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)

Interactions between the histone deacetylase (HDAC) inhibitors suberanoylanilide hydroxamic acid (SAHA) and sodium butyrate (SB) and the heat shock protein (Hsp) 90 antagonist 17-allylamino 17-demethoxygeldanamycin (17-AAG) have been examined in Bcr-Abl(+) human leukemia cells (K562 and LAMA84), including those sensitive and resistant to STI571 (imatinib mesylate). Cotreatment with 17-AAG and SAHA or SB synergistically induced mitochondrial dysfunction (cytochrome c and apoptosis-inducing factor release), caspase-3 and -8 activation, apoptosis, and growth inhibition. Similar effects were observed in LAMA84 cells and K562 cells resistant to STI571, as well as in CD34(+) cells isolated from the bone marrows of three patients with chronic myelogenous leukemia. These events were associated with increased binding of Bcr-Abl, Raf-1, and Akt to Hsp70, and inactivation of extracellular signal-regulated kinase 1/2 and Akt. In addition, 17-AAG/SAHA abrogated the DNA binding and the transcriptional activities of signal transducer and activator of transcription (STAT) 5 in K562 cells, including those ectopically expressing a constitutively active STAT5A construct. Cotreatment with 17-AAG and SAHA also induced down-regulation of Mcl-1, Bcl-xL, and B-Raf; up-regulation of Bak; cleavage of 14-3-3 proteins; and a profound conformational change in Bax accompanied by translocation to the membrane fraction. Moreover, ectopic expression of Bcl-2 attenuated cell death induced by this regimen, implicating mitochondrial injury in the lethality observed. Together, these findings raise the possibility that combining HDAC inhibitors with the Hsp90 antagonist 17-AAG may represent a novel strategy against Bcr-Abl(+) leukemias, including those resistant to STI571.
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PMID:Cotreatment with suberanoylanilide hydroxamic acid and 17-allylamino 17-demethoxygeldanamycin synergistically induces apoptosis in Bcr-Abl+ Cells sensitive and resistant to STI571 (imatinib mesylate) in association with down-regulation of Bcr-Abl, abrogation of signal transducer and activator of transcription 5 activity, and Bax conformational change. 1562 78

Aberrant overexpression of antiapoptotic members of the Bcl-2 protein family, including Bcl-2 and Bcl-X(L), contributes to malignant transformation and subsequent resistance to traditional chemotherapeutics. Thus, these proteins represent attractive targets for novel anticancer agents. The small molecule, gossypol, was initially investigated as a contraceptive agent, but subsequently has been shown to possess anticancer properties in vitro and in vivo. Recently gossypol has been found to bind to Bcl-X(L) and, with less affinity, to Bcl-2. Here we investigate the ability of the (-) enantiomer of gossypol, (-)-gossypol, to overcome the apoptosis resistance conferred by Bcl-2 or Bcl-X(L) overexpression in Jurkat T leukemia cells. (-)-Gossypol potently induced cell death in Jurkat cells overexpressing Bcl-2 (IC50, 18.1+/-2.6 micromol/L) or Bcl-X(L) (IC50, 22.9+/-3.7 micromol/L). Vector-transfected control cells were also potently killed by (-)-gossypol (IC50, 7.0+/-2.7 micromol/L). By contrast, the chemotherapy drug etoposide only induced efficient killing of vector-transfected cells (IC50, 9.6+/-2.3 micromol/L). Additionally, (-)-gossypol was more efficient than etoposide at inducing caspase-3 activation and phosphatidylserine externalization in the setting of Bcl-2 or Bcl-X(L) overexpression. (-)-Gossypol-induced apoptosis was associated with Bak activation and release of cytochrome c from mitochondria, suggesting a mitochondrial-mediated apoptotic mechanism. Moreover, (-)-gossypol treatment of isolated mitochondria purified from Bcl-2-overexpressing cells also resulted in cytochrome c release, indicating a possible direct action on Bcl-2 present in the mitochondrial outer membrane. Taken together, these results suggest that (-)-gossypol is a potent and novel therapeutic able to overcome apoptosis resistance by specifically targeting the activity of antiapoptotic Bcl-2 family members. (-)-Gossypol may be a promising new agent to treat malignancies that are resistant to conventional therapies.
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PMID:(-)-Gossypol acts directly on the mitochondria to overcome Bcl-2- and Bcl-X(L)-mediated apoptosis resistance. 1565 50

Interactions between histone deacetylase inhibitors (HDACIs) and the alkyl-lysophospholipid perifosine were examined in human leukemia cells. Coadministration of sodium butyrate, suberoylanilide hydroxamic acid (SAHA), or trichostatin with perifosine synergistically induced mitochondrial dysfunction (cytochrome c and apoptosis-inducing factor release), caspase-3 and -8 activation, apoptosis, and a marked decrease in cell growth in U937 as well as HL-60 and Jurkat leukemia cells. These events were associated with inactivation of extracellular signal-regulated kinase (ERK) 1/2 and Akt, p46 c-jun-NH2-kinase (JNK) activation, and a pronounced increase in generation of ceramide and reactive oxygen species (ROS). They were also associated with up-regulation of Bak and a marked conformational change in Bax accompanied by membrane translocation. Ectopic expression of Bcl-2 delayed but was ultimately ineffective in preventing perifosine/HDACI-mediated apoptosis. Enforced expression of constitutively active mitogen-activated protein kinase kinase (MEK) 1 or myristoylated Akt blocked HDACI/perifosine-mediated ceramide production and cell death, suggesting that MEK/ERK and Akt inactivation play a primary role in these phenomena. However, inhibition of JNK activation (e.g., by the JNK inhibitor SP600125) did not attenuate sodium butyrate/perifosine-induced apoptosis. In addition, the free radical scavenger N-acetyl-L-cysteine attenuated ROS generation and apoptosis mediated by combined treatment. Finally, the acidic sphingomyelinase inhibitor desipramine attenuated HDACI/perifosine-mediated ceramide and ROS production as well as cell death. Together, these findings indicate that coadministration of HDACIs with perifosine in human leukemia cells leads to Akt and MEK/ERK disruption, a marked increase in ceramide and ROS production, and a striking increase in mitochondrial injury and apoptosis. They also raise the possibility that combining these agents may represent a novel antileukemic strategy.
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PMID:Coadministration of histone deacetylase inhibitors and perifosine synergistically induces apoptosis in human leukemia cells through Akt and ERK1/2 inactivation and the generation of ceramide and reactive oxygen species. 1578 58

Protein kinases are critically involved in signaling pathways that regulate cell growth, differentiation, activation, and survival. Lck, a member of the Src family of protein tyrosine kinases, plays a key role in T-lymphocyte activation and differentiation. However, under certain conditions Lck is also involved in the induction of apoptosis. In this issue of Oncogene, Samraj et al. used the Lck-defective JCaM1.6 cell line to demonstrate the critical role of Lck in the apoptotic response of T-cell leukemia cells to several chemotherapeutic drugs. They further showed that Lck controls the mitochondrial death pathway by regulating proapoptotic Bak expression. This chemosensitizing effect of Lck is independent of T-cell receptor signaling and does not require the kinase activity of Lck. These findings demonstrate that Lck might be part of two independent signaling pathways leading to either cell proliferation or apoptosis, and reveal a hitherto unrecognized link between Lck, Bak, and chemosensitivity of human leukemic cells.
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PMID:A novel link between Lck, Bak expression and chemosensitivity. 1611 73

The interaction between retinoids and transforming growth factor-beta1 (TGF-beta1) leading to regulation of proliferation, differentiation and apoptosis is not still fully understood. In this study, we demonstrated that a combination treatment with all-trans retinoic acid (ATRA) and TGF-beta1 led to the enhancement of ATRA-induced suppression of cell proliferation, which is accompanied by inhibition of ATRA-induced apoptosis in human leukemia HL-60 cells. This effect was preceded by the arrest of cells in G0/G1 cell cycle phase linked with pRb protein dephosphorylation, continuous accumulation of p21 and transiently increased level of p27, inhibitors of cyclin-dependent kinases. Inhibition of ATRA-induced apoptosis by TGF-beta1 was associated with an increased level of Mcl-1 protein, an anti-apoptotic member of Bcl-2 family, but not with inhibition of mitochondrial membrane depolarization. Levels of other Bcl-2 family proteins (Bcl-2, Bcl-X(L), Bad, Bak, Bax) were unaffected by simultaneous ATRA and TGF-beta1 treatment, when compared to ATRA alone. Upregulation of c-FLIP(L) protein, an inhibitor of apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), correspond with inhibition of ATRA-induced (autocrine TRAIL-mediated) caspase-8 activation and apoptosis. These results suggest that apoptosis inhibition associated with proliferation block could depend on modulation of the TRAIL apoptotic pathway and regulation of the Mcl-1 protein level. In summary, we demonstrate that the balance of processes leading to regulation of proliferation and differentiation of myeloid cells can modulate cell sensitivity to apoptosis-inducing stimuli.
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PMID:Transforming growth factor-beta1 inhibits all-trans retinoic acid-induced apoptosis. 1624 18

In the present study, we aimed to elucidate the mechanism responsible for the interactive effects of histone deacetylase (HDAC) inhibitors [suberoylanilide hydroxamic acid (SAHA), MS-275, m-carboxycinnamic acid bishydroxamide (CBHA), and trichostatin-A (TSA)] and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) on apoptosis in leukemia cells. HDAC inhibitors enhance the apoptosis-inducing potential of TRAIL in leukemia cells (HL60, Jurkat, K562, and U937) through multiple mechanisms; up-regulation of DR4, DR5, Bak, Bax, Bim, Noxa and PUMA, down-regulation of IAPs, Mcl-1, Bcl-2, Bcl-XL and cFLIP, release of mitochondrial proteins (cytochrome c, Smac/DIABLO and Omi/Htr2) to the cytosol, induction of p21WAF1/CIP1 and p27KIP1, activation of caspase-3 and cleavage of poly(ADP-ribose) polymerase (PARP). The sequential treatment of cells with HDAC inhibitors followed by TRAIL was more effective in inducing apoptosis than the concurrent treatment or single agent alone. The up-regulation of death receptors and inhibition of cFLIP by HDAC inhibitors will increase the ability of TRAIL to induce apoptosis, due to enhance activation of caspase-8, cleavage of Bid, and release of mitochondrial proteins to the cytosol, and subsequent activation of caspase-9 and caspase-3. Thus, the combination of HDAC inhibitors and TRAIL can be used as a new therapeutic approach for the treatment of leukemia.
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PMID:Interactive effects of histone deacetylase inhibitors and TRAIL on apoptosis in human leukemia cells: involvement of both death receptor and mitochondrial pathways. 1627 96

The WT1 gene is overexpressed in human primary leukemia and a wide variety of solid cancers. The WT1 gene is alternatively spliced at two sites, yielding four isoforms: 17AA(+)KTS(+), 17AA(+)KTS(-), 17AA(-)KTS(+), and 17AA(-)KTS(-). Here, we showed that 17AA(+)WT1-specific siRNA induced apoptosis in three WT1-expressing leukemia cell lines (K562, HL-60, and Kasumi-1), but not in WT1-non-expressing lymphoma cell line (Daudi). 17AA(+)WT1-specific siRNA activated caspase-3 and -9 in the intrinsic apoptosis pathway but not caspase-8 in the extrinsic one. On the other hand, 17AA(-)WT1-specific siRNA did not induce apoptosis in the three WT1-expressing cell lines. The apoptosis was associated with activation of proapoptotic Bax, which was activated upstream of the mitochondria. Constitutive expression of 17AA(+)WT1 isoforms inhibited apoptosis of K562 leukemia cells induced by apoptosis-inducing agents, etoposide and doxorubicin, through the protection of mitochondrial membrane damages, and DNA-binding zinc-finger region of 17AA(+)WT1 isoform was essential for the antiapoptotic functions. We further studied the gene(s) whose expression was altered by the expression of 17AA(+)WT1 isoforms and showed that the expression of proapoptotic Bak was decreased by the expression of 17AA(+)KTS(-)WT1 isoform. Taken together, these results indicated that 17AA(+)WT1 isoforms played antiapoptotic roles at some points upstream of the mitochondria in the intrinsic apoptosis pathway.
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PMID:Antiapoptotic function of 17AA(+)WT1 (Wilms' tumor gene) isoforms on the intrinsic apoptosis pathway. 1651 14

Apoptosis has become recognized as a crucial mechanism involved in a wide range of physiological and pathological processes. Following an initial pro-apoptotic signal, controlling phases allow the cell to reinforce or downgrade signals leading to the irrevocable entry into apoptosis. Bak (Bcl-2-antagonist killer) is a mitochondrial pore-forming pro-apoptotic effector inhibited through titration by the anti-apoptotic protein Mcl-1 (Myeloid cell leukemia-1). Viruses have taken advantage of proteasome-dependent degradation of Bak as a mechanism to prevent apoptosis in infected cells. It is not clear however whether regulation of Bak protein level is involved in other physiological processes. In this report, we show that Mcl-1 level is paralleled by Bak while a Mcl-1 non-interacting mutant of Bak does not accumulate in cells. This mechanism is proteasome independent. Following serum withdrawal, Bak accumulation becomes independent of Mcl-1 level and cells are sensitized to pro-apoptotic stimuli. Based on these results, we propose that regulation of Mcl-1-Bak steochiometry is a control mechanism used as a checkpoint to prevent or allow entry into apoptosis.
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PMID:Accumulation of the pro-apoptotic factor Bak is controlled by antagonist factor Mcl-1 availability. 1654 91

AML1-ETO, a leukemia-associated fusion protein generated by the frequently occurred chromosome translocation t(8;21) in acute myeloid leukemia, was shown to exert dichotomous functions in leukemic cells, that is, growth arrest versus differentiation block. By the analysis of oligonucleotide microarray, AML1-ETO was shown to modulate the expressions of an impressive array of pro- and anti-apoptotic genes. Here, we investigate potential effects of the ecdysone inducible AML1-ETO expression on apoptosis of leukemic U937 cell line. We show that AML1-ETO significantly stabilizes death receptor Fas protein and increases proapoptotic Bak in addition to reducing Bcl-2 expression. Accordingly, inducible AML1-ETO expression is followed by apoptosis to a lower degree. Especially, AML1-ETO endows leukemic cells with the susceptibility to anti-Fas agonist antibody, ultraviolet light and camptothecin analog NSC606985-induced apoptosis with increased activation of caspase-3/8. Considering that apoptosis-enhancing effect of AML1-ETO would not be favorable to the leukemogenesis harboring the t(8;21) translocation, it must be overcome to fulfill their leukemogenic potential. Complementary to this prediction is that two AML1-ETO-carrying leukemic cells, Kasumi-1 and SKNO-1, present similar sensitivity to apoptosis induction with AML1-ETO-negative leukemic cells. Therefore, genetic and/or epigenetic screenings of apoptosis-related genes modulated by AML1-ETO deserve to be explored for understanding the mechanisms of AML1-ETO-induced leukemogenesis.
Leukemia 2006 Jun
PMID:Inducible expression of AML1-ETO fusion protein endows leukemic cells with susceptibility to extrinsic and intrinsic apoptosis. 1659 1

The constitutive androstane receptor (CAR) modulates xeno- and endobiotic hepatotoxicity by regulating detoxification pathways. Whether activation of CAR may also protect against liver injury by directly blocking apoptosis is unknown. To address this question, CAR wild-type (CAR+/+) and CAR knockout (CAR-/-) mice were treated with the CAR agonist 1,4-bis[2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP) and then with the Fas agonist Jo2 or with concanavalin A (ConA). Following the administration of Jo2, hepatocyte apoptosis, liver injury, and animal fatalities were abated in TCPOBOP-treated CAR+/+ but not in CAR-/- mice. Likewise, acute and chronic ConA-mediated liver injury and fibrosis were also reduced in wild-type versus CAR(-/-) TCPOBOP-treated mice. The proapoptotic proteins Bak (Bcl-2 antagonistic killer) and Bax (Bcl-2-associated X protein) were depleted in livers from TCPOBOP-treated CAR+/+ mice. In contrast, mRNA expression of the antiapoptotic effector myeloid cell leukemia factor-1 (Mcl-1) was increased fourfold. Mcl-1 promoter activity was increased by transfection with CAR and administration of TCPOBOP in hepatoma cells, consistent with a direct CAR effect on Mcl-1 transcription. Indeed, site-directed mutagenesis of a putative CAR consensus binding sequence on the Mcl-1 promoter decreased Mcl-1 promoter activity. Mcl-1 transgenic animals demonstrated little to no acute liver injury after administration of Jo2, signifying Mcl-1 cytoprotection. In conclusion, these observations support a prominent role for CAR cytoprotection against Fas-mediated hepatocyte injury via a mechanism involving upregulation of Mcl-1 and, likely, downregulation of Bax and Bak.
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PMID:Constitutive androstane receptor (CAR) ligand, TCPOBOP, attenuates Fas-induced murine liver injury by altering Bcl-2 proteins. 1679 68


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