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

Rapid consumption of oxygen by leucocytes can result in erroneous diagnosis of severe hypoxaemia in patients with extreme leucocytosis. We report a case of chronic myeloid leukaemia, extreme leucocytosis and arterial hypoxaemia which was out of proportion to the clinical and radiological evidence of lung disease. The pseudohypoxaemia was confirmed by pulse oximeter and became less significant after successful reduction of leucocyte counts following leucophoresis and chemotherapy. Serial arterial blood gas analysis also demonstrated a slower initial rate of decay of PaO2 as the leucocyte count decreased with treatment.
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PMID:Spurious hypoxaemia in a patient with leukaemia and extreme leucocytosis. 1295 35

Tannins are a group of widely distributed plant polyphenols, some of which are beneficial to health because of their chemopreventive activities. In the present study, we investigated the effects and action mechanisms of woodfordin I, a macrocyclic ellagitannin dimer, on human chronic myelogenous leukemia (CML) K562 cells. The results showed that woodfordin I was able to suppress the proliferation and induce apoptosis in K562 cells. Apoptosis was evaluated by cytomorphology, internucleosomal DNA fragmentation, and externalization of phosphatidylserine. Woodfordin I treatment caused a rapid and sustained loss of mitochondrial transmembrane potential (MMP), transient generation of reactive oxygen species (ROS), transient elevation of intracellular Ca2+ concentration, and cytosolic accumulation of cytochrome c. The activation of caspase-9 and 3, but not caspase-8, was also demonstrated, indicating that the apoptotic signaling triggered by woodfordin I was mediated through the intrinsic mitochondria-dependent pathway. Western blot and immunofluorescence analysis revealed that the anti-apoptotic Bcl-2 and Bcl-xL levels were downregulated, together with the pro-apoptotic Bax protein. Significantly, woodfordin I-induced apoptosis was associated with a decline in the levels of c-Abl, Bcr-Abl, and cellular protein tyrosine phosphorylation. Considering the consequence of all the events in the process of woodfordin I-induced apoptosis, the mitochondrial dysfunction is directly responsible for the pro-apoptotic effects on K562 cells. Furthermore, because CML is a malignancy of pleuripotent hematopoietic cells caused by the dysregulated tyrosine kinase activity of Bcr-Abl, these findings suggest that woodfordin I may be a potential lead compound against CML.
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PMID:Mitochondrial dysfunction as an early event in the process of apoptosis induced by woodfordin I in human leukemia K562 cells. 1473 95

c-Abl is activated by oxidative stress but its precise function in cell response to this stress is elusive. Studies of c-Abl(-/-) osteoblasts revealed that c-Abl played a negative role in the induction of peroxiredoxin I (Prx I, Prdx I), an anti-oxidant protein with tumor suppression activity. In contrast, Atm, a signaling molecule that interacts with c-Abl and is required for c-Abl activation, served a totally different function. The significance of these findings is discussed here in the context of aging and tumorigenesis and their links to reactive oxygen species. c-Abl and its derivatives BCR-ABL and v-Abl were discovered more than twenty years ago. BCR-ABL and v-Abl acquire elevated tyrosine kinase activities by fusing to BCR and gag respectively and are capable of transforming myeloid and fibroblast cells. BCR-ABL is also the underlying cause in the development of most cases of chronic myeloid leukemia (CML) in humans. In contrast, c-Abl takes on an auto-inhibiting conformation and its activation requires post-translational modifications such as phosphorylation and myristoylation. The physiological functions of c-Abl remain elusive.
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PMID:c-Abl in oxidative stress, aging and cancer. 1565 64

Recent studies have described malignant stem cells as central to the initiation, growth, and potential relapse of acute and chronic myelogenous leukemia (AML and CML). Because of their important role in pathogenesis, rare and biologically distinct leukemia stem cells (LSCs) represent a critical target for therapeutic intervention. However, to date, very few agents have been shown to directly target the LSC population. The present studies demonstrate that parthenolide (PTL), a naturally occurring small molecule, induces robust apoptosis in primary human AML cells and blast crisis CML (bcCML) cells while sparing normal hematopoietic cells. Furthermore, analysis of progenitor cells using in vitro colony assays, as well as stem cells using the nonobese diabetic/severe combined immunodeficient (NOD/SCID) xenograft model, show that PTL also preferentially targets AML progenitor and stem cell populations. Notably, in comparison to the standard chemotherapy drug cytosine arabinoside (Ara-C), PTL is much more specific to leukemia cells. The molecular mechanism of PTL-mediated apoptosis is strongly associated with inhibition of nuclear factor kappa B (NF-kappaB), proapoptotic activation of p53, and increased reactive oxygen species (ROS). On the basis of these findings, we propose that the activity of PTL triggers LSC-specific apoptosis and as such represents a potentially important new class of drugs for LSC-targeted therapy.
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PMID:The sesquiterpene lactone parthenolide induces apoptosis of human acute myelogenous leukemia stem and progenitor cells. 1568 34

Methyl protodioscin is a furostanol bisglycoside with antitumor properties. The present study investigated its effects on human chronic myelogenous leukemia K562 cells. Cell cycle analysis showed that methyl protodioscin caused distinct G2/M arrest, with the appearance of polyploidy population. The levels of cyclin B1 decreased, whereas Cdc2 kept at a steady level. Subsequent apoptosis after G2/M blockage was demonstrated through DNA fragmentation and the annexin V staining assay. Methyl protodioscin induced a biphasic alteration (i.e. an early hyperpolarization, followed by depolarization) in mitochondrial membrane potential of K562 cells. The transient decline of intracellular Ca2+ concentration was observed at early stage. The generation of reactive oxygen species was also detected. The anti-apoptotic Bcl-x(L) transiently increased and then decreased. And the pro-apoptotic Bax was markedly up-regulated. Taken together, these data demonstrated that methyl protodioscin inhibits K562 cell proliferation via G2/M arrest and apoptosis, with mitochondrial hyperpolarization and the disruption of Ca2+ homeostasis playing important roles.
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PMID:Methyl protodioscin induces G2/M arrest and apoptosis in K562 cells with the hyperpolarization of mitochondria. 1591 74

The BCR/ABL kinase has been targeted for the treatment of chronic myelogenous leukemia (CML) by imatinib mesylate. While imatinib has been extremely effective for chronic phase CML, blast crisis CML and Ph+ acute lymphoblastic leukemia (ALL) are often resistant. In particular, mutation of the T315 residue in the bcr/abl activation loop renders cells highly resistant to imatinib and to second-generation kinase inhibitors such as BMS-354825 or AMN107. Adaphostin is a tyrphostin that was originally intended to inhibit the BCR/ABL kinase by competing with its peptide substrates. Recent findings have in addition implicated reactive oxygen species (ROS) in the cytotoxic mechanism of adaphostin. In view of this unique mode of action, we examined the effects of adaphostin on numerous imatinib-resistant leukemia models, including imatinib-resistant CML and Ph+ ALL cell lines, cells harboring point mutations in BCR/ABL, and specimens from imatinib-resistant CML patients, using assays for intracellular ROS, apoptosis, and clonogenicity. Every model of imatinib resistance examined remained fully sensitive to adaphostin-induced cell death. Collectively, these data suggest that ROS generation by adaphostin overcomes even the most potent imatinib resistance in CML and Ph+ ALL.
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PMID:Adaphostin-induced oxidative stress overcomes BCR/ABL mutation-dependent and -independent imatinib resistance. 1629 94

Novel photosensitizers beta-(hydroquinon-2-yl)-5,10,15,20-tetra(4-hydroxylphenyl)porphyrinato zinc(II) (Zn(II)P) and beta-(hydroquinon-2-yl)-5,10,15,20-tetra(4-hydroxylphenyl)porphyrinato copper(II) (Cu(II)P) were synthesized and characterized. Their ability of producing singlet oxygen under irradiation was detected by the measurement of decomposition of 1,3-diphenylisobenzofuran (DPBF). The preliminary biological activity studies show that the Zn(II)P has photo-toxicity on human chronic myelogenous leukemia cell (K562) and could cleave supercoiled DNA (pBR 322 DNA), while the Cu(II)P has inferior biological activity. Results showed Zn(II)P having high anti-tumor activity, which presents a promising photosensitizer for photodynamic therapy.
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PMID:Zinc(II) and copper(II) complexes of beta-substituted hydroxylporphyrins as tumor photosensitizers. 1654 Mar 16

Trichosanthin (TCS), a type I ribosome-inactivating protein, induces cell death in various cell types including several tumor cell lines. However, the mechanism remains largely uncharacterized. In this study, we investigated the possible mechanism underlying its cytotoxicity by using human chronic myeloid leukemia cell line K562. We found that TCS induced apoptosis in K562 cells in a time- and concentration-dependent manner and can be blocked by caspase-3 inhibitors. Interestingly, TCS treatment induced a transient elevation in intracellular calcium concentration and a slow increase in reactive oxygen species production, while calcium chelators and antioxidants had no obvious effect on TCS-induced apoptosis, suggesting that calcium changes and reactive oxygen species may not be involved in TCS-mediated apoptosis in K562 cells. Instead we found that TCS partly inhibited PKC activity. Indeed, the PKC activator, PMA, inhibited while the PKC inhibitor, calphostin c, enhanced TCS-induced apoptosis. These PKC modulators had similar effects on TCS-induced cleavage of caspase-3, and caspase-3 inhibitors prevented calphostin c-enhanced apoptosis induced by TCS. In summary, we conclude that TCS induces apoptosis in K562 cells partly via PKC inhibition and caspase-3 activation.
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PMID:PKC inhibition is involved in trichosanthin-induced apoptosis in human chronic myeloid leukemia cell line K562. 1694 56

The malignant phenotype of chronic myeloid leukemia (CML) is due to the abnormal tyrosine kinase activity of the Bcr-Abl oncoprotein. We have previously reported that expression of the Bach2 transcription factor, which induces apoptosis in response to oxidative stress, is greatly reduced in CML cells. Because these cells are resistant to apoptosis, we tested whether Bach2 could also be regulated through posttranslational mechanisms that promote inhibition of the apoptotic response to mutagenic stimuli in CML. We found that Bach2 is phosphorylated on S521 via the phosphatidylinositol-3/S6 kinase pathway, and substitution of this site to alanine leads to nuclear accumulation of the protein, indicating that this phosphorylation is important for its subcellular localization. Ectopic expression of the S521 mutant imparts greater impairment to CML cell growth than the wild-type factor. Furthermore, we showed that Bach2 transcriptionally represses heme oxygenase-1, an antiapoptotic factor up-regulated in CML. Because CML cells are known to produce high levels of intracellular reactive oxygen species, overexpression of heme oxygenase-1 resulting from inhibition of Bach2 activity may contribute to their genomic instability and leukemic phenotype.
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PMID:Bcr-Abl signaling through the PI-3/S6 kinase pathway inhibits nuclear translocation of the transcription factor Bach2, which represses the antiapoptotic factor heme oxygenase-1. 1701 62

Several lines of evidence suggest that both advanced glycation end products (AGEs) and oxidation processes play key roles in the physiology of aging and age-related pathologies, leading to irreversible proteins modifications in both tissues and the extracellular matrix. Such an accelerated accumulation of these modifications has been reported to be present in several age-related chronic diseases, such as atherosclerosis, diabetes, arthritis, and neurodegenerative diseases. The current literature reveals that the specific inhibition of AGEs may constitute an innovative therapeutic goal. In experimental animals, the use of sartans significantly reduces blood pressure and kidney pentosidine content, improving both histologic renal damage and proteinuria. In this study, 12 subjects who were affected by diabetes mellitus and hypertension were subjected to oral antihypertensive therapy with valsartan (class of sartans) with timed sampling of plasma and urine pentosidine, N(epsilon)-(carboxymethyl)lysine (CML), malondialdehyde, and isoprostanes levels, respectively, at baseline and after both 3 and 6 months, with parallel ongoing evaluation of glycemic control and blood pressure levels. Valsartan elicited a good antihypertensive effect with a 30% decrease in plasma pentosidine levels (P < .05) after 3 months of therapy, followed by a slight increase after 6 months. Urinary pentosidine concentrations exhibited a 40% decrease after 3 months (215 +/- 19 vs 129 +/- 23 nmol/24 h) and a further significant reduction after 6 months of therapy (105 +/- 24 nmol/24 h). Plasma CML levels showed a progressive decrease after 3 months (23.15 +/- 3.215 vs 19.88 +/- 1.684 micromol/mL) and achieved a further slight reduction after 6 months of therapy (19.48 +/- 1.339 micromol/mL); for urinary CML, a statistically significant reduction was gained after the sixth month of therapy (48.51 +/- 5.70 vs 30.30 +/- 2.77 micromol/24 h after 3 months and 27.02 +/- 4.13 micromol/24 h after 6 months; F = 7.62, P < .005). Plasma and urinary concentrations of malondialdehyde were slightly modified by valsartan treatment; the mean levels after both 3 and 6 months did not significantly differ from baseline. Urinary 15-F2t-isoprostanes (2.96 +/- 0.45 ng/24 h) levels displayed a progressive decrease after both 3 (2.27 +/- 0.31 ng/24 h) and 6 months (1.70 +/- 0.23 ng/24 h) with statistical significance achieved only at the end of the study (P < .05). The present data suggest interesting in vivo antiglycation and antioxidation effects of this angiotensin II receptor antagonist with reductions in plasma and urinary pentosidine, plasma CML, and urinary isoprostanes levels. The present study supports an antagonistic role of valsartan in the production of AGEs precursors through the chelation of transition metals and an antioxidant activity that scavenges reactive oxygen species. This property of valsartan may broaden the scope of newly developed pharmacologic inhibitors of advanced glycoxidation.
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PMID:Effects of valsartan therapy on protein glycoxidation. 1714 34


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