Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023467 (acute myeloid leukemia)
 35,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Over-expression of P-glycoprotein (Pgp+) has been related to resistance to classical Topo II inhibitors used in the treatment of AML and is common in patients with poor-prognosis, such as those with secondary AML (sAML). Since clinical trials with amonafide, a unique ATP-independent Topo II inhibitor, in combination with cytarabine, have shown significant efficacy for remission induction in patients with sAML, we compared the cytotoxic effect of amonafide (amonafide l-malate, Xanafide) to the classical Topo II inhibitors (daunorubicin, doxorubicin, idarubicin, etoposide, and mitoxantrone) in K562 leukemia cells and in the MDR subline, K562/DOX. Pgp expression was found to be approximately 6.5-fold greater in K562/DOX and causes the rapid efflux of these drugs from the leukemia cell. As a consequence, the LC(50) values for the classical Topo II inhibitor drugs tested were each increased up to 3 log units. A similar result was also observed in murine P388 and P388/ADR leukemia cells. Addition of cyclosporin A reversed K562/DOX resistance for the classical Topo II inhibitors, decreasing their LC(50) values to the levels observed with wild type cells but had no effect on amonafide potency in Pgp+ or wild type cells. Further examination of amonafide in bidirectional Caco-2 and MDR1-MDCK models confirmed that amonafide is neither a substrate nor inhibitor of Pgp. These observations suggest that amonafide is a promising therapeutic candidate directed toward bypassing this common mechanism of drug resistance encountered in the treatment of patients with AML, and possibly in other resistant hematological malignancies as well.
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PMID:Amonafide, a topoisomerase II inhibitor, is unaffected by P-glycoprotein-mediated efflux. 1782 29

Protein kinases play a pivotal role in cell signaling, and dysregulation of many kinases has been linked to disease development. A large number of kinase inhibitors are therefore currently under investigation in clinical trials, and so far seven inhibitors have been approved as anti-cancer drugs. In addition, kinase inhibitors are widely used as specific probes to study cell signaling, but systematic studies describing selectivity of these reagents across a panel of diverse kinases are largely lacking. Here we evaluated the specificity of 156 validated kinase inhibitors, including inhibitors used in clinical trials, against 60 human Ser/Thr kinases using a thermal stability shift assay. Our analysis revealed many unexpected cross-reactivities for inhibitors thought to be specific for certain targets. We also found that certain combinations of active-site residues in the ATP-binding site correlated with the detected ligand promiscuity and that some kinases are highly sensitive to inhibition using diverse chemotypes, suggesting them as preferred intervention points. Our results uncovered also inhibitor cross-reactivities that may lead to alternate clinical applications. For example, LY333'531, a PKCbeta inhibitor currently in phase III clinical trials, efficiently inhibited PIM1 kinase in our screen, a suggested target for treatment of leukemia. We determined the binding mode of this inhibitor by x-ray crystallography and in addition showed that LY333'531 induced cell death and significantly suppressed growth of leukemic cells from acute myeloid leukemia patients.
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PMID:A systematic interaction map of validated kinase inhibitors with Ser/Thr kinases. 1807 63

Chromosomal aberrations are important prognostic parameters in acute myeloid leukemia (AML). Indicators of poor prognosis include del(5q)/-5, del(7q)/-7, abnormal 3q or complex karyotype. In recent years, it has become clear that aberrations in 17p represent one of the indicators of poor prognosis in haematological malignancies. In AML, deletions in 17p have been shown to indicate a dismal prognosis; genetic aberrations in 9p have also been discussed as influencing long-term survival in AML. In this study, we correlated genetic abnormalities in chromosomes 9 and 17 in patients with de novo AML to in vitro cytotoxicity of conventional anti-leukemic drugs, and long-term overall survival. Blast cells were isolated from 387 patients diagnosed with AML. Chromosomal analysis was successful in 336 cases. All samples were tested for in vitro cytotoxicity against fludarabine, amsacrine, mitoxantrone, etoposide, daunorubicin and Ara-C after being cultured for 4 days, using an ATP assay. Among the 336 patients, five main groups were identified. Abnormal chromosome 17 (n = 22), abnormal 9p (n = 13), monosomy 7 or deletion 7q (n = 35), complex karyotype (n = 52) and normal karyotype (n = 132). Patients with abnormalities of chromosome 17 showed significantly greater resistance to all drugs tested and significantly shorter overall survival compared with patients with normal and complex karyotypes (p = 0.0001 and 0.041, respectively). All patients with abnormalities of chromosome 17 died within 11 months of diagnosis. A tendency towards shorter overall survival and greater drug resistance was also noted when comparing chromosome 17 abnormalities with del(7q)/-7, but the differences did not reach statistical significance. Patients with abnormal 9p showed significantly shorter overall survival but did not differ significantly as regards in vitro drug resistance compared with patients presenting with a normal karyotype. Chromosomal abnormalities affecting the p53 pathway have a significant impact on cytostatic drug resistance and survival in AML. Developing new drugs targeting the p53 pathway could be a way to improve treatment of AML.
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PMID:Chromosomal aberrations in 17p predict in vitro drug resistance and short overall survival in acute myeloid leukemia. 1829 13

The demonstration that the small synthetic molecule reversine [2-(4-morpholinoanilino)-N6-cyclohexyladenine] promotes the dedifferentiation of committed cells into multipotent progenitor-type cells has raised hopes on the exploitation of this small chemical tool for the generation of stem cells. Here, we show that reversine causes a failure in cytokinesis and induces polyploidization. These effects of reversine are due to the inhibition of Aurora A and B, two related kinases that are implicated in several aspects of mitosis and that are frequently amplified and overexpressed in human tumors. Reversine inhibits the phosphorylation of histone H3, a direct downstream target of Aurora kinases. Similarly to the Aurora kinase inhibitor VX-680, which has recently entered phase II clinical trials for cancer treatment, reversine inhibited colony formation of leukemic cells from patients with acute myeloid leukemia but was significantly less toxic than VX-680 on cells from healthy donors. The crystal structure of the reversine-Aurora B kinase complex shows that reversine is a novel class of ATP-competitive Aurora kinase inhibitors. Thus, although our studies raise serious doubts on the application of reversine in regenerative medicine, they support the paradigm that reversine might be a useful agent in cancer chemotherapy.
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PMID:Reversine, a novel Aurora kinases inhibitor, inhibits colony formation of human acute myeloid leukemia cells. 1848 2

As the pathophysiology of acute myelogenous leukemia (AML) involves a block of myeloid maturation, a desirable therapeutic strategy is to induce leukemic cell maturation to increase the efficacy and to avoid the side effects of traditional chemotherapeutics. Through a compound library screen, 6-benzylthioinosine (6BT) was identified as a promising differentiation-inducing agent. 6BT induces monocytic differentiation of myeloid leukemia cell lines such as HL-60 and OCI-AML3, as well as primary patient samples as evidenced by morphology, immunophenotyping, and nitroblue tetrazolium reduction. Not only can 6BT induce differentiation but a subset of AML cell lines such as MV4-11 and HNT34 instead undergo 6BT-mediated cell death. Despite inducing cell death in some leukemic cells, 6BT exhibits extremely low toxicity on several nonmalignant cells such as fibroblasts, normal bone marrow, and endothelial cells. This toxicity profile may relate to the function of 6BT as an inhibitor of the nucleoside transporter, ent1, which is thought to prevent it from entering many cell types. In contrast, 6BT likely enters at least some leukemic cell lines as shown by its requirement for phosphorylation for its differentiation activity. 6BT is also able to synergize with currently used myeloid differentiation agents such as ATRA and decitabine. Early studies indicate that the mechanism of action of this compound may involve ATP depletion that leads to growth inhibition and subsequent differentiation. Besides in vitro activity, 6BT also shows the ability to impair HL-60 and MV4-11 tumor growth in nude mice. 6BT is a promising new monocytic differentiation agent with apparent leukemic cell-specific activity.
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PMID:Identification of 6-benzylthioinosine as a myeloid leukemia differentiation-inducing compound. 1851 98

Histone deacetylase 6 (HDAC6) is a heat shock protein 90 (hsp90) deacetylase. Treatment with pan-HDAC inhibitors or depletion of HDAC6 by siRNA induces hyperacetylation and inhibits ATP binding and chaperone function of hsp90. Treatment with 17-allylamino-demothoxy geldanamycin (17-AAG) also inhibits ATP binding and chaperone function of hsp90, resulting in polyubiquitylation and proteasomal degradation of hsp90 client proteins. In this study, we determined the effect of hsp90 hyperacetylation on the anti-hsp90 and antileukemia activity of 17-AAG. Hyperacetylation of hsp90 increased its binding to 17-AAG, as well as enhanced 17-AAG-mediated attenuation of ATP and the cochaperone p23 binding to hsp90. Notably, treatment with 17-AAG alone also reduced HDAC6 binding to hsp90 and induced hyperacetylation of hsp90. This promoted the proteasomal degradation of HDAC6. Cotreatment with 17-AAG and siRNA to HDAC6 induced more inhibition of hsp90 chaperone function and depletion of BCR-ABL and c-Raf than treatment with either agent alone. In addition, cotreatment with 17-AAG and tubacin augmented the loss of survival of K562 cells and viability of primary acute myeloid leukemia (AML) and chronic myeloid leukemia (CML) samples. These findings demonstrate that HDAC6 is an hsp90 client protein and hyperacetylation of hsp90 augments the anti-hsp90 and antileukemia effects of 17-AAG.
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PMID:HDAC6 inhibition enhances 17-AAG--mediated abrogation of hsp90 chaperone function in human leukemia cells. 1859 80

Hepatic ischemia-reperfusion (I/R) injury occurs in a variety of clinical settings and generates the release of endogenous noninfectious ligands called damage-associated molecular pattern (DAMP) signal molecules from damaged cells. This study investigates the effect of DAMP molecules released by Kupffer cells (KC) in I/R injury on the expression of liver manganese superoxide dismutase (MnSOD), a key mitochondrial antioxidant enzyme. We show that MnSOD expression levels are increased in rats and remain high for 24 h after 30 min of ischemia. KC were damaged and depleted after I/R, in association with MnSOD upregulation. Causality was established by treatment with gadolinium chloride, known to selectively destroy KC, which also increased MnSOD levels. Recovery from the early damage (6 h) to the liver tissue was evidenced after 24 h. A physiological protective role for MnSOD was also confirmed by the increased susceptibility of MnSOD-knockdown AML-12 hepatocyte cells to I/R-induced cell death. Inhibition of DAMP molecule high-mobility group box-1 activity by injection of neutralizing antibody partially abolished the increase in liver MnSOD after I/R. Direct injection of ATP, to animals or cells, stimulated MnSOD upregulation. Another DAMP molecule, monosodium urate, also induced MnSOD expression in hepatocyte AML-12 and FaO cell cultures. In conclusion, a connection between danger signals and upregulation of the antioxidant defense system is shown here for the first time in the context of I/R liver injury.
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PMID:Antioxidant defense in hepatic ischemia-reperfusion injury is regulated by damage-associated molecular pattern signal molecules. 1867 99

KIT mutations have been identified in several malignancies, including acute myeloid leukemia (AML) and systemic mastocytosis (SM). Mast cell leukemia (MCL) is the most aggressive mast cell neoplasm, but has not been well studied due to its rarity. We identified novel KIT transcripts in two patients with MCL and two patients with SM with an associated hematological disorder, but not from two patients with SM. Similar novel KIT transcripts were also observed in normal CD34+ cells from bone marrow and umbilical cord blood, suggesting that altered KIT isoforms may be specific to the blast stage of hematopoietic precursors. The novel KIT proteins lack several domains including the ATP binding site, and one was inactive in a functional test for autophosphorylation. Our discovery of novel KIT transcripts underscores the importance of analysing entire protein encoding regions when studying genes of interest.
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PMID:The identification and characterisation of novel KIT transcripts in aggressive mast cell malignancies and normal CD34+ cells. 1876 58

The Src-family protein-tyrosine kinase (PTK) Lyn is the most important Src-family kinase in B cells, having both inhibitory and stimulatory activity that is dependent on the receptor, ligand, and developmental context of the B cell. An important role for Lyn has been reported in acute myeloid leukemia and chronic myeloid leukemia, as well as certain solid tumors. Although several Src-family inhibitors are available, the development of Lyn-specific inhibitors, or inhibitors with reduced off-target activity to Lyn, has been hampered by the lack of structural data on the Lyn kinase. Here we report the crystal structure of the non-liganded form of Lyn kinase domain, as well as in complex with three different inhibitors: the ATP analogue AMP-PNP; the pan Src kinase inhibitor PP2; and the BCR-Abl/Src-family inhibitor Dasatinib. The Lyn kinase domain was determined in its "active" conformation, but in the unphosphorylated state. All three inhibitors are bound at the ATP-binding site, with PP2 and Dasatinib extending into a hydrophobic pocket deep in the substrate cleft, thereby providing a basis for the Src-specific inhibition. Analysis of sequence and structural differences around the active site region of the Src-family PTKs were evident. Accordingly, our data provide valuable information for the further development of therapeutics targeting Lyn and the important Src-family of kinases.
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PMID:Crystal structures of the Lyn protein tyrosine kinase domain in its Apo- and inhibitor-bound state. 1898 83

FLT3 is a tyrosine kinase (TK), member of the class III TK receptor family, normally expressed in hematopoietic, immune and neural systems, also playing an important role in the pathogenesis of acute leukemias, particularly acute myeloid leukemia (AML), where it is present in constitutively activated mutated forms, correlated with poor prognosis, in a notable percentage of patients. For these reasons FLT3 soon appeared as a promising target for the therapeutic intervention for this severe and aggressive malignancy; the recent determination of the crystal structure of the autoinhibited form of FLT3 gave new trend for the design and the synthesis of potent inhibitors. Small molecules tyrosine kinase inhibitors represent one of the largest drug family currently targeted by pharmaceutical companies for the treatment of cancer. Exciting examples of such molecules have reached advanced clinical trials and have been recently approved by FDA for the treatment of different solid or haematological tumors. Usually TK inhibitors share common features, namely two hydrophobic/aromatic regions bearing one or more hydrogen bonding substituents. These two regions can be connected by different spacers and almost all the molecules contain a component resembling the ATP purine structure. This review will deal with FLT3 synthetic inhibitors, reporting not only the most important molecules that are in clinical trials, but also the new compounds that have appeared in literature in the last few years. Our attention will be focused on chemical structures, mechanisms of action and structure-activity relationships.
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PMID:Small molecules ATP-competitive inhibitors of FLT3: a chemical overview. 1907 57


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