inhibition by arsenic trioxide (As2O3) in the orthotopic metastasis model of androgen-independent prostate cancer. 1145 88


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