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)

Most human non-small cell lung cancer (NSCLC) cell lines are refractory to all-trans-retinoic acid (ATRA). Recently, N-(4-hydroxyphenyl)retinamide (4HPR) was found to induce apoptosis in various tumor cells. In this study, we compared and contrasted the effects of 4HPR and ATRA on the growth and apoptosis of 10 NSCLC cell lines and normal human bronchial epithelial (NHBE) cells. All of the cancer cell lines and the NHBE cells were sensitive to 10 microM 4HPR, and their numbers decreased to <20% of the controls after a 5-day treatment, whereas ATRA decreased cell numbers to about 50% of the controls in three cell lines and was less effective in the rest of the tumor cell lines. ATRA inhibited the growth of the NHBE cells by 70-80%. 4HPR induced apoptosis in most of the cells, including the ATRA-resistant ones, as evidenced by a DNA fragmentation assay. No correlation was found between growth inhibition by 4HPR and the expression of retinoic acid receptor beta (determined by Northern blotting and PCR), p53, or Bcl-2 proteins (analyzed by Western blotting). These results demonstrate that 4HPR is more potent than ATRA in inducing apoptosis in NSCLC cells and suggest that further clinical trials for prevention and therapy of NSCLC using 4HPR are warranted.
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PMID:Higher potency of N-(4-hydroxyphenyl)retinamide than all-trans-retinoic acid in induction of apoptosis in non-small cell lung cancer cell lines. 960 96

BAG-1 (also known as RAP46) is an anti-apoptotic protein, which has been shown previously to interact with a number of nuclear hormone receptors, including receptors for glucocorticoid, estrogen, and thyroid hormone. We show here that BAG-1 also interacts with retinoic acid receptor (RAR). Gel retardation assays demonstrated that in vitro translated BAG-1 protein could effectively inhibit the binding of RAR but not retinoid X receptor (RXR) to a number of retinoic acid (RA) response elements (RAREs). A glutathione S-transferase-BAG-1 fusion protein also specifically bound RAR but not RXR. Interaction of BAG-1 and RAR could also be demonstrated by yeast two-hybrid assays. In transient transfection assays, co-transfection of BAG-1 expression plasmid inhibited the transactivation activity of RAR/RXR heterodimers but not RXR/RXR homodimers. When stably expressed in breast cancer cell lines, BAG-1 inhibited binding of RAR/RXR heterodimer to a number of RAREs and suppressed RA-induced growth inhibition and apoptosis. In addition, RA-induced suppression of Bcl-2 expression was abrogated by overexpression of BAG-1. These results demonstrate that BAG-1 can regulate retinoid activities through its interaction with RAR and suggest that elevated levels of BAG-1 protein could potentially contribute to retinoid resistance in cancer cells.
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PMID:Interaction of BAG-1 with retinoic acid receptor and its inhibition of retinoic acid-induced apoptosis in cancer cells. 964 62

Neoplastic events are marked by uncontrolled cell proliferation. One major focus of cancer research has been to identify treatments that reduce or inhibit cell growth. Over the years, various compounds, both naturally occurring and chemically synthesized, have been used to inhibit neoplastic cell proliferation. Two such oncostatic agents, melatonin and retinoic acid, have been shown to suppress the growth of hormone-responsive breast cancer. Currently, separate clinical protocols exist for the administration of retinoids and melatonin as adjuvant therapies for cancer. Using the oestrogen receptor (ER)-positive MCF-7 human breast tumour cell line, our laboratory has studied the effects of a sequential treatment regimen of melatonin followed by all-trans retinoic acid (atRA) on breast tumour cell proliferation in vitro. Incubation of hormonally responsive MCF-7 and T47D cells with melatonin (10(-9) M) followed 24 h later by atRA (10(-9) M) resulted in the complete cessation of cell growth as well as a reduction in the number of cells to below the initial plating density. This cytocidal effect is in contrast to the growth-suppressive effects seen with either hormone alone. This regimen of melatonin followed by atRA induced cytocidal effects on MCF-7 cells by activating pathways leading to apoptosis (programmed cell death) as evidenced by decreased ER and Bcl-2 and increased Bax and transforming growth factor beta 1 (TGF-beta1) expression. Apoptosis was reflected morphologically by an increase in the number of lysosomal bodies and perinuclear chromatin condensation, cytoplasmic blebbing and the presence of apoptotic bodies. The apoptotic effect of this sequential treatment with melatonin and atRA appears to be both cell and regimen specific as (a) ER-negative MDA-MB-231 and BT-20 breast tumour cells were unaffected, and (b) the simultaneous administration of melatonin and atRA was not associated with apoptosis in any of the breast cancer cell lines studied. Taken together, the results suggest that use of an appropriate regimen of melatonin and atRA should be considered for preclinical and clinical evaluation against ER-positive human breast cancer.
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PMID:A sequential treatment regimen with melatonin and all-trans retinoic acid induces apoptosis in MCF-7 tumour cells. 964 24

We have cloned a murine homologue of the human Mcl1/EAT gene, a Bcl-2 related gene. Sequence analysis revealed that murine Mcl1/EAT (mMcl1/EAT) has three Bcl-2 homology domains, two PEST sequences, and immediate response boxes (IRB). The presence of IRB indicates that mMcl1/EAT is an immediate-early gene. mMcl1/EAT increases dramatically with exposure to retinoic acid in murine embryonal carcinoma cell lines (F9 and PCC3) as well as embryonic stem cells, both of which are models of early embryogenesis.
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PMID:Up-regulated expression of murine Mcl1/EAT, a bcl-2 related gene, in the early stage of differentiation of murine embryonal carcinoma cells and embryonic stem cells. 965 29

During the process of terminal differentiation toward mature neutrophils, the anti-apoptotic proteins Bcl-2 and Bcl-x become down-regulated and eventually cease to be expressed, whereas the death-promoting Bcl-2 homologue, Bax, persists. Thus, the disappearance of anti-apoptotic homologues was thought to account for the early demise of mature neutrophils. However, although the survival of mature human neutrophils can be prolonged by a variety of factors, no anti-apoptotic Bcl-2 homologues have previously been identified. Human A1 is a Bcl-2 homologue previously shown to be present in endothelial cells and to convey anti-apoptotic function in vitro. We describe here that human A1 mRNA is constitutively expressed in mature neutrophils and is up-regulated by G-CSF and LPS, agonists that promote neutrophil survival. In addition, we show progressive A1 mRNA accumulation in HL-60 cells during all-trans retinoic acid-driven neutrophilic differentiation. Our findings suggest that A1 may have an important role in neutrophilic development and in modulating mature neutrophil survival.
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PMID:A1 is a constitutive and inducible Bcl-2 homologue in mature human neutrophils. 971 1

Cell sensitivity to programmed cell death is primarily modulated by members of the Bcl-2 family, as the balance of homodimer or heterodimer formation between proapoptotic and antiapoptotic members defines apoptosis susceptibility in the great majority of cellular contexts. It is, therefore, important to clarify if the Bax protein is limiting for activation of the genetic program of programmed cell death or can be complemented by different Bcl-2 family members, such as Bak or Bad. To gain some insight into the role of Bax in the molecular mechanisms of apoptosis of myeloid cells, we inhibited this gene in all-trans-retinoic acid (ATRA)-treated HL60 cells using the methodology of antisense oligodeoxynucleotides (AS-ODN). Our results indicate that Bax inhibition has no effect on the proliferation and differentiation capacity of HL60 cells. Instead, the survival rate of terminally differentiated Bax-inactivated HL60 (Bax(-) HL60) cells is almost three times higher in respect to control cultures, indicating that in mature granulocytes Bax is not efficiently complemented by others members of the Bcl-2 family proteins.
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PMID:Antisense inhibition of Bax mRNA increases survival of terminally differentiated HL60 cells. 974 71

The regulation of chondrocyte apoptosis in articular cartilage may underlay age-associated changes in cartilage and the development of osteoarthritis. Here we demonstrate the importance of Bcl-2 in regulating articular chondrocyte apoptosis in response to both serum withdrawal and retinoic acid treatment. Both stimuli induced apoptosis of primary human articular chondrocytes and a rat chondrocyte cell line as evidenced by the formation of DNA ladders. Apoptosis was accompanied by decreased expression of aggrecan, a chondrocyte specific matrix protein. The expression of Bcl-2 was downregulated by both agents based on Northern and Western analysis, while the level of Bax expression remained unchanged compared to control cells. The importance of Bcl-2 in regulating chondrocyte apoptosis was confirmed by creating cell lines overexpressing sense and antisense Bcl-2 mRNA. Multiple cell lines expressing antisense Bcl-2 displayed increased apoptosis even in the presence of 10% serum as compared to wild-type cells. In contrast, chondrocytes overexpressing Bcl-2 were resistant to apoptosis induced by both serum withdrawal and retinoic acid treatment. Finally, the expression of Bcl-2 did not block the decreased aggrecan expression in IRC cells treated with retinoic acid. We conclude that Bcl-2 plays an important role in the maintenance of articular chondrocyte survival and that retinoic acid inhibits aggrecan expression independent of the apoptotic process.
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PMID:Evidence of a direct role for Bcl-2 in the regulation of articular chondrocyte apoptosis under the conditions of serum withdrawal and retinoic acid treatment. 977 27

Cisplatin exerts its cytotoxicity by inducing apoptosis. Similarly, all-trans retinoic acid (ATRA) causes apoptosis in certain cells. We studied the interaction of cisplatin and ATRA in human ovarian adenocarcinoma cells 2008, in human head and neck squamous carcinoma cells UMSCC10b, and in their respective cisplatin-resistant sub-lines. ATRA enhanced the cytotoxicity of cisplatin. The interaction of the drugs was synergistic in combination index-isobologram analyses (combination index >0.5 at 50% cell survival) in all of the cell lines tested. ATRA inhibited the cellular accumulation of the cisplatin analogue [3H] cis-dichloroethylenediamineplatinum(II) by 22-33% in three of four cell lines tested but did not alter the cellular content of reduced glutathione. The expression of Bcl-2 relative to Bax decreased more after combined treatment with cisplatin and ATRA than after either drug alone. The apoptotic mechanism of cell death was confirmed by demonstrating cleavage of poly(ADP-ribose)polymerase and by morphological analysis. The combined treatment with ATRA and cisplatin induced apoptosis in significantly more cells than either drug alone. We conclude that ATRA enhances the cytotoxicity of cisplatin by facilitating apoptosis in ovarian and head and neck carcinoma cells.
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PMID:all-trans retinoic acid enhances cisplatin-induced apoptosis in human ovarian adenocarcinoma and in squamous head and neck cancer cells. 981 94

Retinoids play an important role in the control of lymphocyte function and homeostasis in the thymus. In this study, we show that the induction of growth arrest and apoptosis in a variety of T-cell lymphoma cell lines, including Jurkat and Molt-4 cells, is highly specific for the synthetic retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (AHPN) since all-trans retinoic acid (RA), the RAR-selective retinoid TTAB, the RXR-selective retinoid SR11217 and the retinoid SR11302 exhibiting selective anti-AP1 activity, do not induce apoptosis or cause growth arrest. These findings support the concept that the effects of AHPN on proliferation and induction of apoptosis are mediated by a novel signaling pathway. AHPN-induced apoptosis is associated with an induction of internucleosomal DNA-fragmentation, increased annexin V binding and a 30-fold stimulation of caspase-3-like activity. Overexpression of Bcl-2 in Molt-4 cells greatly inhibits the induction of apoptosis by AHPN as indicated by the inhibition of DNA-fragmentation, annexin V binding and caspase-3-like activity. However, Bcl-2 overexpression does not interfere with the ability of AHPN to cause growth arrest or accumulation of cells in the early S-phase of the cell cycle, indicating that the effects of AHPN on growth arrest can be uncoupled from the effects on apoptosis. The caspase inhibitor Z-VAD-FMK, at concentrations that totally block caspase activity, delays but does not prevent cell death and does not affect the accumulation of cells in the S-phase of the cell cycle. Our results show that induction of caspase-3-like activity plays an important role in the execution of AHPN-induced apoptosis but cells can undergo cell death in the absence of this activity suggesting that AHPN-induced cell death involves caspase-dependent and -independent mechanisms.
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PMID:Induction of apoptosis by the novel retinoid AHPN in human T-cell lymphoma cells involves caspase-dependent and independent pathways. 984 84

Most prostate cancers eventually develop resistance to hormonal therapy and chemotherapies. Many mechanisms for resistance to chemotherapy have been identified. Mutations or inactivation of the p53 suppressor gene and overexpression of bcl-2 are among such mechanisms. Mutations in the p53 gene can lead to resistance to certain chemotherapy agents, and such mutations are seen more often in metastatic than in primary prostate cancers. Thus, agents that are active in the setting of mutated p53 may have some advantage in prostate cancer. Overexpression of bcl-2 occurs frequently in prostate cancer and is associated with both hormonal therapy and chemotherapy resistance. In experimental systems, bcl-2 overexpression occurs after androgen deprivation and transfection of bcl-2 into sensitive cell lines makes them resistant to chemotherapy and hormonal therapies. Bcl-2 can be inactivated by phosphorylation as occurs with taxanes. The retinoids, as a class, can inhibit the growth of resistant cell lines that overexpress bcl-2, and the combination of interferon (IFN) and cis-retinoic acid (CRA) demonstrated increased antitumor activity. In our cell line model the combination of IFN and CRA greatly enhanced the cytotoxicity of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ). Based on these observations, we conducted a phase I/II trial of CRA and IFN-alpha in patients with biochemical recurrence of prostate cancer. Twenty-six percent achieved a decrease of prostate-specific antigen (PSA), which was correlated to elevated serum transforming growth factor-beta. We then conducted a phase I trial of 13-CRA, IFN-alpha, and escalating doses of paclitaxel. Eighteen patients were treated with 1 mg/kg CRA and 1x10(6) unit IFN on days 1 to 4 and paclitaxel at doses from 100 to 175 mg/m2. Eleven patients received the 175 mg/m2 paclitaxel dose. Two patients in the phase I study achieved partial responses (one cervix and one prostate cancer). We subsequently initiated a phase II study of 13-CRA, IFN-alpha, and paclitaxel in hormone refractory prostate cancer. For entry patients must show progressive disease after androgen ablation. To test the mechanism of action, we are assaying peripheral blood monocytes and, when possible, tumor tissue for bcl-2 expression. As our understanding of the mechanisms of tumor resistance to chemotherapy improves, we will be able to design better approaches in treatment targeted to overcome the mechanisms of resistance.
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PMID:Overcoming bcl-2- and p53-mediated resistance in prostate cancer. 1019 Jul 92


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