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)

Arsenic trioxide inhibits growth and promotes apoptosis in many different cancer cell lines. The National Cancer Institute is working cooperatively with research centers across the U.S. to evaluate its clinical activity in hematologic malignancies, such as acute promyelocytic leukemia, acute myeloid leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, non-Hodgkin's lymphoma, Hodgkin's disease, chronic lymphocytic leukemia, myelodysplastic syndrome, and multiple myeloma. It is also supporting research in solid tumors, such as advanced hormone-refractory prostate cancer and renal cell cancer and in cervical cancer and refractory transitional cell carcinoma of the bladder. The safety and pharmacokinetics of arsenic trioxide are also being evaluated in pediatric patients with refractory leukemia and lymphoma. The results of these ongoing studies should provide important insights into the clinical utility of arsenic trioxide in these diseases.
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PMID:Clinical trials of arsenic trioxide in hematologic and solid tumors: overview of the National Cancer Institute Cooperative Research and Development Studies. 1133 37

Bcr-Abl-positive leukemias include chronic myelogenous leukemia (CML), both myeloid and lymphoid blast-phase CML, and some cases of acute lymphoblastic leukemia. The chimeric bcr-abl gene codes for a tyrosine kinase that is constitutively activated in the leukemic cells and plays the central role in leukemogenesis. Hematologic malignancies, including Bcr-Abl-positive leukemias, also frequently have overactivity of the Ras signaling pathway, leading to abnormal transduction of growth and survival signals. New and investigational therapeutic options that target these specific molecular defects of leukemic cells include the tyrosine kinase inhibitor imatinib mesylate (STI571) and farnesyltransferase inhibitors (R115777, SCH66336), which block localization of Ras proteins to the cell membrane. While single-agent therapy with these new agents may produce hematologic and cytogenetic remissions in patients with Bcr-Abl-positive leukemias, molecular remissions are less common, and resistance may develop. Therefore, the development of a multifaceted therapeutic approach to these leukemias is of great interest. Arsenic trioxide (ATO), which has significant activity in patients with relapsed and refractory acute promyelocytic leukemia, is a potential addition to the therapeutic arsenal. While some of the molecular activities of ATO are specific to acute promyelocytic leukemia, arsenicals also have a broad variety of antineoplastic properties that may be useful in combination therapy with agents that target specific molecular defects of Bcr-Abl-positive leukemias.
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PMID:Multifaceted approach to the treatment of bcr-abl-positive leukemias. 1196 Dec 7

Arsenic trioxide induces differentiation and apoptosis of malignant cells in vitro and in vivo, but the mechanisms by which such effects occur have not been elucidated. In the present study we provide evidence that arsenic trioxide induces activation of the small G-protein Rac1 and the alpha and beta isoforms of the p38 mitogen-activated protein (MAP) kinase in several leukemia cell lines. Such activation of Rac1 and p38-isoforms results in downstream engagement of the MAP kinase-activated protein kinase-2 and is enhanced by pre-treatment of cells with ascorbic acid. Interestingly, pharmacological inhibition of p38 potentiates arsenic-dependent apoptosis and suppression of growth of leukemia cell lines, suggesting that this signaling cascade negatively regulates induction of antileukemic responses by arsenic trioxide. Consistent with this, overexpression of a dominant-negative p38 mutant (p38betaAGF) enhances the antiproliferative effects of arsenic trioxide on target cells. To further define the relevance of activation of the Rac1/p38 MAP kinase pathway in the induction of arsenic-dependent antileukemic effects, studies were performed using bone marrows from patients with chronic myelogenous leukemia. Arsenic trioxide suppressed the growth of leukemic myeloid (CFU-GM) progenitors from such patients, whereas concomitant pharmacological inhibition of the p38 pathway enhanced its growth-suppressive effects. Altogether, these data provide evidence for a novel function of the p38 MAP kinase pathway, acting as a negative regulator of arsenic trioxide-induced apoptosis and inhibition of malignant cell growth.
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PMID:Activation of Rac1 and the p38 mitogen-activated protein kinase pathway in response to arsenic trioxide. 1223 15

Arsenic trioxide (As(2)O(3)) was recently demonstrated to be an effective inducer of apoptosis in patients with relapsed acute promyelocytic leukemia (APL) as well as in patients with APL in whom all-trans-retinoic acid and conventional chemotherapy failed. Chronic myelogenous leukemia cells are highly resistant to chemotherapeutic drugs. To determine if As(2)O(3) might be useful for the treatment of chronic myelogenous leukemia, we examined the ability of As(2)O(3) to induce apoptosis in K562 cells. In vitro cytotoxicity of As(2)O(3) was evaluated in K562 cells by a MTT assay; the IC(50) value for As(2)O(3) was determined to be 10 microM. When analyzed by agarose gel electrophoresis, the DNA fragments became evident after incubation of the cells with 20 microM As(2)O(3) for 24 h. We also found morphological changes and chromatin condensation of the cells undergoing apoptosis. Activation of caspase-3 was observed 6 h after treatment with 20 microM As(2)O(3) by a Western blot analysis. Next, we examined the MAP kinase-signaling pathway of As(2)O(3)-induced apoptosis in K562 cells. As(2)O(3) at 10 microM strongly induced the activation of p38 and JNK 1/2, while ERK 1/2 was inhibited. In addition, pretreatment of SB203580, a specific inhibitor of p38, inhibited As(2)O(3) induced apoptotic cell death. These results suggest that As(2)O(3) is able to induce the apoptotic activity in K562 cells, and its apoptotic mechanism may be associated with the activation of p38.
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PMID:Arsenic trioxide induces apoptosis in chronic myelogenous leukemia K562 cells: possible involvement of p38 MAP kinase. 1229 96

Molecular targeting therapies for hematological malignant diseases such as monoclonal antibodies and small molecules have been reviewed. Imatinib mesylate (STI571) targets the tyrosine kinase activity of the BCR-ABL fusion protein in CML, and was superior to IFN-alpha plus low-dose cytarabine in newly diagnosed chronic-phase CML in a phase III randomized study. Imatinib induced apoptosis in BCR-ABL-positive cells in vitro, and activates several signaling pathways such as PI3K/Akt, STAT5 and Ras/MAPK. Combination therapies with imatinib and new strategies for downregulation of intracellular BCR-ABL protein levels have also been investigated from the phenomenon of resistance to imatinib. Anti-CD20 (rituximab) became the first monoclonal antibody approved for the treatment of a relapsed/refractory follicular/low-grade NHL and promising results were obtained from a phase III randomized study. Although antibody-dependent cell-mediated cytotoxicity and complement-mediated cytotoxicity are likely to be the major effectors of B-cell depletion in vivo, direct cytotoxicity by CD20 monoclonal antibody on B-cell lines in vitro has been reported. Anti-CD33 (Mylotarg) and FLT3 inhibitors for AML have also been used in clinical trials and signaling pathways induced by these agents are under intensive investigation. Arsenic trioxide, like all-TRANS-retinoic acid (ATRA), downregulates promyelocytic leukemia protein/retinoic acid receptor-alpha (PML/RARalpha) fusion protein and induced apoptosis in APL cells, and promising results were obtained from ATRA-resistant APL patients. Finally we show our promising in vitro and in vivo data of R-etodolac (a non-steroidal anti-inflammatory drug lacking cyclooxygenase inhibitor activity) against chronic lymphocytic leukemia (CLL) cells.
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PMID:Apoptosis induced by molecular targeting therapy in hematological malignancies. 1464 49

Leukemia is the most common childhood cancer. Trisenox, the active ingredient of which is trivalent arsenic, is the first line of treatment for acute promyelocytic leukemia. Since drug action usually requires uptake of the drug, it is of importance to determine the transport system responsible for Trisenox uptake. Recently, human aquaglyceroporin 9 (AQP9) has been shown to transport As(III) in Xenopus oocytes. In this study we report to show that AQP9 expression modulates the drug sensitivity of leukemic cells. AQP9 was transfected into the chronic myelogenous leukemia cell line K562. The transfectants became hypersensitive to Trisenox and Sb(III). The promyelocytic leukemia cell line HL60 treated with vitamin D showed higher expression of AQP9 and hypersensitivity to Trisenox and Sb(III). This sensitivity was due to higher rates of uptake of the trivalent metalloids by the cell lines overexpressing AQP9. Trisenox hypersensitivity results from increased expression of AQP9 drug uptake system. The possibility of using pharmacological agents to increase expression of AQP9 gene delivers the promise of new therapies for the treatment of leukemia. Thus, drug hypersensitivity can be correlated with increased expression of the drug uptake system. This is the first demonstration that AQP9 can modulate drug sensitivity in cancer.
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PMID:Drug uptake and pharmacological modulation of drug sensitivity in leukemia by AQP9. 1533 39

Arsenic trioxide (As2O3) is an effective drug for treatment of acute promyelocytic leukemia (APL) and malignant tumors. However, it is not commonly known to researchers that sensitivity has been associated with As2O3 concentration in target cells. Cell lines and cell strains of leukemia and solid cancer cells were treated with different concentrations of As2O3, and the concentrations were compared to apoptosis detected by FITC-annexin V and propidium iodide (PI) double staining. Results showed that intracellular and intercellular concentrations of arsenic in different cell lines differed. Our study noted that the cell lines had concentrations of arsenic trioxide in decreasing order, as follows: APL primary cell > K562 > CML primary cell > HL-60 > AML-M2 primary cell > HeLa > H-22. Higher intracellular As2O3 concentrations in cell lines APL, NB4, and K562 can be obtained by treating in culture medium with lower As2O3 concentration for longer times than the transient higher concentration. These results indicate that different leukemia and solid carcinoma cell lines have different intracellular arsenic concentrations, which correlate with different sensitivities to As2O3 in clinical treatment. The intracellular As2O3 concentration is higher; in addition, we note apoptosis, a very important observation in our study. As2O3 inhibited the growth of these cell lines significantly. Novel techniques by maintaining continuous low but effective arsenic levels inside the target leukemic cells in APL may improve the complete remission rate and overall survival with minimum cost and drug toxicity.
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PMID:Significance of intracellular arsenic trioxide for therapeutic response in acute promyelocytic leukemia. 1568 19

Arsenic trioxide (As2O3) is a potent inducer of apoptosis of leukemic cells in vitro and in vivo, but the precise mechanisms by which it mediates such effects are not well defined. We provide evidence that As2O3 induces activation of the mitogen- and stress-activated kinase 1 (MSK1) and downstream phosphorylation of its substrate, histone H3, in leukemia cell lines. Such activation requires upstream engagement of p38 MAPK, as demonstrated by experiments using pharmacological inhibitors of p38 or p38alpha knock-out cells. Arsenic-induced apoptosis was enhanced in cells in which MSK1 expression was decreased using small interfering RNA and in Msk1 knock-out mouse embryonic fibroblasts, suggesting that this kinase is activated in a negative feedback regulatory manner to regulate As2O3 responses. Consistent with this, pharmacological inhibition of MSK1 enhanced the suppressive effects of As2O3 on the growth of primary leukemic progenitors from chronic myelogenous leukemia patients. Altogether, these findings indicate an important role for MSK1 downstream of p38 in the regulation of As2O3 responses.
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PMID:Activation of the mitogen- and stress-activated kinase 1 by arsenic trioxide. 1676 16

Arsenic trioxide (As(2)O(3)) induces differentiation and apoptosis of leukemic cells in vitro and in vivo, but the precise mechanisms that mediate such effects are not known. In the present study, we provide evidence that the kinases MAPK kinase 3 (Mkk3) and Mkk6 are activated during treatment of leukemic cell lines with As(2)O(3) to regulate downstream engagement of the p38 mitogen-activated protein kinase. Using cells with targeted disruption of both the Mkk3 and Mkk6 genes, we show that As(2)O(3)-dependent activation of p38 is defective in the absence of Mkk3 and Mkk6, establishing that these kinases are essential for As(2)O(3)-dependent engagement of the p38 pathway. Pharmacologic inhibition of p38 enhances As(2)O(3)-dependent activation of the c-jun NH(2)-terminal kinase (JNK) and subsequent induction of apoptosis of chronic myelogenous leukemia (CML)- or acute promyelocytic leukemia (APL)-derived cell lines. In addition, in APL blasts, inhibition of p38 enhances myeloid cell differentiation in response to As(2)O(3), as well as suppression of Bcl-2 expression and loss of mitochondrial membrane potential. Similarly, induction of As(2)O(3)-dependent apoptosis is enhanced in mouse embryonic fibroblasts (MEF) with targeted disruption of both the Mkk3 and Mkk6 genes, establishing a key role for this pathway in the regulation of As(2)O(3)-induced apoptosis. In other studies, we show that the small-molecule p38 inhibitors SD-282 and SCIO-469 potentiate As(2)O(3)-mediated suppression of myeloid leukemic progenitor growth from CML patients, indicating a critical regulatory role for p38 in the induction of antileukemic responses. Altogether, our data indicate that the Mkk3/6-p38 signaling cascade is activated in a negative regulatory feedback manner to control induction of As(2)O(3)-mediated antileukemic effects.
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PMID:Role of the p38 mitogen-activated protein kinase pathway in the generation of arsenic trioxide-dependent cellular responses. 1681 52

Arsenic trioxide (As2O3) is highly efficacious in acute promyelocytic leukemia (APL). Aquaglyceroporin 9 (AQP9) is a transmembrane protein that may be involved in arsenic uptake. In 10 of 11 myeloid and lymphoid leukemia lines, quantitative polymerase chain reaction (Q-PCR) and Western blotting showed that AQP9 expression correlated positively with As2O3-induced cytotoxicity. As a proof-of-principle, transfection of EGFP-tagged AQP9 to the hepatoma line Hep3B, not expressing AQP9 and As2O3 insensitive, led to membrane AQP9 expression and increased As2O3-induced cytotoxicity. Similarly, the chronic myeloid leukemia line K562 expressed low levels of AQP9 and was As2O3 insensitive. The K562(EGFP-AQP9) transfectant accumulated significantly higher levels of intracellular arsenic than control K562(EGFP) when incubated with As2O3, resulting in significantly increased As2O3-induced cytotoxicity. Pretreatment of the myeloid leukemia line HL-60 with all-trans retinoic acid (ATRA) up-regulated AQP9, leading to a significantly increased arsenic uptake and As2O3-induced cytotoxicity on incubation with As2O3, which might explain the synergism between ATRA and As2O3. Therefore, AQP9 controlled arsenic transport and might determine As2O3 sensitivity. Q-PCR showed that primary APL cells expressed AQP9 significantly (2-3 logs) higher than other acute myeloid leukemias (AMLs), which might explain their exquisite As2O3 sensitivity. However, APL and AML with maturation expressed comparable AQP9 levels, suggesting that AQP9 expression was related to granulocytic maturation.
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PMID:Relationship of expression of aquaglyceroporin 9 with arsenic uptake and sensitivity in leukemia cells. 1696 95


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