Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CD40 plays a critical role in the humoral immune response, especially in B-cell proliferation, differentiation, production of antibody, secretion of cytokines, and apoptosis. Here, we examined CD40 expression on six head and neck cancer cell lines by flow cytometry. Only the HTC/C3 cell line, which originated from a thyroid cancer, expressed CD40 on the surface of the cells. Coculture with anti-CD40 mAb inhibited colony formation of HTC/C3 cells. CD40 stimulation enhanced Fas expression on HTC/C3 cells. Although HTC/C3 cells are sensitive to Fas-mediated apoptosis, CD40 stimulation inhibited Fas-mediated apoptosis in HTC/C3 cells. CD40 stimulation enhanced Bcl-2 expression, and antisense oligonucleotide against bcl-2 canceled the inhibition of HTC/C3 cell growth caused by CD40 stimulation. Additionally, more anti-CD40 mAb-treated HTC/C3 cells were accumulated in G1 phase, and fewer in S phase, compared to nontreated cells. These results suggest that CD40 stimulation might be involved in the slow growth rate of CD40-bearing cancer cells, and they suggest a new biological approach to the treatment of cancers.
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PMID:CD40 stimulation inhibits cell growth and Fas-mediated apoptosis in a thyroid cancer cell line. 1022 18

The dramatically increased number of new cases of disseminated children thyroid cancer in Belarus after the Chernobyl accident requires development of novel strategies to treat this disease. In addition to conventional therapy using radioiodine, chemotherapy with new effective drugs can be an alternative kind of treatment. We tested the antitumor activity of (E)-2'-fluoromethylene-2'-deoxycytidine (MDL-101,731), a ribonucleoside diphosphate reductase inhibitor against three thyroid carcinoma cell lines established from anaplastic (8505C), papillary (B-CPAP) and poorly differentiated papillary (BHT-101) cancer. MDL-101,371 decreased both cell growth and DNA synthesis of tumor cells at concentrations lower than 100 nM, while the concentrations higher than 5000 nM showed only moderate effects on growth of normal human fibroblasts. The effects of MDL-101, 371 on tumor cells were associated with induction of apoptosis, as demonstrated by DNA fragmentation assay. Flow cytometric analysis of the expression of apoptosis-related genes revealed the increased levels of Fas-antigen, whereas the levels of Bcl-2 were not significantly influenced in thyroid cancer cells treated with MDL-101,731. These results demonstrated that MDL-101,731 is a potent antitumor agent against cultured thyroid cancer cells due to its ability to induce apoptosis in association with increased Fas expression.
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PMID:Selective cytotoxic activity of a novel ribonucleoside diphosphate reductase inhibitor MDL-101,731 against thyroid cancer in vitro. 1073 Aug 87

To determine whether the apoptotic machinery of thyroid cancer cells is functional and could be activated for tumoricidal purposes, we examined the apoptosis induced by the cytokines TNF-alpha, Fas and TRAIL in thyroid cancer cell lines, NPA and SW579. Interestingly, out of these cytokines, only TRAIL was able to trigger significant apoptosis. The tumoricidal effect of TRAIL was further enhanced by CHX, suggesting the presence of CHX-sensitive inhibitor(s) of apoptosis in these thyroid cancer cell lines. The anti-apoptotic proteins like FLAME-1, Bcl-2 and Bcl-xL are believed to be such CHX-sensitive inhibitors in various types of cancer cells. We, however, provide the evidence using NPA and SW579 cell lines that these proteins were not affected by the CHX treatment in thyroid cancer cells. The apoptosis of thyroid cancer cells was mediated by the classical activation of caspases that in turn activated the DNA Fragmentation Factor (DFF-45). To elucidate the role of individual caspases in TRAIL-mediated apoptosis, the inhibitory effects of several general and specific tetrapeptide caspase inhibitors were studied. The inhibitors of caspase-1, -6, -8, and -9 as well as general upstream inhibitors of apoptosis could dramatically inhibit TRAIL-induced apoptosis in thyroid cancer cells. Caspase-2 and -3 inhibitors, on the other hand, had no significant effect. When the cells were treated with either agonistic Fas antibody (CH11) or TNF-alpha, no apoptotic changes were observed. The apoptosis induced by agonistic Fas Ab could be seen only after a prolonged exposure (24 h) to CHX, whereas TNF-alpha had no effect even in the presence of CHX. The efficacy of TRAIL was also tested on other types of thyroid cancer cells like ARO, FRO (anaplastic carcinoma) and TPC-1 (papillary carcinoma) and compared to that triggered by other death inducing cytokines FasL and TNF-alpha. Again TRAIL was more potent in triggering apoptosis than Fas and TNF-alpha. Since TRAIL is effective in selectively killing thyroid tumor cells without affecting normal thyrocytes and also does not cause organ toxicity and inflammation in vivo, its potential for the treatment of thyroid cancer seems very promising.
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PMID:TRAIL-induced apoptosis of thyroid cancer cells: potential for therapeutic intervention. 1091 93

Gemcitabine (Gem) is a deoxycytidine analog that is effective against pancreatic cancer and other malignancies following conversion to the 5'-O-mono-, di- and tri-phosphate forms. We evaluated the cytotoxicity of GemMP[10], a novel multimeric form of 2'-deoxy-2',2"-difluorocytidine-5'-O-monophosphate (gemcitabine monophosphate) against three thyroid carcinoma cell lines established from anaplastic (8505C), papillary (B-CPAP) and poorly-differentiated papillary (BHT-101) cancer. GemMP[10] decreased tumor cell growth at concentrations ranging from 1 to 50 nM. These concentrations were 5- to 10-fold lower than those required for inhibition of tumor cell growth by monomeric Gem. GemMP[10] cytotoxicity occurred via induction of apoptosis. Flow cytometric analysis of GemMP[10] treated cells revealed growth arrest in S-phase. Fas-antigen expression was increased in thyroid cancer cells treated with GemMP[10], whereas Fas-L and Bcl-2 expression were not significantly affected. These results demonstrated that GemMP[10] is a potent cytotoxic agent that serves to induce apoptosis in association with increased Fas expression in cultured thyroid cancer cell lines.
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PMID:Antineoplastic activity of a novel multimeric gemcitabine-monophosphate prodrug against thyroid cancer cells in vitro. 1106 1

7-Hydroxystaurosporine (UCN-01) is a selective protein kinase C (PKC) inhibitor and is being developed as a novel anticancer agent. Because of reports that PKC may be involved in the pathogenesis of some forms of thyroid cancers, we examined four thyroid carcinoma lines (FRO, KAT5, NPA, and WRO). These cells were found to have different susceptibility to UCN-01 treatment, and there appeared to be a correlation between UCN-01-induced death and expression levels of endogenous Bcl-2. KAT5 cells, which normally express a low amount of Bcl-2, exhibited significantly higher sensitivity to UCN-01-induced death than the other cell lines. Of interest, susceptibility did not relate to PKC activity or its inhibition by UCN-01. In order to investigate the role of Bcl-2 in UCN-01-induced death, KAT5 cells were transfected to overexpress Bcl-2. KAT5/Bcl-2 cells were capable of conferring resistance to UCN-01-induced death. Furthermore, upregulating of Bcl-2 by 1alpha,25-dihydroxyvitamin D3 (VD3) could protect primary thyroid cell from death induced by UCN-01. Both in situ TUNEL staining and the flow cytometric analysis of cytokeratin-18 (CK18) cleavage confirmed that UCN-01 was indeed inducing apoptosis, and that this effect was inhibited by increased expression of Bcl-2. These results suggest that the Bcl-2 can block the UCN-01-activated cell death pathway and that the expression of Bcl-2 is inversely related to thyroid carcinoma cell susceptibility to UCN-01. Therefore, the analysis of the expression of apoptosis suppressors provides a basis for the use of UCN-01 in the treatment of thyroid cancer.
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PMID:Susceptibility of thyroid cancer cells to 7-hydroxystaurosporine-induced apoptosis correlates with Bcl-2 protein level. 1152 64

We investigated the mechanisms responsible for the widespread refractoriness to chemotherapeutic drugs observed in thyroid cancers. We show that malignant epithelial cells from papillary, follicular, and anaplastic thyroid carcinomas express high levels of Bcl-2 and Bcl-xL. Exogenous expression of either Bcl-2 or Bcl-xL in normal thyrocytes was sufficient to prevent chemotherapeutic drug-induced cytotoxicity. All of the histological thyroid cancer variants examined produced interleukin-4 (IL-4) and interleukin-10 (IL-10), which increased Bcl-2 and Bcl-xL levels and protected thyroid cells from chemotherapeutic agents. Exposure to neutralizing antibodies against IL-4 and IL-10 resulted in down-modulation of Bcl-2 and Bcl-xL, death of a considerable percentage of thyroid cancer cells, and sensitization of the residual tumor population to cytotoxic drug-induced apoptosis. In conclusion, autocrine production of IL-4 and IL-10 promotes thyroid tumor cell progression and resistance to chemotherapy through the up-regulation of antiapoptotic proteins. Thus, IL-4 and IL-10 may represent new therapeutic targets for the treatment of thyroid cancer.
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PMID:Thyroid cancer resistance to chemotherapeutic drugs via autocrine production of interleukin-4 and interleukin-10. 1458 74

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in many human cancer cells but not in normal cells. Thyroid cancer cells, however, appear to be relatively resistant to TRAIL-induced apoptosis. We therefore investigated the effect of chemotherapy on TRAIL-induced apoptosis in thyroid cancer cells. We used six thyroid cancer cell lines: TPC-1, FTC-133, FTC-236, FTC-238, XTC-1, and ARO82-1. We used flow cytometry to measure apoptosis, dimethyl-thiazol-diphenyltetrazolium bromide (MTT) assay to measure antiproliferation effects and Western blot to determine the expression of Bcl family proteins. Troglitazone, paclitaxel, geldanamycin, and cycloheximide were used for pretreatment. We used the Student's t test and analysis of variance (ANOVA) for statistical analysis. All thyroid cancer cell lines, except the TPC-1 cell line, were resistant to TRAIL, and growth inhibition was less than 20% at concentration of 800 ng/mL of TRAIL. In both TPC-1 (TRAIL-sensitive) and FTC-133 (TRAIL-resistant) thyroid cancer cell lines, pretreatment with troglitazone, cycloheximide, and paclitaxel enhanced TRAIL-induced cell death significantly but pretreatment with geldanamycin did not. There were no significant changes in Bcl-2, Bcl-xl, and Bax protein expression after troglitazone treatment. In conclusion, TRAIL in combination with troglitazone, paclitaxel, and cycloheximide induces apoptosis in thyroid cancer cells at suboptimal concentrations that cannot be achieved using TRAIL alone.
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PMID:Modulation of tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis by chemotherapy in thyroid cancer cell lines. 1475 Oct 30

IL-4, a pleiotropic cytokine mainly produced by activated helper T lymphocytes type 2 (Th2), is known to protect thyroid cells from autoimmune damage. Acting via its receptors (IL-4Ralpha), IL-4 has antiproliferative and apoptotic effects in many malignancies. Its effect in thyroid cancer is unknown. We found that surgical specimens of thyroid carcinomas express both IL-4Ralpha and IL-4 in the majority of cases. Thyroid glands affected by Graves' disease also express IL-4. We also studied a panel of eight thyroid cancer cell lines from different histotypes and found that thyroid cancer cells express high levels of IL-4Ralpha although they do not express IL-4. We then compared the biological effects of IL-4 in TPC-1, a thyroid cancer cell line, and in MCF-7 breast cancer cells. IL-4 very weakly stimulated thyroid cancer cell proliferation, but it was very effective in protecting thyroid cancer cells from apoptosis induced by staurosporin. The protective effect of IL-4 was similar in magnitude to that of IGF-I and was associated with up-regulation of the antiapoptotic molecule Bcl-2 and weak down-regulation of the proapoptotic molecule Bax. Moreover, IL-4 slightly potentiated the survival effect of IGF-I. In contrast, IL-4 reduced growth and induced apoptosis in MCF-7 cells. Taken together, these findings suggest that thyroid cancer cells receive significant protection from apoptosis by IL-4 produced in the thyroid gland by activated T lymphocytes when concomitant Graves' disease is present.
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PMID:Interleukin-4 stimulates papillary thyroid cancer cell survival: implications in patients with thyroid cancer and concomitant Graves' disease. 1518 Oct 72

Histone deacetylases (HDAC) and histone acetyltransferases exert opposing enzymatic activities that modulate the degree of acetylation of histones and other intracellular molecular targets, thereby regulating gene expression, cellular differentiation, and survival. HDAC inhibition results in accumulation of acetylated histones and induces differentiation and/or apoptosis in transformed cells. In this study, we characterized the effect of two HDAC inhibitors, suberoylanilide hydroxamic acid (SAHA) and m-carboxycinnamic acid bis-hydroxamide, on thyroid carcinoma cell lines, including lines originating from anaplastic and medullary carcinomas. In these models, both SAHA and m-carboxycinnamic acid bis-hydroxamide induced growth arrest and caspase-mediated apoptosis and increased p21 protein levels, retinoblastoma hypophosphorylation, BH3-interacting domain death agonist cleavage, Bax up-regulation, down-regulation of Bcl-2, A1, and Bcl-x(L) expression, and cleavage of poly(ADP-ribose) polymerase and caspase-8, -9, -3, -7, and -2. Transfection of Bcl-2 cDNA partially suppressed SAHA-induced cell death. SAHA down-regulated the expression of the apoptosis inhibitors FLIP and cIAP-2 and sensitized tumor cells to cytotoxic chemotherapy and death receptor activation. Our studies provide insight into the tumor type-specific mechanisms of antitumor effects of HDAC inhibitors and a framework for future clinical applications of HDAC inhibitors in patients with thyroid cancer, including histologic subtypes (e.g., anaplastic and medullary thyroid carcinomas) for which limited, if any, therapeutic options are available.
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PMID:Novel histone deacetylase inhibitors in the treatment of thyroid cancer. 1589 98

We have investigated the effect of dexamethasone (DEX) on the apoptosis induced by TRAIL (tumour necrosis factor-related apoptosis inducing ligand) in follicular undifferentiated thyroid (FRO) cancer cells. Apoptosis was measured by percent hypodiploid nuclei, caspase-3 and -8 activation, and mitochondrial membrane depolarisation. DEX nearly abolished TRAIL-induced apoptosis. The DEX protective effect was reverted by the steroid receptor antagonist RU486 suggesting that the DEX action is mediated by glucocorticoid receptor (GR) activation. The role of Bcl proteins in the DEX effect was then investigated. In FRO cells DEX stimulated in a time-dependent fashion the expression of Bcl-xL, but not that of Bcl-2, Bax and Bad. In addition, Bcl-xL mRNA was significantly increased in the presence of DEX, suggesting a transcriptional regulation by the steroid. Transfection of the cells with siRNAs against Bcl-xL inhibited both basal and DEX-stimulated Bcl-xL expression and restored apoptosis in TRAIL-stimulated cells treated with DEX. These results demonstrate that dexamethasone protects thyroid cancer cells from apoptosis induced by TRAIL. DEX acts via GR activation and up-regulation of the expression of the anti-apoptotic protein Bcl-xL.
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PMID:Dexamethasone inhibits TRAIL-induced apoptosis of thyroid cancer cells via Bcl-xL induction. 1707 Jun 82


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