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)

Central nervous system (CNS) damage occurs during retroviral infection in both man and animals. As a model of human disease, we studied the distribution and extent of CNS damage during retroviral infection with two molecularly cloned, neurotropic murine leukemia viruses. Both viruses mediate a spongiform encephalopathy involving predominantly the brainstem and spinal cord. During the course of disease, immune reactivity for synaptophysin (SYN) (to identify presynaptic elements) and microtubule-associated protein-2 (MAP-2) (to identify postsynaptic elements) were quantified using confocal laser microscopy. Immunostaining of SYN in the cerebral cortex (an area not exhibiting spongiform lesions) was similar in viral infected and age-matched control mice. However, compared to age matched controls, SYN staining in the brainstem (an area exhibiting spongiform lesions) of viral infected mice progressively declined during the course of disease. Quantitative analysis showed greater reduction of MAP-2 immunostaining in viral-infected mice compared to age-matched controls. In infected mice, both regions with and without spongiform lesions showed diminished MAP-2 staining. Widely distributed microscopic vacuolation of dendritic processes was observed in confocal preparations. These findings suggest primary dendritic damage in murine retroviral infection of the CNS similar to what has been described in human immunodeficiency virus-1 encephalitis.
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PMID:Synaptic and dendritic pathology in murine retroviral encephalitis. 828 27

Cytoskeletal changes have been known to occur in cell transformation. Vinca alkaloids which bind to the tubulin dimer and inhibit microtubule (MT) assembly as well as disrupting the MT network and mitotic spindle, have been used as cancer chemotherapeutic agents. It has been proposed that apart from their anti-mitotic activity, these drugs act on the peripheral MT of malignant cells to produce their cytolytic effects. In this paper we demonstrate the presence of an altered cytoplasmic MT network in MOLT-4 and HuT-78 leukemic cells (human T-cell leukemic lines) compared to normal human peripheral blood lymphocytes stimulated with mitogens. In addition, using a selective extraction protocol we have compared microtubule-associated proteins (MAPs) profiles of G1/S synchronized leukemic human T-cells and 20 h mitogen-stimulated human peripheral blood T-cells. We observed a dramatic decrease in the expression of a MAP of apparent molecular weight 52 kDa and pI 5.2 in the leukemic cells synchronized at the G1/S border of the cell cycle. These results suggest that altered MT network morphology and MAP synthesis may be components of the malignant phenotype in the T-lymphocytic leukemias studied here.
Leukemia 1993 Jan
PMID:Microtubule network and microtubule-associated proteins in leukemic T lymphocytes. 841 79

We reported previously that pironetin and its derivatives were potent inhibitors of cell cycle progression at the M-phase and showed antitumour activity against a murine tumour cell line, P388 leukaemia, transplanted in mice. In this paper, we investigated the mechanism of action of pironetins in antitumour activity and cell cycle arrest at the M-phase. As reported previously for murine leukaemia P388 cells, pironetin showed antitumour activity in a dose-dependent manner in the human leukaemia cell line HL-60. Since DNA fragmentation was observed in both P388 and HL-60 cells, the antitumour activity of pironetin is thought to be due to the induction of apoptosis. Pironetin also induced the rapid phosphorylation of Bcl-2 before formation of the DNA ladder in HL-60 cells, as seen with several tubulin binders. These results suggest that the antitumour activity of pironetin is due to apoptosis caused by the phosphorylation of Bcl-2, and that pironetin targets the microtubules. Pironetin and demethylpironetin exhibited reversible disruption of the cellular microtubule network in normal rat fibroblast 3Y1 cells. However, epoxypironetin, which contains epoxide instead of the double bond of pironetin, showed only weak activity. Since the concentrations that inhibit cell cycle progression at the M-phase were the same as those for disruption of the microtubule network, it was suggested that the mitotic arrest induced by pironetin was the result of the loss of the mitotic spindle. These compounds also inhibited the microtubule-associated protein-induced and glutamate-induced tubulin assembly in vitro. Pironetin inhibited the binding of [3H]vinblastine, but not that of [3H]colchicine, to tubulin, and the Kd values revealed that the affinity of pironetin for tubulin is stronger than that of vinblastine. These results suggest that pironetins are novel antitumour agents which inhibit microtubule assembly.
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PMID:Apoptosis induction via microtubule disassembly by an antitumour compound, pironetin. 1033 83

Platonin is a photosensitizer used for photodynamic therapy. In this study, we tested the effect of platonin on human leukemic cells. Treatment with platonin in the dark markedly reduced cell membrane integrity, and induced significant G(0)/G(1) arrest of a panel of human leukemic cell lines, including U937, HL-60, K562, NB4 and THP-1. Development of hypodiploid cells was not evident in these cell lines within 24 h, but was noted in U937, HL-60 and NB4 cells after 24 h. No myeloid differentiation of these cells was noted after five-day treatment. Intriguingly, exposure of monoblastic U937 cells to platonin caused changes characteristic of autophagy, including appearance of cytoplasmic membranous vacuoles and formation of acidic vesicular organelles (AVO) in more than 95% of cells. The platonin-induced autophagy was accompanied by localization of microtubule-associated protein 1 light chain 3 to autophagosomes. Pretreatment with pancaspase inhibitor Z-VAD-fmk abrogated the platonin-induced hypodiploidity, but had no effect on growth inhibition and formation of AVO, indicating a caspase-independent autophagy-associated cell death. Pretreatment of cells with 3-methyladenine attenuated platonin-mediated growth inhibition and formation of AVO. Platonin augmented the expression of BNIP3 in both U937 and K562 cells, whereas had an opposite effect on phosphorylation of mTOR downstream molecule p70S6K. Platonin, at the condition inducing autophagy, induced the mitochondrial membrane permeation. These results suggest that the platonin is capable of inhibiting growth as well as inducing cell death, mainly autophagy-associated, in leukemic cells via a mitochondria-mediated and caspase-independent pathway. A markedly less viability inhibition was noted to human monocytes, the normal counterpart of these myeloid leukemic cells. Platonin, other than a photodynamic agent, may offer significant promise as a therapeutic agent against leukemia.
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PMID:Platonin induces autophagy-associated cell death in human leukemia cells. 1906 47

The elimination of tumor cells by apoptosis is the main mechanism of action of chemotherapeutic drugs used in current treatment protocols of acute lymphoblastic leukemia (ALL). Despite the rapid cytoreduction achieved, serious acute and late complications are frequent, and resistance to chemotherapy develops. During the past decade, new strategies to kill cancer cells by nonapoptotic mechanisms have flourished and many mediators of alternate cell death pathways have been identified. In the present study we have evaluated the efficacy of an mTOR inhibitor, RAD001 (Everolimus), to induce autophagy in an in vivo model of childhood ALL. In particular we found that RAD001 increased Beclin 1 expression, the conversion of the soluble form of microtubule-associated protein 1 light chain 3 (LC3) to the autophagic vesicle-associated form LC3-II and the occurence of lysosomes/autophagosomes. Focal degradation of cytoplasmic areas sequestered by autophagic structures was demonstrated by electron microscopy. This effect was associated with massive reduction of leukemic mass and a strong survival advantage for mice treated with RAD001. The discovery of alternative pathways involved in cell death execution and the role that it plays in leukemia suggest mTOR inhibitors should be included in future chemotherapy protocols of ALL.
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PMID:RAD001 (Everolimus) induces autophagy in acute lymphoblastic leukemia. 1936

Autophagy, a tightly regulated lysosome-dependent catabolic pathway, is important in the regulation of cancer development and progression and in determining the response of tumor cells to anticancer therapy. However, the role of autophagy in leukemia still remains largely unknown. Here we show that high-mobility group box 1 (HMGB1), the best characterized damage-associated molecular pattern, was released from leukemia cell lines after chemotherapy-induced cytotoxicity and activated autophagy to protect against injury. Treatment with HMGB1-neutralizing antibodies increased the sensitivity of leukemia cells to chemotherapy; whereas, exogenous HMGB1 rendered these cells more resistant to drug-induced cytotoxicity. Moreover, exogenous HMGB1 increased autophagy as evaluated by increased expression of the autophagic marker microtubule-associated protein light chain 3-II, degradation of sequestosome 1 (p62) and autophagosome formation. Furthermore, knockdown or pharmacological inhibition of either phosphoinositide 3-kinase-III or extracellular signal-regulated kinase kinase mitogen-activated protein kinase kinase/extracellular signal-regulated protein kinase inhibited HMGB1-induced autophagy. Taken together, these results suggest that HMGB1 release after chemotherapy is a critical regulator of autophagy and a potential drug target for therapeutic interventions in leukemia.
Leukemia 2011 Jan
PMID:HMGB1-induced autophagy promotes chemotherapy resistance in leukemia cells. 2092 32

Damage-associated molecular pattern molecules (DAMPs) are cellularly derived molecules that can initiate and perpetuate immune responses following trauma, ischemia and other types of tissue damage in the absence of pathogenic infection. High mobility group box 1 (HMGB1) is a prototypical DAMP and is associated with the hallmarks of cancer. Recently we found that HMGB1 release after chemotherapy treatment is a critical regulator of autophagy and a potential drug target for therapeutic interventions in leukemia. Overexpression of HMGB1 by gene transfection rendered leukemia cells resistant to cell death; whereas depletion or inhibition of HMGB1 and autophagy by RNA interference or pharmacological inhibitors increased the sensitivity of leukemia cells to chemotherapeutic drugs. HMGB1 release sustains autophagy as assessed by microtubule-associated protein 1 light chain 3 (LC3) lipidation, redistribution of LC3 into cytoplasmic puncta, degradation of p62 and accumulation of autophagosomes and autolysosomes. Moreover, these data suggest a role for HMGB1 in the regulation of autophagy through the PI3KC3-MEKERK: pathway, supporting the notion that HMGB1-induced autophagy promotes tumor resistance to chemotherapy.
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PMID:DAMP-mediated autophagy contributes to drug resistance. 2106 41

Chemoresistance has become a major obstacle to the successful treatment of leukemia. Autophagy, a regulated process of degradation and recycling of cellular constituents, has recently caught increasing attention for its roles in conferring resistance to various commonly used anticancer therapies. Here we showed that the member of the S100 calcium-binding protein family, S100A8, is a critical regulator of chemoresistance in the autophagy process. It positively correlated with the clinical status in childhood acute myeloblastic leukemia (AML) and it was released from leukemia cells after chemotherapy-induced cytotoxicity. Knockdown of S100A8 expression increased the sensitivity of leukemia cells to chemotherapy and apoptosis. Moreover, suppressing S100A8 expression decreased autophagy as evaluated by the increased expression of the autophagic marker microtubule-associated protein light chain 3 (LC3)-II, degradation of SQSTM1/Sequestosome 1 (p62) and formation of autophagosomes. Furthermore, stimuli that enhanced reactive oxygen species (ROS) promoted cytosolic translocation of S100A8 and thereby enhanced autophagy. S100A8 directly interacted with the autophagy protein Beclin1 displacing Bcl-2. These results suggest that S100A8 is a critical pro-autophagic protein that enhances cell survival and regulates chemoresistance in leukemia cells likely through disassociating the Beclin1-Bcl-2 complex.
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PMID:S100A8-targeting siRNA enhances arsenic trioxide-induced myeloid leukemia cell death by down-regulating autophagy. 2197 85

Prior studies demonstrated that resistance to the ERBB1/2 inhibitor lapatinib could be overcome by the B cell CLL/lymphoma-2 (BCL-2) family antagonist obatoclax (GX15-070). Coadministration of lapatinib with obatoclax caused synergistic cell killing by eliciting autophagic cell death that was dependent upstream on mitochondrial reactive oxygen species generation and increased p62 levels and downstream on activation of p38 mitogen-activated protein kinase and inactivation of mammalian target of rapamycin. By immunohistochemical analysis, in drug combination-treated cells, microtubule-associated protein light chain 3 (LC3) associated with mitochondrial (cytochrome c oxidase), autophagosome (p62), and autolysosome (lysosomal associated membrane protein 2) proteins. Treatment of cells with 3-methyladenine or knockdown of beclin 1 was protective, whereas chloroquine treatment had no protective effect. Expression of myeloid cell leukemia-1 (MCL-1), compared with that of BCL-2 or BCL-2-related gene long isoform, protected against drug combination lethality. Lapatinib and obatoclax-initiated autophagy depended on NOXA-mediated displacement of the prosurvival BCL-2 family member, MCL-1, from beclin 1, which was essential for the initiation of autophagy. Taken together, our data argue that lapatinib and obatoclax-induced toxic autophagy is due to impaired autophagic degradation, and this disturbance of autophagic flux leads to an accumulation of toxic proteins and loss of mitochondrial function.
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PMID:Obatoclax and lapatinib interact to induce toxic autophagy through NOXA. 2221 88

Cardiac structures and functions change with advanced age, but the underlying mechanisms are not well understood. Autophagy and apoptosis play important roles in the process of cardiac remodeling. This study was designed to explore changes in cell autophagy and apoptosis during age-related left ventricular remodeling and to determine whether the mitogen-activated protein kinase (MAPK) pathway is an underlying mechanism. Eight 5-month-old (adult group) and eight 24-month-old male C57bl/6 mice (aged group) were studied. The heart mass index, left ventricular mass index and hydroxyproline content of both groups were compared. Western Blotting was used to quantitate the protein expression of microtubule-associated protein 1 light chain 3 (LC3), Beclin-1, caspase-3, B-cell leukemia-2 (Bcl-2) and MAPKs in the left ventricles of adult and aged mice. Our results showed that the heart mass index, left ventricular mass index and hydroxyproline content in the left ventricles of the aged mice were increased significantly compared with the adult mice, indicating that left ventricular remodeling occurs with aging. The expression of LC3 and Beclin-1 in the left ventricles of aged mice were decreased significantly compared to adult mice. Meanwhile, the level of myocardial caspase-3 in adult mice remained the same in aged mice, and the level of myocardial Bcl-2 increased significantly in aged mice. There were no differences in the expression level of myocardial extracellular signal-regulated kinase 1/2 (ERK1/2), activated/phospho-ERK1/2, c-Jun N-terminal kinase 1/2 (JNK1/2) and p38 between aged and adult mice. However, the expression of myocardial activated/phospho-JNK1/2 increased significantly in aged mice, while activated/phospho-p38 decreased significantly. These findings indicate that autophagy decreases without a concurrent change in apoptosis during age-related left ventricular remodeling in mice. The MAPK pathway may be involved in the regulation of age-related left ventricular remodeling by modulating autophagy.
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PMID:Changes in cell autophagy and apoptosis during age-related left ventricular remodeling in mice and their potential mechanisms. 2320 4


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