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)

Taxol and Taxotere propagate apoptosis in Jurkat T cells via molecular signals that coincide with the appearance of two distinct cell populations. Cell cycle arrest in G2-M phase and activation of cell cycle-dependent kinases begin within 2 h and extend to most cells by 16 h. Phosphorylation of Bcl-2 also begins within 2 h and intensifies from 2-16 h. Cell cycle arrest, activation of mitotic kinases, and phosphorylation of Bcl-2 coincided with the appearance of a population of metastable cells that accumulate YO-PRO-1 dye, are resistant to the caspase inhibitor carbobenzoxy-L-aspartyl-alpha-[(2,6-dichlorobenzoyl)oxy]methane, and have intact genomic DNA. Phosphorylation and deactivation of kinases that relay survival/mitogenesis signals in T cells begin after 8 h and are prominent by 12-16 h. Deactivated kinases include c-Raf-1, p44 extracellular receptor kinase, and the tyrosine kinases c-Lck and ZAP-70. Activation of Mr 40,000 and Mr 52,000 kinases is also prominent by 12-16 h. The modulation of all these kinases coincided with the activation of caspase-3 at 12 h and the appearance of a population of apoptotic cells that accumulate YO-PRO-1, are susceptible to the caspase inhibitor carbobenzoxy-L-aspartyl-alpha-[(2,6-dichloro-benzoyl)oxy]methane, and contain fragmented genomic DNA. This distinctive apoptosis signaling pathway may help account for the superior cytotoxic efficacy of taxanes in certain types of cancer.
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PMID:Taxanes propagate apoptosis via two cell populations with distinctive cytological and molecular traits. 971 85

Up-regulation of Bcl-2 protein may contribute to drug resistance, by decreasing apoptosis after treatment, in pre-B and B-cell leukemias in pediatric patients. By contrast, augmented caspase-3 activity, an effector caspase, may be indicative of drug sensitivity due to increased cellular apoptosis. We have reported the development of an in vitro human T-lymphoblastic leukemia model resistant to ara-C and/or native E. coli L-asparaginase (ASNase), mimicking the drug resistance to the Capizzi II regimen. We have investigated the potential drug synergism between Idarubicin (IDA) and Taxotere (TXR) that may be active in the ara-C and ASNase double drug-resistant cell lines. The additive or synergistic activity between IDA and TXR is drug concentration-dependent in inducing caspase-3 activation and cellular apoptosis. We exposed two human drug-resistant cell lines that do not express the MDRI phenotype, one resistant to ASNase alone (CEM/ASNase-1-3) and the other resistant to both ara-C and ASNase (CEM/ara-C/I/ASNase-0.5-2), to physiologically achievable concentrations of IDA, TXR, or their combination. Both lines showed either synergistic drug activity to the combination regimen in comparison to either drug used alone, as determined by MTT assay, or additivity as demonstrated by flow cytometry after Annexin V and propidium iodide (PI) staining. After exposure of the ASNase-resistant line to various concentrations, the intracellular levels of Bcl-2 protein decreased to near zero relative to untreated control cells. The Bcl-2 protein reductions in these cells ranged from 30% to <1%, 49% to <1%, and 27% to 3% when treated with IDA or TXR as a single drug or IDA + TXR combination, respectively. Similarly, intracellular Bcl-2 levels in the double-resistant cell line decreased with reductions ranging from 24% to <1%, 87% to <1%, and 46% to <1% of the untreated control after treatment with IDA, TXR, or their combination, respectively. Conversely, the caspase-3 activity increased in a dose-dependent manner and inversely-correlated with loss of cell viability (r= 0.91) after exposure to IDA + TXR combination in the double drug-resistant line to both ara-C and ASNase. We conclude that the combination of the IDA + TXR regimen is highly synergistic or additive in drug resistant human leukemic cell clones. The molecular mechanism of action is due to the down-regulation of Bcl-2 protein and up-regulation of caspase-3 activity. This drug combination warrants further investigation for use in the treatment of patients with ara-C and/or ASNase refractory leukemias.
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PMID:The combination regimen of idarubicin and taxotere is effective against human drug-resistant leukemic cell lines. 1216 12

Docetaxel, a member of the taxane family, has been shown to induce apoptosis in a variety of cancer cells. However, toxicity at therapeutic doses has precluded the use of docetaxel alone for the management of cancer patients. PSK, a protein-bound polysaccharide, is widely used in Japan as an immunopotentiating biological response modifier for cancer patients. Our previous study showed that PSK induced downregulation of several invasion-related factors, suggesting an interaction of PSK with transcriptional factors. In this study, we showed that PSK dose dependently enhanced apoptosis induced by 1 nM of docetaxel in a human pancreatic cancer cell line NOR-P1. Furthermore, PSK inhibited docetaxel-induced nuclear factor kappa B (NF-kappaB) activation. Moreover, the expression of cellular inhibitor of apoptosis protein (cIAP-1), which is transcriptionally regulated by NF-kappaB and functions as an antiapoptotic molecule through interrupting the caspase pathway, was also inhibited by treatment with PSK plus docetaxel. As a result, PSK enhanced the docetaxel-induced caspase-3 activation. In addition, treatment by transfection of NF-kappaB decoy oligodeoxynucleotides (ODNs), but not scramble ones, inhibited the expression of cIAP-1 in NOR-P1 cells and induced a significant increase in docetaxel-induced apoptosis. Our data indicate that PSK suppresses the docetaxel-induced NF-kappaB activation pathway. Combination of PSK with a low dose of docetaxel may be a new therapeutic strategy to treat patients with pancreatic cancer.
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PMID:PSK-mediated NF-kappaB inhibition augments docetaxel-induced apoptosis in human pancreatic cancer cells NOR-P1. 1268 11

We reported previously a significant increase in survival of nude rats harboring orthotopic A549 human non-small cell lung cancer tumors after treatment with a combination of exisulind (Sulindac Sulfone) and docetaxel (D. C. Chan, Clin. Cancer Res., 8: 904-912, 2002). The purpose of the current study was to determine the biochemical mechanisms responsible for the increased survival by an analysis of the effects of both drugs on A549 orthotopic lung tumors and A549 cells in culture. Orthotopic A549 rat lung tissue sections from drug-treated rats and A549 cell culture responses to exisulind and docetaxel were compared using multiple apoptosis and proliferation analyses [i.e., terminal deoxynucleotidyl transferase-mediated nick end labeling, active caspase 3, the caspase cleavage products cytokeratin 18 and p85 poly(ADP-ribose) polymerase, and Ki-67]. Immunohistochemistry was used to determine cyclic GMP (cGMP) phosphodiesterase (PDE) expression in tumors. The cGMP PDE composition of cultured A549 cells was resolved by DEAE-Trisacryl M chromatography and the pharmacological sensitivity to exisulind, and additional known PDE inhibitors were determined by enzyme activity assays. Exisulind inhibited A549 cell cGMP hydrolysis and induced apoptosis of A549 cells grown in culture. PDE5 and 1 cGMP PDE gene family isoforms identified in cultured cells were highly expressed in orthotopic tumors. The in vivo apoptosis rates within the orthotopic tumors increased 7-8-fold in animals treated with the combination of exisulind and docetaxel. Exisulind increased the in vivo apoptosis rates as a single agent. Docetaxel, but not exisulind, decreased proliferative rates within the tumors. The data indicate that exisulind-induced apoptosis contributed significantly to the increased survival in rats treated with exisulind/docetaxel. The mechanism of exisulind-induced apoptosis involves inhibition of cGMP PDEs, and these results are consistent with a cGMP-regulated apoptosis pathway.
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PMID:Exisulind-induced apoptosis in a non-small cell lung cancer orthotopic lung tumor model augments docetaxel treatment and contributes to increased survival. 1274 10

Apoptosis-resistant K562 cells and apoptosis-proficient HL-60 acute myelomonocytic leukemia cells were selected to study the cell-type-specific characteristics of docetaxel. The kinetics of cytotoxicity of docetaxel showed a delayed response of K562 cells compared to HL-60 cells. After treatment with 10(-8)M docetaxel, DNA fragmentation and sub-G0/G1 cells were evident in HL-60 cells in less than 6 h, while K562 cells gradually arrested in G2/M phase of the cell cycle and appeared normal for 24 h before developing similar apoptotic changes. The delayed apoptotic changes in K562 cells were accompanied by delayed activation of caspase-3. Additionally, NADPH oxidase inhibition with diphenylene iodonium showed that reactive oxygen species (ROS) burst mediated critically in the caspase-3 activation and apoptosis in HL-60 cells but was only partially involved in those events of K562 cells. These results suggested that docetaxel exposure triggered the delayed apoptosis in K562 cells and the different ROS-dependent or independent signal pathways might account for this phenomenon. Docetaxel elicited ROS production from NADPH oxidase, which in turn triggered activation of caspase-3, leading to apoptosis in HL-60 cells. While in K562 cells, docetaxel induced apoptosis after G2/M accumulation through ROS-independent or partially dependent pathways.
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PMID:Comparison of burst of reactive oxygen species and activation of caspase-3 in apoptosis of K562 and HL-60 cells induced by docetaxel. 1533 Nov 78

Apoptosis induced by docetaxel that interferes with microtubule polymerization dynamics and is used clinically to treat advanced cancers, has not been fully defined in squamous cell carcinoma. In this study, apoptotic events involved in docetaxel treatment were investigated. When the human oral squamous cell carcinoma cell line HSC-3 was exposed to docetaxel for 72 h, a dose-dependent effect was observed in apoptosis using the TUNEL method. We observed activation of caspase cascade including activities like caspase-3, -8, and -9. And the pan-caspase inhibitor z-VAD-fmk prevented apoptosis induced by docetaxel (0.1 microM), showing participation of caspases in this process. Since an antagonistic CD95-antibody (ZB4) exerted no effect on docetaxel-induced apoptosis, CD95/CD95L interaction was not involved in this pathway. The caspase-8-like activity was inhibited not only by IETD-fmk (caspase-8) but also by DEVD-fmk (caspase-3). The results indicate that the caspase-8-like activation occurred downstream of DEVDase. Docetaxel promoted the formation of reactive oxygen species (ROS) in mitochondria, and preincubation of cells with anti-oxidants such as N-acetyl cysteine and pyrrolidine dithiocarbamate, protected against apoptosis mediated by docetaxel. Furthermore, treatment with docetaxel elicited reduction of mitochondrial membrane potential, and release of cytochrome c to cytosol, after 48 h of treatment. We observed binding activity to NF-kappaB consensus site and interference with the mitochondrial function via NF-kappaB after docetaxel treatment. Preventing pro-apoptotic property of NF-kappaB inhibited docetaxel-induced apoptosis. Thus, these results suggest that, following the activation of NF-kappaB by docetaxel, apoptosis is elicited through a mitochondria-dependent pathway.
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PMID:Involvement of NF-kappaB and mitochondrial pathways in docetaxel-induced apoptosis of human oral squamous cell carcinoma. 1575 30

Docetaxel (Taxotere, DTX) is a promoter of apoptosis in cancer cells. Since cytotoxic mechanisms of DTX are not yet fully understood, we have investigated the effects of DTX on apoptosis and ras-->Erk-mediated signal transduction in human epidermoid KB, colon HT-29 and breast HCC1937 cancer cells. We have found that the exposure to 0.78 or 1.56 or 2.5 ng/ml DTX for 48 h induced apoptosis and growth inhibition in about 50 % of KB, HCC1937 and HT-29 cell population, respectively. In these experimental conditions, PARP and caspase 3 cleavage was also showed in all cell lines. KB and HCC1937 cells express a wild type p53 while HT-29 display a mutated form. Interestingly, we have found that DTX reduces the expression of mutated p53 in HT-29 and increases the expression of wild type in KB and HCC1937 cells. Moreover, DTX reduces ubiquitination of the wild type p53 in KB and HCC1937 cells and increases the ubiquitin-conjugated form of mutated p53 in HT-29 cells. Furthermore, exposure of cancer cells to DTX for 48 h increases the expression and activity of Ras and up-regulates Raf-1 and the phosphorylated isoforms of Erk-1/2. On the bases of these data, we have hypothesized that the increased activity of the ras-->erk-dependent pathway induced by DTX could be a protective signalling from the apoptosis caused by the drug. Therefore, we have used R115777, a farnesyl transferase inhibitor that inactivates ras, in combination with DTX. The combined treatment with DTX and R115777 resulted in a strong synergism in growth inhibition in the three cell lines. These data suggest the use of the combination in these therapeutic settings even if further experiments are required for the clinical translation.
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PMID:Docetaxel induces p53-dependent apoptosis and synergizes with farnesyl transferase inhibitor r115777 in human epithelial cancer cells. 1597 May 18

The hierarchy of events accompanying induction of apoptosis by the microtubule inhibitor docetaxel was investigated in HL-60 human leukemia cells. Treatment of HL-60 cells with docetaxel resulted in the production of reactive oxygen species (ROS), activation of caspase-3 (-like) protease, c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) activation, bcl-2 phosphorylation and apoptosis. Docetaxel elicited ROS production from NADPH oxidase as demonstrated by specific oxidase inhibitor diphenylene iodonium (DPI). ROS mediated the caspase-3 activation and apoptosis in HL-60 cells. The caspase inhibitor acetyl-Asp-Glu-Val-Asp-aldehyde (Ac-DEVD-CHO) effectively inhibited JNK/SAPK activation, bcl-2 phosphorylation and partially attenuated the ROS production induced by docetaxel. Docetaxel-induced bcl-2 phosphorylation was completely blocked by expression of dominant negative JNK or the JNK/SAPK inhibitor SP600125. Overexpression of bcl-2 partially prevented docetaxel-mediated ROS production and subsequent caspase-3 activation, thereby inhibiting apoptotic cell death. It is thus conferred that such sequent events as ROS production, caspase activation, JNK/SAPK activation, bcl-2 phosphorylation and the further generation of ROS should be parts of an amplification loop to increase caspase activity, thereby facilitating the apoptotic cell death process.
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PMID:Amplification loop cascade for increasing caspase activity induced by docetaxel. 1614 76

Taxol (paclitaxel) and Taxotere (docetaxel) are considered as two of the most important anti-cancer chemotherapy drugs. The cytotoxic action of these drugs has been linked to their ability to inhibit microtubule depolymerization, causing growth arrest and subsequent cell death. Studies by a number of laboratories have also linked suppression of MEK1/2 signaling to enhanced Taxol toxicity in vitro and in vivo. The present study examined the interactions of the semi-synthetic taxane Taxotere with MEK1/2 inhibitors in epithelial tumor cells. In vitro colony formation studies demonstrated that Taxotere and the MEK1/2 inhibitor PD184352 interacted in a sequence dependent fashion to synergistically kill human mammary carcinoma cells (MDA-MB-231, MCF7) as well as in other tumor cell types; e.g. prostate and renal cell carcinoma. Athymic mice were implanted in the rear flank with either MDA-MB-231 or MCF7 cells and tumors permitted to form to a volume of approximately 100 mm3 prior to a two day exposure of either Vehicle, PD184352 (25 mg/kg), Taxotere (15 mg/kg) or the drug combination. Tumor volume was measured every other day and tumor growth determined over the following approximately 30 days. Transient exposure of MDA-MB-231 tumors or MCF7 tumors to PD184352 did not significantly alter tumor growth rate or the mean tumor volume in vivo approximately 15-30 days after drug administration. Transient Taxotere exposure of MDA-MB-231 or to a lesser extent MCF7, tumors modestly reduced the mean tumor volume in vivo approximately 15-30 days after drug administration. In contrast, combined treatment with PD184352 and Taxotere significantly reduced MDA-MB-231 and MCF7 tumor growth. The tumor control values for MDA-MB-231 cells and MCF7 cells were 0.43 and 0.71, respectively. Fractionated irradiation of MDA-MB-231 tumors during drug exposure or single dose irradiation prior to drug administration did not significantly further suppress tumor growth beyond that of cells exposed to Taxotere and MEK1/2 inhibitor. Single dose irradiation of tumors after drug exposure, however, caused a significant further suppression of tumor growth below that caused by drug exposure. These findings were also reflected in ex vivo colony formation analyses of isolated tumor cells. Collectively, these findings argue that Taxotere and MEK1/2 inhibitors have the potential to suppress mammary tumor growth in vivo which is enhanced by sequence-dependent exposure to ionizing radiation. Based on the cell lines used in these studies, our findings argue that the interaction of Taxotere and PD184352 is independent of p53 status, estrogen dependency, caspase 3 levels or oncogenic K-RAS expression.
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PMID:MEK1/2 inhibition promotes Taxotere lethality in mammary tumors in vivo. 1695 20

Docetaxel (DTX) is used for the treatment of advanced hormone refractory prostate cancer. Connexin 43 (Cx43) is a tumor suppressor gene, and transfection of the Cx43 gene increases sensitivity to several chemotherapeutic agents. The objective of this study was to evaluate the effectiveness of combination therapy of Cx43-expressing plasmid DNA (pCMV-Cx43) and DTX both in vitro and in vivo using a non-viral vector in human prostate cancer PC-3 cells. Transfection of pCMV-Cx43 into the cells neither inhibited tumor growth nor increased gap junctional intercellular communication; however, combination therapy of pCMV-Cx43 and DTX significantly inhibited cell growth. Forced expression of Cx43 in the cells induced apoptotic cells by down-regulation of Bcl-2 expression and significantly more up-regulation of caspase-3 activity than either treatment alone. The combination of repeated intratumoral injection of pCMV-Cx43 (10 microg/tumor) with non-viral vector and a single intravenous injection of DTX (15 mg/kg) was compared with a repeated injection of Cx43 alone and a single injection of DTX alone on PC-3 tumor xenografts. Significant antitumoral effects were observed in mice receiving combined treatment, compared with DTX alone. The data presented here provide a rational strategy for treating patients with advanced hormone refractory prostate cancer.
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PMID:Combination of non-viral connexin 43 gene therapy and docetaxel inhibits the growth of human prostate cancer in mice. 1714 33


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