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)

Apoptosis plays a key role in the control of rapidly renewing tissues, such as the hematopoietic system and leukemia cells invariably have abnormalities in one or more apoptotic pathways, determining a survival advantage of these cells and the development of drug resistance. These defects are also frequently associated with a low rate of response to standard chemotherapy and with a poor survival in acute myeloid leukemia (AML). The major form of apoptosis proceeds through the mitochondrial pathway, with the mitochondrial outer membrane permeabilization, leading to the release of proteins normally found in the space between the inner and outer mitochondrial membranes (cytochrome C, AIF and others). Higher levels of anti-apoptosis proteins bcl-2, bcl-x(L), Mcl-1 block permeabilization of the membrane and are reported in AML patients presenting a poor outcome. On the contrary, activated pro-apoptotic bax or bad proteins allow this permeabilization and are correlated to a good prognosis in AML. Defects in the mitochondrial pathway induce multidrug-resistance and confer important prognostic information in AML. High ratios of bcl-2 to bax protein confer a poor prognosis with decreased rates of complete remission and overall survival. The prognostic information from the ratio of the proteins is greater than bcl-2 levels alone. Recently, we confirmed the impressive impact of the bax/bcl-2 ratio, determined by flow cytometry, on AML prognosis (complete remission and overall survival) in 255 AML patients. Bcl-2 down regulation might lower the apoptotic threshold of leukemic cells and, through this mechanism, favor response to chemotherapy. Phase II studies of oblimersen (antisense Bcl-2), cytarabine and daunorubicin or oblimersen plus gentuzumab, a cytotoxic antibody directed against CD33+ cells in relapsed AMLs, showed promising results. Defects in apoptosome proteins, such as APAF-1, are frequent in AML and treatment with 5-aza-2'-deoxycytidine, a specific inhibitor of DNA methylation, restored APAF-1 expression in leukemic cells. In conclusion, targeted therapies that are designed to induce apoptosis in leukemic cells, are the most promising anti-leukemia strategies. The elucidation of the apoptotic machinery and of its defects in AML lays the basis for developing new drugs able to trigger apoptosis and overcome therapy resistance.
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PMID:Deregulation of the mitochondrial apoptotic machinery and development of molecular targeted drugs in acute myeloid leukemia. 1847 34

Although it has been previously reported that bee venom (BV) can induce apoptosis in many cancer cell lines, there is no information on the effect of BV on human cervical cancer cells and its molecular mechanisms of action are not fully elucidated. In this study, the possible mechanisms of apoptosis by which BV acts on human cervical cancer Ca Ski cells were investigated. BV induced morphological changes and decreased the percentage of viable Ca Ski cells in a dose- and time-dependent manner. Flow cytometric analysis demonstrated that BV induced the production of reactive oxygen species, increased the level of cytoplasmic Ca2+, reduced mitochondrial membrane potential which led to cytochrome c release, and promoted the activation of caspase-3 which then led to apoptosis. BV also induced an increase in the levels of Fas, p53, p21 and Bax, but a decrease in the level of Bcl-2. The activities of both caspase-8 and caspase-9 were enhanced by BV, promoting caspase-3 activation, leading to DNA fragmentation. Based on the DNA fragmentation and DAPI staining, BV-induced apoptosis was mitochondrial-dependent and caspase-dependent. BV also promoted the expression of AIF and Endo G in the Ca Ski cells. Both AIF and Endo G proteins were released from the mitochondria, and then induced apoptosis which was not through activation of caspase. In conclusion, our data demonstrated that BV-induced apoptosis occurs via a Fas receptor pathway involving mitochondrial-dependent pathways and is closely related to the level of cytoplasmic Ca2+ in Ca Ski cells.
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PMID:Bee venom induced cell cycle arrest and apoptosis in human cervical epidermoid carcinoma Ca Ski cells. 1850 26

This study examined the apoptotic effects of crude saponins acquired from the roots of Platycodon grandiflorum (SPR) in HT-29 human colon cancer cells. SPR decreased HT-29 cell proliferation in dose- and time-dependent manners by inducing apoptosis via DNA fragmentation and poly (ADP-ribose) polymerase (PARP) cleavage. The apoptosis induced by SPR was associated with the activation of initiator caspases-8 and -9, as well as the effector caspase-3. SPR stimulated Bid cleavage, indicating that the apoptotic action of caspase-8-mediated Bid cleavage leads to the activation of caspase-9. SPR increased the expression of the pro-apoptotic protein, Bax, and decreased the expression of the anti-apoptotic protein, Bcl-2. SPR also increased the expression of the caspase-independent mitochondrial apoptosis factor, AIF, in HT-29 cells. These results indicate that SPR inhibits HT-29 cell proliferation by inducing apoptosis, which may be mediated via both caspase-dependent and -independent pathways.
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PMID:Induction of apoptosis in HT-29 colon cancer cells by crude saponin from Platycodi Radix. 1895 3

NG108-15 cells differentiate into neurons by 1 mM sodium butyrate (NaB) treatment. Differentiated cells resulted more resistant to staurosporine (STS) than proliferating cells. In particular, STS treatment decreased Bcl-2 and Bcl-x(L) content in mitochondria of proliferating cells, but not in mitochondria of differentiated cells. Bad was phosphorylated and downregulated only in differentiated cells. Bax accumulated in the mitochondria of proliferating but not differentiated cells. Mitochondrial release of cytochrome c was observed in proliferating cells, whereas mitochondria of differentiated cells retained cytochrome c. Proliferating cells treated with STS accumulated Endo G and AIF in the nucleus. By contrast, differentiated cells did not show such nuclear accumulation. Treatment of differentiated cells with Insulin-like Growth Factor-1 (IGF-1) and STS resulted in a 17.1% increase of cell viability. The survival role of IGF-1 was demonstrated by treating differentiated cells with an anti-IGF-1 neutralizing antibody. Such treatment significantly increased STS-induced cell death. Electrophysiology studies showed that in STS-treated cells membrane potential oscillations were reduced in amplitude and did not give rise to spontaneous action potentials (APs). However, the percentage of cells yielding overshooting APs returned to control values after STS removal. It is concluded that neuronal differentiation of NG108-15 cells induces resistance to apoptotic cell death and that IGF-1 plays a central role in sustaining this mechanism.
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PMID:Insulin-like growth factor-1 inhibits STS-induced cell death and increases functional recovery of in vitro differentiated neurons. 1909 25

Mitochondria have emerged as the central components of both caspase-dependent and independent apoptosis signalling pathways through release of different apoptogenic proteins. We previously documented that parental and differentiated Friend's erythroleukemia cells were induced to apoptosis by oligomycin and H(2)O(2) exposure, showing that the energy impairment occurring in both cases as a consequence of a severe mitochondrial F(0)F(1)ATPsynthase inactivation was a common early feature. Here we provide evidence for AIF and Endo G mitochondrio-nuclear relocation in both cases, as a component of caspase-independent apoptosis pathways. No detectable change in mitochondrial transmembrane potential and no variation in mitochondrial levels of Bcl-2 and Bax are observed. These results point to the osmotic rupture of the mitochondrial outer membrane as occurring in response to cell exposure to the two energy-impairing treatments under conditions preserving the mitochondrial inner membrane. A critical role of the mitochondrial F(0)F(1)ATP synthase inhibition in this process is also suggested.
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PMID:Caspase-independent apoptosis in Friend's erythroleukemia cells: role of mitochondrial ATP synthesis impairment in relocation of apoptosis-inducing factor and endonuclease G. 1918 84

Cervical cancer is the most common cancer in Indian females and is associated with infection with high risk Human papillomaviruses (HPVs). Curcumin (Diferuloyl methane), a chemopreventive agent, is a natural compound extracted from Curcuma longa that allows suppression of carcinogenesis. The objective of this study was to identify the molecular mechanism of curcumin induced apoptosis in HPV positive cervical cancer HeLa, SiHa and Ca Ski cells. Curcumin causes distinct inhibition of human telomerase reverse transcriptase (hTERT) the catalytic core of telomerase thereby reducing proliferation of cancer cells. Curcumin mediated apoptosis in these cells appears to be due to upregulation of proapoptotic Bax, AIF, release of cytochrome c and down regulation of antiapoptotic Bcl-2, Bcl-XL in HeLa and SiHa. This was accompanied by an increase in caspase-3 and -9 activity, suggesting the role of mitochondria in curcumin mediated apoptotic cell death. Curcumin acts as an anti-inflammatory and anti-proliferative agent by causing down regulation of COX-2, iNOS and cyclin D1 in all the three cell lines but to different extent.
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PMID:Molecular mechanism of curcumin induced cytotoxicity in human cervical carcinoma cells. 1919 Oct 10

(-)-Epigallocatechin-3-gallate (EGCG) is a major constituent of green tea and has been identified as an excellent anticancer agent. Nevertheless, there are no reports to date about the molecular mechanisms and signal pathways of EGCG on the induction of apoptosis in human adrenal NCI-H295 cancer cells. The purpose of this study was to investigate the anticancer effect and molecular mechanisms of EGCG on human adrenal NCI-H295 cancer cells. The results showed that EGCG induced growth inhibition in a dose- and time-dependent manner. Moreover, it exerted low cytotoxicity on Detroit 551 normal human embryonic skin cell. When NCI-H295 cells were treated with 20 microM EGCG, the mitochondrial membrane potential decreased and intracellular free Ca(2+) increased in a time-dependent manner as analysed by flow cytometry. EGCG decreased the protein levels of Bcl-2, Bcl-xl, xIAP, cIAP, Hsp70 and Hsp90, but increased the protein expression of Bad, Bax, Fas/CD95, cytochrome c, Apaf-1, AIF, GADD153, GRP78, and caspase-3, -7,-8 and -9 as observed by Western blotting examination. EGCG promoted caspase-8, -9 and -3 activities in a time-dependent manner. However, pretreatment of cells with inhibitors of caspase-8, -9 and -3 led to a decrease in caspase-8, -9 and -3 activities and an increase in the percentage of viable cells. Based on the above findings, it was confirmed that EGCG may be a drug candidate for the treatment of human adrenal cancer in the future.
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PMID:(-)-Epigallocatechin gallate induced apoptosis in human adrenal cancer NCI-H295 cells through caspase-dependent and caspase-independent pathway. 1941 99

This study was performed to elucidate the apoptotic pathways by thiosulfinates, major biologically active components of Allium tuberosum L., in HT-29 human colon cancer cells. Thiosulfinates significantly induced cell death in dose- and time-dependent manners in HT-29 cells, which is associated with apoptosis. Thiosulfinates activated the initiator caspase-8, and -9, and the effector caspase-3. In the present study, thiosulfinates were found to stimulate Bid cleavage, indicating that the apoptotic action of caspase-8-mediated Bid cleavage leads to the activation of caspase-9. Thiosulfinates down-regulated the expression of the anti-apoptotic protein Bcl-2, and up-regulated the expression of the pro-apoptotic protein Bax. We also found that thiosulfinates increased the expression of AIF, a caspase-independent mitochondrial apoptosis factor, and induced DNA fragmentation and chromatin condensation in HT-29 cells. These results indicate that thiosulfinates from A. tuberosum L. inhibited cell proliferation and activated both the caspase-dependent and caspase-independent apoptotic pathways in HT-29 cells.
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PMID:Mechanisms of thiosulfinates from Allium tuberosum L.-induced apoptosis in HT-29 human colon cancer cells. 1944 47

This study was performed to elucidate the anti-proliferative effects and the apoptotic mechanisms of extracts from Lethariella zahlbruckneri in HT-29 human colon cancer cells. Both the acetone extract (AEL) and methanolic extract (MEL) of L. zahlbruckneri decreased viable cell numbers in a dose- and time-dependent manner in HT-29 cells. The AEL showed stronger cytotoxicity than MEL. Cell death induced by AEL increased cell populations in the sub-G1 phase, as well as the formation of apoptotic bodies and nuclear condensation, whereas MEL did not. Therefore, the potential of AEL to induce apoptosis was examined. Apoptosis induced by AEL was associated with the activation of initiator caspases-8 and -9, as well as the effector caspase-3. AEL stimulated Bid cleavage. This indicated that the apoptotic action of caspase-8-mediated Bid cleavage leads to the activation of caspase-9. AEL increased the expression of the pro-apoptotic protein, Bax, and decreased the expression of the anti-apoptotic protein, Bcl-2. AEL also increased the expression of the caspase-independent mitochondrial apoptosis factor, AIF, in HT-29 cells. These results indicate that AEL inhibited HT-29 cell proliferation by inducing apoptosis, which might be mediated via both caspase-dependent and -independent pathways.
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PMID:Anti-proliferative effects of Lethariella zahlbruckneri extracts in human HT-29 human colon cancer cells. 1950 Nov 27

Neuroblastoma is a pediatric extracranial tumor and a major cause of death in children under age 2. Conventional therapy shows inefficacy in most cases and thus development of new therapeutic strategies is urgently needed. We explored the efficacy of combination of the small molecule Bcl-2 inhibitor HA14-1 (HA) and the isoflavonoid genistein (GST) in human malignant neuroblastoma SK-N-BE2 and SH-SY5Y cells. Combination of 10 microM HA and 250 microM GST was optimal for SK-N-BE2 cells and combination of 5 microM HA and 100 microM GST was optimal for SH-SY5Y cells for induction of apoptosis. Phase-contrast microscopy and Wright staining showed morphological features of apoptosis. Cell cycle analysis and Annexin V-FITC/PI binding assay showed that combination of HA and GST was more effective in inducing apoptosis in both cell lines than either HA or GST alone. Western blotting showed that combination of HA and GST caused upregulation of Bax and down regulation of Bcl-2 resulting in increased Bax:Bcl-2 ratio and mitochondrial release of cytochrome c, Smac, and AIF. Down regulation of survival factors such as NF-kappaB, N-Myc, and survivin promoted apoptosis. Activation of caspase-8, calpain, and caspase-3 occurred in course of apoptosis. Increased calpain and caspase-3 activities were confirmed in the degradation of alpha-spectrin to 145 kD spectrin break down product (SBDP) and 120 kD SBDP, respectively. Thus, combination of HA and GST could serve as a promising therapeutic strategy for increasing apoptosis in different human malignant neuroblastoma cells.
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PMID:Bcl-2 inhibitor HA14-1 and genistein together adeptly down regulated survival factors and activated cysteine proteases for apoptosis in human malignant neuroblastoma SK-N-BE2 and SH-SY5Y cells. 1950 41


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