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

We have previously shown that all-trans retinoic acid (ATRA) increases the number of CFU-GM colonies grown from unseparated human bone marrow cells with crude sources of colony stimulating factors. In this study, we further characterized the effect of ATRA on the growth of CFU-GM stimulated by individual cytokines from multiple samples of CD34+ enriched or purified human bone marrow cells. The number of IL-3- or GM-CSF-induced CFU-GM with 3 x 10(-7) M ATRA was 3.25+/-1.13, and 2.17+/-0.8-fold greater respectively, compared to controls without ATRA, while G-CSF had no effect and the ratio of colony-induced with or without ATRA was 1.06+/-0.17 (P = 0.00012). No colonies grew with ATRA + IL-6 or ATRA without a cytokine. Maximum enhancing effect on IL-3-induced CFU-GM occurred when ATRA was added on day 2, gradually diminished when delaying ATRA, and in cultures of day 9 or older adding ATRA had no effect. In 14 days liquid cultures of purified CD34+ cells with IL-3, ATRA increased the number of myeloid differentiated cells to 91-95%, compared to 37-70% with IL-3 alone. In addition, the number of apoptotic cells using the annexin V method increased after 14 days from 5.1% with IL-3 to 17.1% with IL-3 + ATRA and by the TUNEL in situ method from 10-26% to 60-95%, respectively. This study demonstrates that ATRA consistently enhances the growth of myeloid progenitors from CD34+ cells. This effect is dependent on the stimulating cytokine, suggesting the myeloid cells responding to ATRA are the less mature CFU-GMs that are targets of IL-3 and GM-CSF and not the G-CSF-responding mature progenitors. The growth stimulation by ATRA and IL-3 is also associated with granulocyte differentiation and increased apoptosis. These studies further suggest a potential role of pharmacological doses of ATRA on the development of normal human hematopoietic cells.
Leukemia 2000 May
PMID:All-trans-retinoic acid effects the growth, differentiation and apoptosis of normal human myeloid progenitors derived from purified CD34+ bone marrow cells. 1080 20

The immunosuppressant FTY720 induces a drastic decrease in blood lymphocytes, especially T cells; a decrease which is assumed to be the immunosuppressive mechanism of this drug. FTY720 causes cell death in vitro in lymphocytes and leukemia cells. However, the deletion mechanism of blood lymphocytes in vivo remains unclear. We investigated whether administration of FTY720 induced lymphocyte apoptosis in blood circulation. A marked decrease in the number of blood lymphocytes was observed within an hour after a single oral administration of FTY720 at doses of 5-10 mg/kg in rats and mice. Experiments using fluorescein isothiocyanate (FITC)-Annexin V and APO-BRDU methods revealed that FTY720 induced blood lymphocyte apoptosis in a dose-dependent manner. On the other hand, lymphocyte homing to Peyer's patches was proposed as the mechanism underlying the blood lymphocyte decrease at these doses. However, similar results were obtained when using aly/aly mice, which lack Peyer's patches and lymph nodes. Thus, we concluded that apoptosis of blood lymphocytes was induced immediately after administration of FTY720, and the cells could be immediately scavenged by phagocytes or the reticuloendothelial system in addition to Peyer's patches homing. We also concluded that T cells were highly sensitive to FTY720, which induced apoptosis in vivo.
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PMID:Evidence that FTY720 induces T cell apoptosis in vivo. 1082 91

PD180970 is a novel pyrido[2,3-d]pyrimidine class of ATP-competitive inhibitor of protein tyrosine kinases. We found that PD180970 inhibited in vivo tyrosine phosphorylation of p210Bcr-Abl (IC50 = 170 nM) and the p210BcrAbl substrates Gab2 and CrkL (IC50 = 80 nM) in human K562 chronic myelogenous leukemic cells. In vitro, PD180970 potently inhibited autophosphorylation of p210Bcr-Abl (IC50 = 5 nM) and the kinase activity of purified recombinant Abl tyrosine kinase (IC50 = 2.2 nM). Incubation of K562 cells with PD180970 resulted in cell death. Results of nuclear staining, apoptotic-specific poly(ADP-ribose) polymerase cleavage, and annexin V binding assays indicated that PD180970 induced apoptosis of K562 cells. In contrast, PD180970 had no apparent effects on the growth and viability of p210Bcr-Abl-negative HL60 human leukemic cells. Thus, PD180970 is among the most potent inhibitors of the p210Bcr-Abl tyrosine kinase, which is present in almost all cases of human chronic myelogenous leukemia. These findings indicate that PD180970 is a promising candidate as a novel therapeutic agent for Bcr-Abl-positive leukemia.
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PMID:The pyrido[2,3-d]pyrimidine derivative PD180970 inhibits p210Bcr-Abl tyrosine kinase and induces apoptosis of K562 leukemic cells. 1086 98

Jurkat leukemia cells induced to undergo apoptosis by treatment with an antibody against the Fas receptor have two annexin V (AV)-binding subpopulations: (a) single-positive cells that bind AV but not propidium iodide (PI); and (b) double-positive cells that bind AV and PI. The single-positive population is thought to represent an early stage of apoptosis. We have examined the relationship between AV binding and a classical characteristic of apoptosis, DNA fragmentation. Time course studies with Jurkat cells treated for 1, 2, or 4 h with anti-Fas indicated that the proportion of AV-binding cells was increased after 2 h. A significant increase in DNA fragmentation was observed only at 4 h as measured by the mean tail moment determined with the alkaline single cell gel electrophoresis (comet) assay. This correlation suggests a temporal relationship between the two parameters, but does not provide direct evidence of what happens in individual cells. We developed a method to measure fluorescent markers of cellular structure or function with a laser scanning cytometer and then perform the comet assay on the same cells. Cells in each AV-binding subpopulation were re-examined before and after electrophoresis. Most AV-/PI- cells had no DNA damage, although a few cells showed a pattern of damage characteristic for apoptosis. Double-positive cells all had damaged DNA; approximately half had the apoptotic pattern, and the rest had a pattern typical for necrosis. Nearly all of the single-positive cells had damaged DNA with the apoptotic pattern. Both AV-positive populations contained cells with little or no detectable DNA after electrophoresis, indicating that the DNA was highly fragmented. These results indicate that AV binding is an excellent marker for apoptotic cells, but that these cells already have fragmented DNA.
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PMID:The DNA of annexin V-binding apoptotic cells is highly fragmented. 1096 16

Etoposide, a clinically useful anticancer drug, is a potent inhibitor of topoisomerase II. The DNA strand breaks caused by this epipodophyllotoxin lead to apoptotic death of tumor cells. Flow cytometry was used to investigate the relationship between the effects of the drug on the cell cycle of human leukemia HL-60 cells and the variations of the mitochondrial transmembrane potential (DeltaPsi(mt)). Three cationic fluorescent probes, DiOC(6), JC-1, and TMRM, were used to measure drug-induced changes of DeltaPsi(mt). In all three cases, we found that the arrest in the G2/M phase of the cells treated with 0.5 microM etoposide is associated with an increase in the potential of mitochondrial membranes whereas treatment with a tenfold higher drug concentration trigger massive apoptosis and a collapse of DeltaPsi(mt). DNA fragmentation (TUNEL assay) and externalization of phosphatidylserine residues in the outer leaflet of the plasma membrane (annexin V binding) were measured to characterize the apoptotic cell population.
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PMID:Relationship between cell cycle changes and variations of the mitochondrial membrane potential induced by etoposide. 1115 26

Hematopoietic stem cells (HSCs) are characterized by their dual abilities to undergo differentiation into multiple hematopoietic cell lineages or to undergo self-renewal. The molecular basis of these properties remains poorly understood. Recently the piwi gene was found in the embryonic germline stem cells (GSCs) of Drosophila melanogaster and has been shown to be important in GSC self-renewal. This study demonstrated that hiwi, a novel human homologue of piwi, is also present in human CD34(+) hematopoietic progenitor cells but not in more differentiated cell populations. Placing CD34(+) cells into culture conditions that supported differentiation and rapid exit from the stem cell compartment resulted in a loss of hiwi expression by day 5 of a 14-day culture period. Expression of the hiwi gene was detected in many developing fetal and adult tissues. By means of 5' RACE cloning methodology, a novel putative full-length hiwi complementary DNA was cloned from human CD34(+) marrow cells. At the amino acid level, the human HIWI protein was 52% homologous to the Drosophila protein. The transient expression of hiwi in the human leukemia cell line KG1 resulted in a dramatic reduction in cellular proliferation. Overexpression of hiwi led to programmed cell death of KG1 cells as demonstrated by the Annexin V assay system. These studies suggest that hiwi maybe an important negative developmental regulator, which, in part, underlies the unique biologic properties associated with hematopoietic stem and progenitor cells.
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PMID:Human CD34(+) stem cells express the hiwi gene, a human homologue of the Drosophila gene piwi. 1115 19

The antitumor effect of cepharanthin (CR), a biscoclaurine alkaloid, was examined as to its direct action on tumor cells and inhibitory action on angiogenesis in tumors. The effect of CR on in vitro invasion by murine RL-[symbol: see text] 1 leukemia cells and Colon 26 tumor cells was studied using a biocoat matrigel invasion chamber. One hundred micrograms/ml of CR inhibited tumor cell invasion. Early induction of apoptosis was assayed by the binding of annexin V and phosphatidylserine (PS) in the cellular membrane CR (10 and 100 micrograms/ml) induced apoptosis in human Daudi and Raji B lymphoblastoid cells. Treatment with CR (1 and 10 micrograms/ml) also inhibited the in vitro growth of Daudi and Raji cells. Ten micrograms/ml of CR also inhibited the growth of human umbilical vein endothelial cells (HUVEC) and human dermal microvascular endothelial cells (HMVEC). These results indicate that CR has diversified antitumor functions, i.e., an enhancement of a sequential immune mechanism, a direct cytotoxic effect and inhibitory action of angiogenesis in tumors.
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PMID:[Antitumor effect of the plant alkaloid preparation, cepharanthin]. 1124 48

Water-soluble chitosan oligomer (WSCO) has been reported to have anticancer activity, immuno-enhancing effect and antimicrobial activity. However, other biological activities are unknown. Herein, we have shown that WSCO is able to inhibit proliferation of human leukemia HL-60 cells and induce these cells to differentiate. Treatment with WSCO for 4 days resulted in a concentration-dependent reduction in HL-60 cell growth as measured by cell counting and MTT assay. This effect was accompanied by a marked increase in the proportion of G(0)/G(1) cells as measured by flow cytometry. WSCO also induced differentiation of the cells as measured by phorbol ester-dependent reduction of NBT, morphological changes as examined by Wright-Giemsa staining and expression of CD11b but not of CD14 as analysed by flow cytometry, indicating differentiation of HL-60 cells toward granulocyte-like cells. A combination of low dose of WSCO with all-trans retinoic acid, a differentiating agent toward granulocyte-like cells, exhibited a synergistic effect on the differentiation. In addition, treatment of HL-60 cells with WSCO for 6 or 8 days resulted in the induction of apoptosis as assayed qualitatively by agarose gel electrophoresis and quantitatively by Annexin V technique using flow cytometry. Collectively, there is a potential for WSCO in the treatment of myeloid leukemia.
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PMID:Induction of granulocytic differentiation in acute promyelocytic leukemia cells (HL-60) by water-soluble chitosan oligomer. 1124 31

In the present study, we investigated the in vitro apoptotic response of leukemic cells to the cellular stress induced by homoharringtonine (HHT), a plant alkaloid with antileukemic activity which is currently being tested for treatment of acute and chronic leukemias. A comparison of leukemic cell lines with different p53 gene status revealed a considerably higher sensitivity to HHT-induced apoptosis in the cells with a wt p53, and apoptotic events in wt p53 leukemia cells (MOLT-3 cell line) were studied in more detail. To this end, we examined components of apoptotic cascades including Bax expression and its intracellular localization, changes of mitochondrial membrane potential (MMP), reactive oxygen species (ROS) levels, cytochrome c release from mitochondria and activation of caspases. Bax protein levels did not increase despite an up-regulation of bax at mRNA level. However, Bax translocation from cytosol towards mitochondria was observed. In addition, we observed a release of cytochrome c from the mitochondria, and the localization changes of both Bax and cytochrome c were found already at the early, annexin V-negative stage of HHT-induced apoptosis. HHT-treated MOLT-3 cells revealed loss of MMP as well as activation of caspases demonstrated by DEVD-, IETD- and LEHD-tetrapeptide cleavage activity in the cell lysates. ROS levels only slightly increased in HHT-treated cells and antioxidants did not prevent apoptosis and MMP changes. Therefore, wt p53 leukemic cells respond to HHT-specific cellular stress by induction of ROS-independent apoptotic pathway characterized by translocation of Bax, mitochondrial cytochrome c release and activation of caspases.
Leukemia 2001 Apr
PMID:Apoptotic response to homoharringtonine in human wt p53 leukemic cells is independent of reactive oxygen species generation and implicates Bax translocation, mitochondrial cytochrome c release and caspase activation. 1136 58

Induction of apoptosis by different types of pathogenic retroviruses is an important step in disease development. We have observed that infection of thymic lymphocytes by the mink cell focus-forming murine leukemia virus (MCF MLV) during the preleukemic period resulted in an enhancement of apoptosis of these cells. To further study the ability of MCF MLVs to induce apoptosis and the role of this process in viral pathogenesis, we have developed an in vitro system of virus-induced apoptosis. MCF13 MLV infection of mink epithelial cells resulted in the production of cytopathic foci. In contrast, infection of mink cells with the 4070A amphotropic MLV did not produce any cytopathic effects. Staining of MCF13 MLV-infected cells with propidium iodide and annexin V-fluorescein isothiocyanate indicated that virus-induced cell death was due to apoptosis. At 6 days postinfection, the percentage of apoptotic MCF13 MLV-infected cells was 27% compared with 2 to 3% for mock- or amphotropic MLV-infected cells, representing a 9- to 14-fold difference. Assays for caspase-3 activation confirmed the detection by flow cytometry of apoptosis of MCF13 MLV-infected cells. Large amounts of unintegrated linear viral DNA were detectable by Southern blot analysis during the acute phase of infection, which indicated that MCF13 MLV is able to superinfect mink cells. Unintegrated viral DNA of only the linear form was detectable in thymic lymphocytes isolated from MCF13 MLV-inoculated mice during the preleukemic period. These results indicated that the ability of MCF13 MLV to induce apoptosis is correlated with its ability to superinfect cells and that this occurs as an early step in thymic lymphoma development.
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PMID:Mink cell focus-forming murine leukemia virus killing of mink cells involves apoptosis and superinfection. 1139 Jun 2


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