Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0026986 (myelodysplastic syndrome)
 14,926 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although recent data shows that arsenic trioxide (As2O3) is capable of inducing cell death via cell cycle arrest and apoptosis both in acute promyelocytic leukemia (APL) and in non-APL cells, the mechanisms of As2O3-mediated cell death are not fully understood. In this study, we investigated the in vitro effects of As2O3 on cell growth inhibition and cell death in human T-lymphocytic leukemia and myelodysplastic syndrome (MDS) cell lines. As2O3 significantly inhibited the proliferation of Molt-4 and Mutz-1 cells in dose- and time-dependent manner. Autophagic cell death (programmed cell death type II) and apoptosis (programmed cell death type I) were activated together in leukemia cell lines after exposed to As2O3. Numerous large cytoplasmic inclusions and vacuoles were observed in As2O3-treated cells using electron microscope. Furthermore, 3-methyladenine (an autophagy inhibitor) significantly reduced autophagic cell death and sequentially induced apoptosis. Finally, leukemia cells treated with 4 microM As2O3 showed a considerable up-regulation of Beclin-1 (a Bcl-2-interacting protein) expression, which was independent of transcription of mRNA and required protein synthesis. In addition, Molt-4 cells treated with As2O3 exhibited the down-regulation of Bax protein expression, suggesting that Bax may be involved in accumulating of Beclin-1 and triggering autophagic cell death in As2O3-treated leukemia cells. These results may lead to a better understanding of the mechanism of action of As2O3, and provide a suggestion that As2O3 may be of therapeutic value for the treatment of patients with human T-lymphocytic leukemia and myelodysplastic syndrome.
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PMID:Arsenic trioxide induces not only apoptosis but also autophagic cell death in leukemia cell lines via up-regulation of Beclin-1. 1688 51

CD34(+) bone marrow blasts from high-risk myelodysplastic syndrome (MDS) patients as well as MDS patient-derived cell lines (P39 and MOLM13) constitutively activate the nuclear factor-kappaB (NF-kappaB) pathway and undergo apoptosis when NF-kappaB is inhibited. Here, we show that the combination of conventional chemotherapeutic agents (daunorubicin, mitoxantrone, 5-azacytidine or camptothecin) with the NF-kappaB inhibitor BAY11-7082 did not yield a synergistic cytotoxicity. In contrast, BAY11-7082 (which targets the NF-kappaB-activating I-kappaB kinase (IKK) complex) or knockdown of essential components of the NF-kappaB system (such as the IKK1 and IKK2 subunits of the IKK complex and the p65 subunit of NF-kappaB), by small interfering RNAs sensitized MDS cell lines to starvation-induced apoptosis. The combination of BAY11-7082 and nutrient depletion synergistically killed the acute myeloid leukemia (AML) cell line U937 as well as primary CD34(+) bone marrow blasts from AML and high-risk MDS patients. The synergistic killing by BAY11-7082, combined with nutrient depletion, led to cell death accompanied by all hallmarks of apoptosis, including an early loss of the mitochondrial transmembrane potential, the release of cytochrome c and apoptosis-inducing factor (AIF) from mitochondria, activation of caspase-3, phosphatidylserine exposure on the plasma membrane surface and nuclear chromatin condensation. Transmission electron microscopy revealed the presence of numerous autophagic vacuoles in the cytoplasm before cells underwent nuclear apoptosis. Nonetheless, cell death was neither inhibited by the pan-caspase inhibitor z-VAD-fmk nor by knockdown of AIF or of essential components of the autophagy pathway (ATG5, ATG6/Beclin-1, ATG10, ATG12). In contrast, external supply of glucose, insulin or insulin-like growth factor-I could retard the cell death induced by BAY11-7082 combined with starvation. These results suggest that in MDS cells, NF-kappaB inhibition can precipitate a bioenergetic crisis that leads to an autophagic stress response followed by apoptotic cell death.
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PMID:NF-kappaB inhibition sensitizes to starvation-induced cell death in high-risk myelodysplastic syndrome and acute myeloid leukemia. 1721 4

Although molecular targeted therapies have recently displayed therapeutic effects in acute myeloid leukemia (AML), limited response and acquired resistance remain common problems. Numerous studies have associated autophagy, an essential degradation process involved in the cellular response to stress, with the development and therapeutic response of cancers including AML. Thus, we review studies on the role of autophagy in AML development and summarize the linkage between autophagy and several recurrent genetic abnormalities in AML, highlighting the potential of capitalizing on autophagy modulation in targeted therapy for AML. Abbreviations: AML: acute myeloid leukemia; AMPK: AMP-activated protein kinase; APL: acute promyelocytic leukemia; ATG: autophagy related; ATM: ATM serine/threonine kinase; ATO: arsenic trioxide; ATRA: all trans retinoic acid; BCL2: BCL2 apoptosis regulator; BECN1: beclin 1; BET proteins, bromodomain and extra-terminal domain family; CMA: chaperone-mediated autophagy; CQ: chloroquine; DNMT, DNA methyltransferase; DOT1L: DOT1 like histone lysine methyltransferase; FLT3: fms related receptor tyrosine kinase 3; FIS1: fission, mitochondrial 1; HCQ: hydroxychloroquine; HSC: hematopoietic stem cell; IDH: isocitrate dehydrogenase; ITD: internal tandem duplication; KMT2A/MLL: lysine methyltransferase 2A; LSC: leukemia stem cell; MDS: myelodysplastic syndromes; MTORC1: mechanistic target of rapamycin kinase complex 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; NPM1: nucleophosmin 1; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; PML: PML nuclear body scaffold; ROS: reactive oxygen species; RB1CC1/FIP200: RB1 inducible coiled-coil 1; SAHA: vorinostat; SQSTM1: sequestosome 1; TET2: tet methylcytosine dioxygenase 2; TKD: tyrosine kinase domain; TKI: tyrosine kinase inhibitor; TP53/p53: tumor protein p53; ULK1: unc-51 like autophagy activating kinase 1; VPA: valproic acid; WDFY3/ALFY: WD repeat and FYVE domain containing 3.
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PMID:The role of autophagy in targeted therapy for acute myeloid leukemia. 3291 24