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

The ganglioside patterns have been shown to dramatically change during cell proliferation and differentiation and in certain cell-cycle phases, brain development, and cancer malignancy. To investigate the significance of the ganglioside GM3 in cancer malignancy, we established GM3-reconstituted cells by transfecting the cDNA of GM3 synthase into a GM3-deficient subclone of the 3LL Lewis lung carcinoma cell line (Uemura, S. (2003) Glycobiology, 13, 207-216). The GM3-reconstituted cells were resistant to apoptosis induced by etoposide and doxorubicin. There were no changes in the expression levels of topoisomerase IIalpha or P-glycoprotein, or in the uptake of doxorubicin between the GM3-reconstituted cells and the mock-transfected cells. To understand the mechanism of the etoposide-resistant phenotype acquired in the GM3-reconstituted cells, we investigated their apoptotic signaling. Although no difference was observed in the phosphorylation of p53 at serine-15-residue site by etoposide between the GM3-reconstituted cells and mock-transfected cells, the activation of both caspase-3 and caspase-9 was specifically inhibited in the former. We found that the anti-apoptotic protein B-cell leukemia/lymphoma 2 (Bcl-2) was increased in the GM3-reconstituted cells. Moreover, wild-type 3LL Lewis lung carcinoma cells, which have an abundance of GM3, exhibited no DNA fragmentation following etoposide treatment and expressed higher levels of the Bcl-2 protein compared with the J5 subclone. Thus, these results support the conclusion that endogenously produced GM3 is involved in malignant phenotypes, including anticancer drug resistance through up-regulating the Bcl-2 protein in this lung cancer cell line.
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PMID:Endogenously produced ganglioside GM3 endows etoposide and doxorubicin resistance by up-regulating Bcl-2 expression in 3LL Lewis lung carcinoma cells. 1657 67

Coriolus versicolor (CV), also called Yunzhi, has been demonstrated to exert anti-tumor effects on various types of cancer cells. Our previous studies have demonstrated that a standardized aqueous ethanol extract prepared from CV inhibited the proliferation of human leukemia cells via induction of apoptosis. The present study aimed to evaluate the underlying mechanisms of apoptosis through modulation of Bax, Bcl-2 and cytochrome c protein expressions in a human pro-myelocytic leukemia (HL-60) cell line, as well as the potential of the CV extract as anti-leukemia agent using the athymic mouse xenograft model. Our results demonstrated that the CV extract dose-dependently suppressed the proliferation of HL-60 cells (IC50 = 150.6 microg/ml), with increased nucleosome production from apoptotic cells. Expression of pro-apoptotic protein Bax was significantly up-regulated in HL-60 cells treated with the CV extract, especially after 16 and 24 h. Meanwhile, expression of anti-apoptotic protein Bcl-2 was concomitantly down-regulated, as reflected by the increased Bax/Bcl-2 ratio. The CV extract markedly, but transiently, promoted the release of cytochrome c from mitochondria to cytosol after 24-h incubation. In vivo studies in the athymic nude mouse xenograft model also confirmed the growth-inhibitory activity of the CV extract on human leukemia cells. In conclusion, the CV extract attenuated the human leukemia cell proliferation in vivo, and in vitro possibly by inducing apoptosis through the mitochondrial pathway. The CV extract is likely to be valuable for the treatment of some forms of human leukemia.
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PMID:Coriolus versicolor (Yunzhi) extract attenuates growth of human leukemia xenografts and induces apoptosis through the mitochondrial pathway. 1686 63

Tanshinone IIA, a diterpene quinone extracted from the traditional herbal medicine, Salvia miltiorrhiza Bunge, is used widely and successfully in clinics in China for treating inflammatory diseases. Recently tanshinone IIA has been reported to have apoptosis inducing effects on a large variety of cancer cells. In this study, the anti-proliferation and apoptosis inducing effects of tanshinone IIA as well as its influence on cell adhesion to and invasion through the extracellular matrix (ECM) on acute promyelocytic leukemia (APL) NB4 cells in vitro were studied. Cell proliferation was assessed by MTT assay, cell apoptosis was observed by Hoechst 33258 staining and flow cytometry (FCM); The variation of caspase-3 and apoptotic related genes were assayed by Western blotting, cell mitochondrial membrane potential as well as cell adhesive and invasive effects were also investigated by using standard methods. The results showed that tanshinone IIA exhibited induction of apoptosis by activation of caspase-3, downregulation of anti-apoptotic protein bcl-2 and bcl-xl and upregulation of pro-apoptotic protein bax, as well as disruption of the mitochondrial membrane potential. Furthermore, treatment by tanshinone IIA could reduce cell adhesion to and invasion through ECM in leukemia NB4 cells. These data provide a potential mechanism for tanshinone IIA-induced apoptosis and cell growth inhibition in leukemia NB4 cells, suggesting that tanshinone IIA may serve as an effective adjunctive reagent for the treatment of APL.
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PMID:Induction of apoptosis and inhibition of cell adhesive and invasive effects by tanshinone IIA in acute promyelocytic leukemia cells in vitro. 1695 48

We have previously shown that UEV1 is up-regulated in all tumor cell lines examined and when SV40-transformed human embryonic kidney cells undergo immortalization; however, it is unclear whether and how UEV1 plays a critical role in this process. UEV1A encodes a ubiquitin conjugating enzyme variant, which is required for Ubc13 (ubiquitin conjugating enzyme) catalyzed poly-ubiquitination of target proteins through Lys63-linked chains. One of the target proteins is NEMO/IKKgamma (nuclear factor-kappaB essential modulator/inhibitor of kappaB protein kinase), a regulatory subunit of IkappaB kinase in the NF-kappaB signaling pathway. In this report, we show that constitutive high-level expression of UEV1A alone in cultured human cells was sufficient to cause a significant increase in NF-kappaB activity as well as the expression of its target anti-apoptotic protein, Bcl-2 (B-cell leukemia/lymphoma 2). Overexpression of UEV1A also conferred prolonged cell survival under serum-deprived conditions, and protected cells against apoptosis induced by diverse stressing agents. All of the effects of Uev1A were reversible upon suppression of UEV1 expression by RNA interference. Our observations presented in this report provide evidence that Uev1A is a critical regulatory component in the NF-kappaB signaling pathway in response to environmental stresses and identify UEV1A as a potential proto-oncogene.
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PMID:Uev1A, a ubiquitin conjugating enzyme variant, inhibits stress-induced apoptosis through NF-kappaB activation. 1704 55

Apoptosis is dysregulated in patients with myelodysplastic syndrome (MDS) and acute myelogenous leukaemia (AML). FLIP (FLICE (FAS-associated death-domain-like IL-1 beta-converting enzyme)-inhibitory protein) has been described as an anti-apoptotic protein. Here, we characterize the expression level of FLIP(LONG) and FLIP(SHORT) mRNA in bone marrow aspirates from 61 patients diagnosed with MDS or AML. FLIP(SHORT) mRNA expression was significantly lower in low risk MDS, compared to high risk MDS, according to FAB classification (RA/RARS versus RAEB/RAEBt, P=0.0127) and IPSS (low risk/intermediate-1 versus intermediate-2/high risk, P=0.0345). Furthermore, FLIP(SHORT) mRNA expression was significantly lower in low risk MDS, compared to MDS-AML/AML de novo (P=0.0006), according to FAB classification. FLIP(LONG) expression did not differ between these groups. Increased levels of FLIP(SHORT) in RAEB and AML may be related to apoptosis resistance in these diseases and to MDS progression.
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PMID:Reduced expression of FLIP SHORT in bone marrow of low risk myelodysplastic syndrome. 1727 Feb 69

CD38 expression is an important prognostic marker in chronic lymphocytic leukemia (CLL) with high levels of CD38 associated with shorter overall survival. In this study, we used gene expression profiling and protein analysis of highly purified cell-sorted CD38(+) and CD38(-) chronic lymphocytic leukemia cells to elucidate a molecular basis for the association between CD38 expression and inferior clinical outcome. Paired CD38(+) and CD38(-) CLL cells derived from the same patient were shown to be monoclonal by V(H) gene sequencing but despite this, CD38(+) CLL cells possessed a distinct gene expression profile when compared with their CD38(-) sub-clones. Importantly, CD38(+) CLL cells relatively over expressed vascular endothelial growth factor (VEGF) and appeared to preferentially utilize an internal autocrine VEGF survival loop. Elevated VEGF expression was associated with increased expression of the anti-apoptotic protein Mcl-1. Inhibition of VEGF receptor signaling also resulted in a reduction in cell viability. In contrast, exogenous VEGF caused a significant increase in CD38(-) CLL cell viability and a marked induction of Mcl-1; both effects were less obvious in CD38(+) CLL cells. Taken together, our data provide a biological rationale for the poor prognosis of CD38(+) CLL and indicate that both VEGF and Mcl-1 may prove to be useful therapeutic targets.
Leukemia 2007 Apr
PMID:Highly purified CD38+ and CD38- sub-clones derived from the same chronic lymphocytic leukemia patient have distinct gene expression signatures despite their monoclonal origin. 1728 49

Gambogic acid (GA) is the major active ingredient of gamboge secreted from a Chinese traditional medicine Garcinia hanburryi possessing potent anti-tumor activity. N-(2-ethoxyethyl)gambogamide (NG-18), a derivative of GA, also efficiently inhibits proliferation of cultured human tumor cells. The inhibition effect of NG-18 is associated with its ability to induce apoptosis. In the present study, NG-18 markedly induced leukemia HL-60 cells apoptosis, and the extrinsic and intrinsic apoptosis pathways were activated almost at the same time. NG-18-induced tumor cell apoptosis was associated with up-regulation of pro-apoptotic Bcl-2 family member Bax, and downregulation of anti-apoptotic protein Bcl-2. The NG-18-induced apoptosis was blocked completely by a pan-caspase inhibitor Z-VAD-FMK, indicating that caspases were functionally and actively involved in this process. The specific inhibition of caspase-8 activity using Z-IETD-FMK significantly blocked NG-18-induced apoptosis. In contrast, inhibition of other initiator caspases, caspase-2 or -9, using Z-VDVAD-FMK or Z-LEHD-FMK respectively had no effect on NG-18-induced apoptosis. Altogether, our data demonstrated that NG-18-induced apoptosis was dependent on caspases and caspase-8 acted as a key executor in the event.
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PMID:Caspase-8 preferentially senses the apoptosis-inducing action of NG-18, a Gambogic acid derivative, in human leukemia HL-60 cells. 1742 47

Kaposi's sarcoma (KS)-associated herpes virus (KSHV) is the causative agent of primary effusion lymphoma and of KS. Primary effusion lymphoma (PEL) is an aggressive proliferation of B cells. Conventional chemotherapy has limited benefits in PEL patients, and the prognosis is very poor. We previously reported that treatment of human T-cell leukemia virus type 1 (HTLV-1)-associated adult T-cell leukemia/lymphoma cells either with arsenic trioxide (As) combined to interferon-alpha (IFN-alpha) or with the bortezomib (PS-341) proteasome inhibitor induces cell cycle arrest and apoptosis, partly due to the reversal of the constitutive nuclear factor-kappaB (NF-kappaB) activation. PEL cells also display an activated NF-kappaB pathway that is necessary for their survival. This prompted us to investigate the effects of PS-341, or of the As/IFN-alpha combination on PEL cells. A dramatic inhibition of cell proliferation and induction of apoptosis was observed in PS-341 and in As/IFN-alpha treated cells. This was associated with the dissipation of the mitochondrial membrane potential, cytosolic release of cytochrome c, caspase activation and was reversed by the z-VAD caspase inhibitor. PS-341 and As/IFN-alpha treatment abrogated NF-kappaB translocation to the nucleus and decreased the levels of the anti-apoptotic protein Bcl-X(L). Altogether, these results provide a rational basis for a future therapeutic use of PS-341 or combined As and IFN-alpha in PEL patients.
Leukemia 2007 Aug
PMID:PS-341 or a combination of arsenic trioxide and interferon-alpha inhibit growth and induce caspase-dependent apoptosis in KSHV/HHV-8-infected primary effusion lymphoma cells. 1756 16

Curcumin (diferuloylmethane), one of the main components of the Indian spice turmeric, is known to possess potent anti-inflammatory and anti-oxidant properties. In addition, curcumin has also been shown to have in vitro and in vivo efficacy against a variety of malignancies. In the current study we examined the cytotoxic effect of curcumin on seven osteosarcoma (OS) cell lines with varying degrees of in vivo metastatic potential. Curcumin inhibited the growth of all OS cell lines tested with half-maximal inhibitory concentration values ranging from 14.4 to 24.6 microM. Growth inhibition was associated with a dose dependent increase in the number of apoptotic cells and accumulation of cells in the G(2)/M phase of the cell cycle. Curcumin treatment also resulted in cleavage of caspase-3 and poly adenosine diphosphate-ribose polymerase. Moreover, curcumin treatment was associated with an increase in cellular levels of the apoptotic B-cell leukemia/lymphoma 2 (Bcl-2)-associated X protein and a decrease in cellular content of the anti-apoptotic protein Bcl-2. In addition, curcumin treatment also inhibited the migration of OS cell lines. These data indicate that the potent cytotoxic activity of curcumin on OS cell lines is mediated by induction of apoptotic processes. Thus, curcumin has potential to be a novel OS chemotherapeutic agent.
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PMID:Cytotoxic effects of curcumin on osteosarcoma cell lines. 1807 34

In pediatric acute lymphoblastic leukemia (ALL), overexpression of murine double minute 2 (MDM2) protein by leukemic cells is typically associated with a wild-type (wt)-p53 phenotype and chemoresistance. A recently developed small-molecule antagonist of MDM2, nutlin-3, inhibits the MDM2-p53 interaction, resulting in induction of p53 activity and apoptosis. In this study, we evaluated the cytotoxic effect of nutlin-3 on ALL cells with different p53 status and MDM2 expression, using 18 cell lines and 30 primary leukemia samples. We found that both ALL cell lines and primary ALL samples with wt-p53 are sensitive to nutlin-3. No cytotoxic effect of nutlin-3 was detected in ALL cells with either p53-mutant or -null phenotype. In wt-p53 ALL cells, there was a significant positive correlation between MDM2 expression levels and sensitivity to nutlin-3. Nutlin-3-induced cell death was mediated by p53-induced activation of proapoptotic proteins and by p53-induced repression of the anti-apoptotic protein survivin. As p53 function is inhibited by MDM2 in chemoresistant, MDM2-overexpressing ALL cells, potent killing of these cells by nutlin-3 suggests that this agent may be a novel therapeutic for refractory ALL.
Leukemia 2008 Apr
PMID:MDM2 antagonist nutlin-3 is a potent inducer of apoptosis in pediatric acute lymphoblastic leukemia cells with wild-type p53 and overexpression of MDM2. 1827 46


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