Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The transcription factor Tax of the oncogenic human T-cell leukemia virus type 1 is likely to be responsible for viral replication in the host organism and for the induction of proliferation in infected cells. To investigate Tax-mediated transcription in vivo, we expressed Tax as well as CREB in Saccharomyces cerevisiae. The activity of these proteins was monitored by expression of a beta-galactosidase reporter gene, which was fused to two viral 21-bp repeats located upstream of the yeast cytochrome c1 oxidase minimal promoter. Coexpression of Tax and CREB in S. cerevisiae led to a 20-fold increase in beta-galactosidase activity in comparison with that in strains expressing either Tax or CREB alone. By screening a human cDNA library, we were able to demonstrate that the Tax transactivation assay using S. cerevisiae can be successfully applied to identify other cellular proteins forming ternary complexes with Tax and 21-bp repeats in vivo. Upon transformation in S. cerevisiae, 1 of 13,500 clones tested positive. Sequencing of the cDNA insert of the rescued plasmid revealed that this DNA encoded the ATF-1 protein. beta-Galactosidase induction was comparable to that of the Tax/CREB coexpression system. This indicates that Tax-mediated transcription is critically dependent on the presence of cellular CREB or ATF-1 in vivo. Stimulation of transcription initiation required an unmasked NH2 terminus of Tax. Fusion of Tax to the yeast Gal4 protein abolished the transactivation potential of Tax. Reconstitution of the transcriptional properties of viral Tax together with the cellular proteins of the ATF-1/CREB family in S. cerevisiae allows the functional characterization of these proteins in vivo.
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PMID:The oncoprotein Tax of the human T-cell leukemia virus type 1 activates transcription via interaction with cellular ATF-1/CREB factors in Saccharomyces cerevisiae. 889 66

If the interplay between caspase proteases and mitochondria decide the fate of the cell during apoptosis, they may constitute useful molecular targets for novel drug design. We have shown that photoactivated merocyanine 540 (pMC540) triggers caspase-mediated apoptosis in HL60 leukemia and M14 melanoma cells. Because pMC540 is a mixture of photoproducts, we set out to purify the biologically active component(s) from this mixture and to investigate their ability to directly activate intracellular caspases and/or trigger mitochondrial events associated with apoptosis. Two photoproducts, namely C1 and C2, purified and characterized by mass spectroscopy and nuclear magnetic resonance (NMR) analysis, effectively induced apoptosis in HL60 and M14 cells. Interestingly, both C1 and C2 induced non-receptor-dependent activation of caspase 8, which was responsible for the downstream activation of caspase 3 and cell death. Both compounds induced the release of cytochrome C from mitochondria of tumor cells and from purified rat liver mitochondria; however, different mechanisms were operative in cytochrome C translocation in response to C1 or C2. C1-induced cytochrome C release was mediated by the mitochondrial permeability transition (MPT) pore and accompanied by a decrease in mitochondrial transmembrane potential (triangle uppsim), whereas cytochrome C release in response to C2 was independent of MPT pore opening. These findings do not exclude the possibility that changes in mitochondrial triangle uppsim are critical for apoptosis in some instances, but support the notion that this may not be a universal step in the apoptotic process. Thus, identification of two novel anticancer agents that directly activate effector components of the apoptotic pathway could have potential implications for the development of newer chemotherapeutic drugs.
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PMID:Purified photoproducts of merocyanine 540 trigger cytochrome C release and caspase 8-dependent apoptosis in human leukemia and melanoma cells. 1036 Nov 6

Induction of mitochondrial permeability transition (MPT) and cytosolic translocation of cytochrome C are considered essential components of the apoptotic pathway. Hence, there is the realization that mitochondrial-specific drugs could have potential for use as chemotherapeutic agents to trigger apoptosis in tumor cells. Recently, we showed that photoproducts of merocyanine 540 (pMC540) induced tumor cell apoptosis. In this study, we focused on identifying mitochondrial-specific compounds from pMC540 and studied their apoptotic potential. One purified fraction, C5, induced a drop in mitochondrial transmembrane potential and cytosolic translocation of cytochrome C in HL60 human leukemia cells. Moreover, the addition of C5 to purified rat liver mitochondria induced MPT as indicated by mitochondrial matrix swelling, which was completely inhibited by cyclosporin A, an inhibitor of the inner-membrane pore. Supernatant of C5-treated mitochondria showed a dose-dependent increase in cytochrome C, which was also inhibited in the presence of cyclosporin A, strongly indicating a direct effect on the inner-membrane pore. Despite the strong mitochondrial reactivity, C5 elicited minimal cytotoxicity (less than 25%) against HL60 leukemia and M14 melanoma cells because of inefficient caspase activation. However, prior exposure to C5 significantly enhanced the apoptotic response to etoposide or the CD95 receptor. Thus, we demonstrate that MPT induction and cytochrome C release by the novel compound C5, in the absence of effective caspase activation, is insufficient for triggering efficient apoptosis in tumor cells. However, when used in combination with known apoptosis inducers, such compounds could enhance the sensitivity of tumor cells to apoptosis. (Blood. 2000;95:1773-1780)
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PMID:Induction of mitochondrial permeability transition and cytochrome C release in the absence of caspase activation is insufficient for effective apoptosis in human leukemia cells. 1068 37

A photosensitive alpha-cyanocinnamylideneacetyl group was coupled to poly(allylamine) to obtain a photosensitive polymer. This photosensitive poly(allylamine alpha-cyanocinnamylideneacetate) can cross-link upon light exposure. Microcapsules were fabricated from alginate in contact with Ca+2 ion, followed by coating with the photosensitive poly(allylamine alpha-cyanocinnamylideneacetate). The microcapsules, thus formed, can be strengthened significantly by the light-induced cross-linking of poly(allylamine alpha-cyanocinnamylideneacetate). Only 16 capsules (out of 50) prepared from the photosensitive poly(allylamine alpha-cyanocinnamylideneacetate) fractured after 48 h of agitation. For microcapsules prepared from the unmodified poly(allylamine), 32 capsules fractured. The photo cross-linked capsular membrane was permeable to cytochrome C, moderately permeable to myoglobin, and least permeable to serum albumin. IW32 (a mouse leukaemia cell line) cells were entrapped and cultured within these microcapsules. The cells proliferated to a density of about 9 x 10(6) cells/ml in the capsules after 7 days of cultivation.
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PMID:A novel cell encapsulation method using photosensitive poly(allylamine alpha-cyanocinnamylideneacetate). 1073 99

Though the term apoptosis was originated in pathology and developmental biology as an alternative to necrosis, the tissue necrosis with inflammation is irrelevant to cell culture conditions where apoptosis is mostly studied. Furthermore, no one single morphological feature is either necessary or sufficient to define apoptosis. The emerging biochemical definition, a cell death with caspase activation, allows the distinction of alternative forms of cell death. Thus, inhibition of caspases delays but does not prevent cell death. Slow cell death without caspase activation may nevertheless be associated with DNA fragmentation. Oncogenic Ras, Raf, and mitogen-activated kinases inhibit apoptosis by affecting the cytochrome C/caspase-9 pathway but may arrest growth and cause slow cell death with delayed DNA fragmentation. Such 'slow' cell death without caspase activation is often caused by chemotherapeutic drugs. Whether a cell will undergo apoptosis or slow death depends not only on a chemotherapeutic agent but also on the readiness of cellular caspases. Therefore, one can distinguish apoptosis-prone (eg leukemia) vs apoptosis-resistant cells. Cell susceptibilities to spontaneous, starvation-induced and drug-induced apoptosis are correlated and characterize an apoptosis-prone phenotype. Finally, distinction of slow cell death allows rephrasing of a question regarding the goal of cancer therapy: apoptosis vs slow cell death, or cancer cell-selectivity regardless of the mode of cell death.
Leukemia 2000 Aug
PMID:Cell death beyond apoptosis. 1094 50

We recently showed that two photoproducts of merocyanine 540, C2 and C5, triggered cytochrome C release; however, C5 was inefficient in inducing caspase activity and apoptosis in leukemia cells, unlike C2. Here we show that HL60 cells acidified upon exposure to C2 but not C5. The intracellular drop in pH and caspase activation were dependent upon hydrogen peroxide production, and were inhibited by scavengers of hydrogen peroxide. On the contrary, caspase inhibitors did not block hydrogen peroxide production. In turn, increased intracellular hydrogen peroxide concentration was downstream of superoxide anion produced within 2 h of exposure to C2. Inhibitor of NADPH oxidase diphenyleneiodonium neither inhibited superoxide production nor caspase activation triggered by C2. However, exposure of purified mitochondria to C2 resulted in significantly increased superoxide production. Furthermore, cytochrome C release from isolated mitochondria induced by C2 was completely inhibited in the presence of scavengers of hydrogen peroxide. Contrarily, scavenging hydrogen peroxide had no effect on the cyclosporin A-sensitive mitochondrial permeability transition induced by C5. Our data suggest a scenario where drug-induced hydrogen peroxide production induces intracellular acidification and release of cytochrome C, independent of the inner membrane pore, thereby creating an intracellular environment permissive for caspase activation.
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PMID:Intracellular acidification triggered by mitochondrial-derived hydrogen peroxide is an effector mechanism for drug-induced apoptosis in tumor cells. 2472 1

We have genotyped over 550 cases of acute leukaemia and 950 matched controls from a population-based case-control study, to investigate the impact cytochrome P450s 2D6, 2C19 and 1A1 have on susceptibility to adult acute leukaemia. Analysis included potential associations between polymorphic status and acute myeloid leukaemia (AML), acute lymphoblastic leukaemia (ALL), plus the FAB and cytogenetic subtypes therein. A significant increased risk was found for CYP2D6 poor metabolizer phenotype and acute leukaemia [odds ratio (OR) = 1.69, 95% confidence interval (CI) 1.17-2.43], a risk also found in AML and ALL. No interaction was found with smoking. However, a significant age-related association between CYP2D6 polymorphism and acute myeloid leukaemia implied that the excess risk was confined to persons aged 40 years and over (OR 2.38, 95% CI 1.53-3.71). Amongst AML cases, increased odds ratios were observed in both de-novo (OR 1.54, 95% CI 1.02-2.32) and secondary leukaemia (OR 2.83, 95% CI 0.91-8.77), and among patients with a chromosomal abnormality (OR 2.00, 95% CI 1.11-3.61). An increased risk was found for the CYP2C19 poor metabolizer phenotype (OR 1.68, 95% CI 0.97-2.92) which was also present in AML and ALL. For this CYP450 locus, an increased risk was suggested in secondary leukaemia (OR 2.67, 95% CI 0.44-16.3) and amongst AML cases with a chromosomal abnormality (OR 6.72, 95% CI 2.22-20.4). No difference in CYP1A1 genotype distribution was found for acute leukaemia, AML, ALL or any other diagnostic classification group used. No significant interactions between CYP2D6, CYP2C19 or CYP1A1 were found.
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PMID:Poor metabolizers at the cytochrome P450 2D6 and 2C19 loci are at increased risk of developing adult acute leukaemia. 1103 2

Bcl-XL, a member of the Bcl-2-related anti-apoptosis protein family, antagonizes a diverse range of apoptosis-inducing stimuli by preventing mitochondrial permeability transition, release of apoptogenic factors including cytochrome C, and caspase activation. We have tested the hypothesis that the susceptibility of Bcl-XL-expressing leukaemic cells to apoptosis induced by VP16 (etoposide) can be enhanced by pharmacological downregulation of Bcl-XL in vivo. Two subcutaneous xenograft models of B-cell leukaemia-employing SEMK-2 and BV173 cell lines were established in severe combined immunodeficient/non-obese diabetic mice followed by 14 d of continuous subcutaneous administration of Bcl-XL-specific second generation oligonucleotides ISIS 16009 or ISIS 15999. Tumours were disaggregated, enabling investigation of Bcl-XL expression and apoptosis susceptibility at single-cell resolution using cytofluorimetry. Marked sequence-specific reduction of Bcl-XL was associated with sequence-specific enhancement of VP16-induced mitochondrial permeability transition, caspase-3 activation and loss of membrane asymmetry. A negative correlation between Bcl-XL expression and apoptosis susceptibility was observed, together with a positive correlation with respect to a reduced redox state. Bcl-XL downregulation reduces the threshold for VP16-induced apoptosis by potentiating mitochondrial dysfunction and its sequelae, and therefore presents a novel therapeutic strategy for reversing chemoresistance.
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PMID:In vivo suppression of Bcl-XL expression facilitates chemotherapy-induced leukaemia cell death in a SCID/NOD-Hu model. 1126 76

Resveratrol, a naturally occurring plant antibiotic has been the focus of a number of studies investigating its biological attributes, which include anti-oxidant activity, anti-platelet aggregation effect, anti-atherogenic property, estrogen-like growth promoting effect, growth inhibiting activity, immunomodulation, and chemoprevention. More recently, since the first report on the apoptosis inducing activity of resveratrol in human cancer cells, the interest in this molecule as a potential chemotherapy agent has significantly intensified. Not only has its role as an anti-cancer agent been corroborated, but the precise mechanism(s) of the anti-cancer activity of resveratrol is/are being elucidated. Our group has been active in studying the cross talk between the caspase family of proteases and mitochondria, in drug-induced apoptosis. In this regard, we have shown that the cancer preventive activity of resveratrol could be attributed to its ability to trigger apoptosis in human leukemia and breast carcinoma cells. The cytotoxicity of resveratrol is restricted against these transformed cell types due to its ability to selectively upregulate CD95-CD95L interaction on the tumor cell surface, unlike normal peripheral blood cells. Despite the involvement of the CD95 signaling pathway, apoptosis induced by resveratrol is not accompanied by robust caspase 8 activation, but involves mitochondrial release of cytochrome C and downstream activation of caspases 9 and 3. We also extrapolate these in vitro findings in a murine model of carcinogensis, and demonstrate in vivo induction of apoptosis in mouse skin papillomas. These findings highlight the chemotherapeutic potential of this polyphenolic compound.
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PMID:Resveratrol--from the bottle to the bedside? 1142 22

The apoptotic pathway activated by chimeric anti-CD20 monoclonal antibodies (rituximab, IDEC.C2B8) was analyzed using the Burkitt lymphoma cell line Ramos. Crosslinking of CD20 (CD20XL) induced apoptosis in Ramos cells, which involved loss of mitochondrial membrane potential (Deltapsi(m)), the release of cytochrome-c (cyt-c), and activation of caspases-9 and -3. Nevertheless, several lines of evidence showed that the apoptotic outcome did not depend on these events. First, under circumstances where Ramos cells display resistance to either CD95- or B cell receptor (BCR)-induced apoptosis, CD20XL-induced apoptosis was not affected, pointing to a distinct pathway. Second, the broad-spectrum caspase inhibitor zVAD-fmk prevented processing of caspase-9, -3 and PARP as well as DNA fragmentation, but did not block apoptosis as measured by annexin V staining, cell size and membrane integrity. Lastly, Bcl-2 overexpression blocked cyt-c release and the decrease in Deltapsi(m), and completely prevented CD95- or BCR-mediated apoptosis; however, it did not affect CD20XL-induced cell death. We conclude that although CD20XL can initiate the mitochondrial apoptosis pathway, CD20-induced apoptosis does not necessarily require active caspases and cannot be blocked by Bcl-2. Since most chemotherapeutic drugs require the activation of caspases to exert their cytotoxicity, these findings provide an important rationale for the use of CD20 mAbs in chemoresistant malignancies.
Leukemia 2002 Sep
PMID:CD20-induced B cell death can bypass mitochondria and caspase activation. 1220 Jun 88


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