Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In traditional Chinese Medicine, the preparation Danggui Longhui Wan has been used for years in the treatment of chronic myelocytic leukemia. The compound indirubin has been shown to be the active constituent. A cell permeable derivative, indirubin-3'-monoxime, is a selective and potent inhibitor of cyclin-dependent kinases (cdk). The ability of indirubin-3'-monoxime to induce apoptosis and tumor cell death in transitional cell cancer cell lines was investigated here. The growth-inhibitory properties were evaluated by EZ4U, a cytotoxic assay; apoptosis induction was determined by immunoblotting of cleaved PARP and flow cytometry of Annexin-V/PI staining during treatment. To evaluate further the underlying molecular action of indirubin-3'-monoxime on the cell cycle, the levels of cdk-1 and survivin, a mitotic spindle checkpoint and apoptosis-regulating protein, respectively, were additionally determined by flow cytometry and immunoblotting. The results indicated that indirubin-3'-monoxime induced reversible growth arrest in all four cell lines and an increase of apoptosis in two of them. The treatment with indirubin-3'-monoxime increased the expression of survivin almost four times in the RT4 cells and more than doubled it in the RT112 and T24 cells. In the SUP cells, the expression of survivin increased more than seven-fold after 72-h incubation. No clear correlation between the low apoptosis induction rate and extent of survivin expression was found. Cdk expression was not significantly altered by indirubin-3'-monoxime. In summary, indirubin-3'-monoxime might be a promising candidate for targeted cancer therapy, however, its molecular action remains to be further evaluated.
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PMID:Indirubin-3'-monoxime, a CDK inhibitor induces growth inhibition and apoptosis-independent up-regulation of survivin in transitional cell cancer. 1682 55

The Bcr-Abl oncoprotein plays a major role in the development and progression of chronic myeloid leukemia and is a determinant of chemotherapy resistance occurring during the blast crisis phase of the disease. The aim of this article was to investigate the possibility of combating the resistance to apoptosis caused by Bcr-Abl by inducing an alternative cell death process. As a model of chronic myeloid leukemia, we employed Bcr-Abl-transfected mouse progenitor 32D cells with low and high Bcr-Abl expression levels corresponding to drug-sensitive and drug-resistant cells, respectively. The drug curcumin (diferuloylmethane), a known potent inducer of cell death in many cancer cells, was investigated for efficacy with Bcr-Abl-expressing cells. Curcumin strongly inhibited cell proliferation and affected cell viability by inducing apoptotic symptoms in all tested cells; however, apoptosis was a relatively late event. G(2)-M cell cycle arrest, together with increased mitotic index and cellular and nuclear morphology resembling those described for mitotic catastrophe, was observed and preceded caspase-3 activation and DNA fragmentation. Mitosis-arrested cells displayed abnormal chromatin organization, multipolar chromosome segregation, aberrant cytokinesis, and multinucleated cells-morphologic changes typical of mitotic catastrophe. We found that the mitotic cell death symptoms correlated with attenuated expression of survivin, a member of the chromosomal passenger complex, and mislocalization of Aurora B, the partner of survivin in the chromosomal passenger complex. Inhibition of survivin expression with small interfering RNA exhibited similar mitotic disturbances, thus implicating survivin as a major, albeit not the only, target for curcumin action. This study shows that curcumin can overcome the broad resistance to cell death caused by expression of Bcr-Abl and suggests that curcumin may be a promising agent for new combination regimens for drug-resistant chronic myeloid leukemia.
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PMID:Curcumin affects components of the chromosomal passenger complex and induces mitotic catastrophe in apoptosis-resistant Bcr-Abl-expressing cells. 1684 21

Chronic myelogenous leukemia (CML) is a myeloproliferative disorder caused by excessive granulopoiesis due to the formation of the constitutively active tyrosine kinase BCR-ABL. An effective drug against CML is imatinib mesylate, a tyrosine kinase inhibitor acting on Abl kinases, c-KIT, and platelet-derived growth factor receptor. Recently, a study revealed that patients treated with imatinib showed impaired CTL responses compared with patients treated with IFN-alpha, which might be due to a treatment-induced reduction in immunogenicity of CML cells or immunosuppressive effects. In our study, we found that inhibition of BCR-ABL leads to a down-regulation of immunogenic antigens on the CML cells in response to imatinib treatment, which results in the inhibition of CML-directed immune responses. By treating CML cells with imatinib, we could show that the resulting inhibition of BCR-ABL leads to a decreased expression of tumor antigens, including survivin, adipophilin, hTERT, WT-1, Bcl-x(L), and Bcl-2 in correlation to a decreased development of CML-specific CTLs. In contrast, this reduction in immunogenicity was not observed when a CML cell line resistant to the inhibitory effects of imatinib was used, but could be confirmed by transfection with specific small interfering RNA against BCR-ABL or imatinib treatment of primary CML cells.
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PMID:BCR-ABL activity is critical for the immunogenicity of chronic myelogenous leukemia cells. 1754 31

The apoptotic mode of cell death is a major regulatory process in all complex organisms. The low proliferative index and slow accumulation of malignant cells in chronic lymphocytic leukemia (CLL), the most frequent type of leukemia in Europe and North America, suggests that the disease is caused by a defect in apoptosis regulation. Classical apoptosis is executed through the activation of caspases, cysteine proteases which are regulated by a number of pro- and anti-apoptotic proteins. One such checkpoint is the control of caspase activation by a relatively new family of inhibitor of apoptosis proteins (IAPs). They block both the mitochondrial-dependent and -independent apoptotic pathways. The IAP family inhibits apoptosis by binding to specific caspases and possibly by other mechanisms. They also participate in the regulation of cellular and intracellular signal transduction. Six human IAPs have been identified: XIAP, cIAP1, cIAP2, NAIP, livin, and survivin. Because of their important role in regulating apoptosis, IAPs are being investigated as a potential prognostic factor as well as a treatment target in cancer patients. Overexpression of several IAPs has been detected in various hematological malignancies, including acute leukemias, myelodysplastic syndrome (MDS), chronic myeloid leukemia (CML), and many types of lymphoid malignancies, such as chronic lymphocytic leukemia (CLL) and diffuse large B-cell lymphoma (DLBCL). Many publications revealed significant correlation between a high level of IAPs, especially of XIAP and survivin, and tumor progression. It seems that overexpression of XIAP in acute myeloid leukemia (AML) and survivin in acute lymphoblastic leukemia (ALL) and DLBCL could become a new unfavorable prognostic factor. Many studies are now concentrating on evaluating the expression and significance of the other proteins of the IAP family. In this paper the current knowledge of the importance of IAPs in hematological malignancies is presented.
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PMID:[The role of the inhibitor of apoptosis protein (IAP) family in hematological malignancies]. 1828 36

Imatinib mesylate is a potent, molecularly targeted therapy against the oncogenic tyrosine kinase BCR-ABL. Although imatinib mesylate has considerable efficacy against chronic myeloid leukemia (CML), advanced-stage CML patients frequently become refractory to this agent. The bone marrow is the predominant microenvironment of CML and is a rich source of both soluble factors and extracellular matrices, which may influence drug response. To address the influence of the bone marrow microenvironment on imatinib mesylate sensitivity, we used an in vitro bone marrow stroma model. Our data show culturing K562 cells, in bone marrow stroma-derived conditioned medium (CM), is sufficient to cause resistance to BCR-ABL inhibitors. Drug resistance correlated with increased pTyrStat3, whereas no increases in pTyrStat5 was noted. Moreover, resistance was associated with increased levels of the Stat3 target genes Bcl-xl, Mcl-1, and survivin. Finally, reducing Stat3 levels with small interfering RNA sensitized K562 cells cultured in CM to imatinib mesylate-induced cell death. Importantly, Stat3 dependency was specific for cells grown in CM, as reducing Stat3 levels in regular growth conditions had no effect on imatinib mesylate sensitivity. Together, these data support a novel mechanism of BCR-ABL-independent imatinib mesylate resistance and provides preclinical rationale for using Stat3-inhibitors to increase the efficacy of imatinib mesylate within the context of the bone marrow microenvironment.
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PMID:Stat3 contributes to resistance toward BCR-ABL inhibitors in a bone marrow microenvironment model of drug resistance. 1885 20

The aim of this study was to investigate the effects of 2-methoxyestradiol (2-ME) on expressions of caspase-3 and survivin in chronic myelocytic leukemia (CML) K562 cells. The experiment was divided into 3 groups: control group, in which K562 cells were cultured in medium without 2-ME; the experimental group, in which K562 cells were cultured in medium containing different concentrations of 2-ME (1, 2, 4, 8 and 16 micromol/L) for 36 hours; the negative control group, in which K562 cells were replaced by distilled water without RNase in medium. The apoptosis rate, the protein and its mRNA expressions of caspase-3 and survivin of K562 cells was detected by TUNEL, flow cytometry (FCM), half-quantitative RT-PCR respectively. The results showed that the apoptosis rate of K562 cells in experimental group was significantly higher than that in control group (p < 0.05). The apoptosis rate of K562 cells detected by FCM was almost the same as that detected by TUNEL method (p < 0.01). The result detected by TUNEL methods was positively correlated with that detected by FCM (gamma = 0.845, p = 0.034). The expression of caspase-3 protein increased in a concentration-dependent manner, and also this expression level in the experimental group was higher than that in the control group (p < 0.05); the expression of survivin protein decreased along with the increasing of 2-ME concentration. and the difference between the experimental group and the control group was statistically significant (p < 0.05). The expression of caspase-3 mRNA was higher in the experimental group than that in the control group (p < 0.01), and the expression of survivin mRNA was lower in the experimental group than that in the control group (p < 0.01). The expression level of caspase-3 mRNA was negatively correlated with that of survivin (gamma = -0.966, p = 0.001). It is concluded that the 2-ME can induce apoptosis of K562 cells in a concentration-dependent manner and indicate its promising potential in the treatment of CML patients.
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PMID:[Effects of 2-methoxyestradiol on the expression of caspase-3 and survivin in chronic myelocytic leukemia K562 cells]. 1937 62

Abnormal numbers, structures and functions of centrosomes in chronic myeloid leukaemia (CML) may influence cell proliferation and genomic instability, which are features of the disease. Centrosomes are regulators of mitotic spindle orientation and can act as scaffolds for centrosome-associated regulators of the cell cycle. This study showed, for the first time, that p210(BCR-ABL1) and p145(ABL1) are both centrosome-associated proteins, as demonstrated by co-immunoprecipitation with the pericentriolar protein, pericentrin. Furthermore, when CML cells were treated with imatinib there was a 55% and 20% reduction of p210(BCR-ABL1) and p145(ABL1) binding to pericentrin, respectively. Cell lines expressing p210(BCR-ABL1) and primary CD34(+) cells from CML patients exhibited more numerical and structural centrosomal abnormalities than p210(BCR-ABL1) negative cells. Primary cells from CML blast crisis (BC) patients exhibited a distinctive amorphous staining pattern of pericentrin compared to normal and CML chronic phase (CP) patients, suggesting a possible defect in pericentrin localisation at the centrosomes. Proteins, such as aurora kinases, pericentrin, survivin and separase, regulate centrosome structure and function, cell cycle and mitotic spindle formation. Levels of the protease, separase are abnormally high in CML CP and BC cells in comparison to normal CD34(+) cells. The data imply that expression of p210(BCR-ABL1) is associated with abnormalities in the centrosome-centriole cycle and increased separase expression.
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PMID:Abnormal centrosome-centriole cycle in chronic myeloid leukaemia? 1956 13

The Bcr-Abl kinase inhibitor, imatinib mesylate, is the front line treatment for chronic myeloid leukaemia (CML), but the emergence of imatinib resistance has led to the search for alternative drug treatments and the examination of combination therapies to overcome imatinib resistance. The pro-apoptotic PBOX compounds are a recently developed novel series of microtubule targeting agents (MTAs) that depolymerise tubulin. Recent data demonstrating enhanced MTA-induced tumour cell apoptosis upon combination with the cyclin dependent kinase (CDK)-1 inhibitor flavopiridol prompted us to examine whether this compound could similarly enhance the effect of the PBOX compounds. We thus characterised the apoptotic and cell cycle events associated with combination therapy of the PBOX compounds and flavopiridol and results showed a sequence dependent, synergistic enhancement of apoptosis in CML cells including those expressing the imatinib-resistant T315I mutant. Flavopiridol reduced the number of polyploid cells formed in response to PBOX treatment but only to a small extent, suggesting that inhibition of endoreplication was unlikely to play a major role in the mechanism by which flavopiridol synergistically enhanced PBOX-induced apoptosis. The addition of flavopiridol following PBOX-6 treatment did however result in an accelerated exit from the G2/M transition accompanied by an enhanced downregulation and deactivation of the CDK1/cyclin B1 complex and an enhanced degradation of the inhibitor of apoptosis protein (IAP) survivin. In conclusion, results from this study highlight the potential of these novel series of PBOX compounds, alone or in sequential combination with flavopiridol, as an effective therapy against CML.
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PMID:Sequential treatment with flavopiridol synergistically enhances pyrrolo-1,5-benzoxazepine-induced apoptosis in human chronic myeloid leukaemia cells including those resistant to imatinib treatment. 2020 41

Chronic myeloid leukemia (CML) is a malignant disease of heampoitic stem cell resulting from clonal expansion of leukemic myeloid cells. Survivin is a recently identified member of the inhibitor of apoptosis protein family. The aim of the work is to analyze the expression of survivin in CML patient in chronic, accelerated and blastic phases and its correlation with other prognostic markers. The study included 50 CML patients (24 females and 26 males) and 10 healthy individuals (4 female and 6 male) as a control group. The studied groups were classified into group (I), 10 healthy individuals as a control group, group (II), 20 CML patients in chronic phase, Group (III), 15 CML patients in accelerated phase and Group (IV), 15 CML patients in blastic phase. The groups were subjected to clinical history and examination, CBC, ESR, BM aspiration (only patients), determination of serum survivin, IL-6 and beta2M levels by ELISA and survivin gene expression by quantitative real time PCR. There was a significant increase of survivin expression in patients as compared to controls (p < 0.001). The accelerated and blastic phases of the disease showed the highest significance (p < 0.001) than the chronic phase. Serum markers; survivin, IL6 and beta2M showed significant increase in the blastic phase, accelerated phase and chronic phase (p < 0.001, p < 0.001 and p < 0.001) respectively. A significant positive correlation was found between level of survivin expression and the other prognostic markers; high leucocytic count (r = 0.52), high peripheral basophile count (r= 0.81) and high peripheral blast cell count (r = 0.66), high level of serum survivin (r = 0.87), beta2 M (r = 0.76) and IL-6 (r= 0.90). On the other hand, a significant negative correlation was found between the survivin expression and hemoglobin concentration (r = 0.50). In conclusion, survivin is expressed in most cases of CML patients and its over expression is associated with bad prognosis.
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PMID:Molecular detection of survivin expression, antiapoptotic gene, and other prognostic markers, how they are correlated and how it could be of prognostic value in chronic myeloid leukemia patient. 2030 57

In 2006 there were 60,000 new cases of cutaneous melanoma in the European Union and 13,000 deaths (www.europeancancerleagues. org). Currently available systemic treatment options for metastatic melanoma, including both cytotoxic and immunologic therapies, produce low rates of response and have modest survival impact. Therefore, there is an urgent need for effective novel therapies. Molecularly targeted treatments have demonstrated efficacy in certain cancers e.g. in HER2- positive breast cancer and in chronic myeloid leukaemia. Several pathways are currently being investigated as potential molecular targets in melanoma. The best studied is BRAF which is frequently mutated in melanoma. A multi tyrosine kinase inhibitor, sorafenib, which targets BRAF, has shown promising activity in preclinical studies and is currently being tested in combination with chemotherapy in patients with metastatic disease. In addition to BRAF, therapies which target other components of the Raf/Ras/MAPK pathway are being investigated. Other novel targets currently being investigated include the PI3/AKT pathway, tyrosine kinases, angiogenesis, poly (ADP ribose) polymerases, survivin and heat shock protein 90. Progress on preclinical and clinical evaluation of these novel targets in melanoma will be reviewed.
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PMID:Prospects for non-immunological molecular therapeutics in melanoma. 2041 21


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