Arsenic trioxide-induced apoptosis in U937 cells involve generation of reactive oxygen species and inhibition of Akt

Choi, Yun-Jung; Park, Jong‐Wook; Suh, Seong-Il; Mun, Kyo‐Cheol; Bae, Jae Hoon; Song, Dae‐Kyu; Kim, Sang-Pyo; Kwon, Taeg Kyu

doi:10.3892/ijo.21.3.603

Cited by 28 publications

(27 citation statements)

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“…Previous studies have demonstrated that ATO could induce apoptosis in AML cell lines (3,6,7,9,10), and that ATO-induced apoptosis is accompanied by decreased Akt activity (15)(16)(17). In the present study, we have confirmed that ATO induces apoptosis of AML HL60 cells.…”

Section: Discussionsupporting

confidence: 88%

“…ATO is also a potent inducer of apoptosis in a number of other cell types such as acute myeloid leukemia (AML) (3), multiple myeloma (4), and lymphocytic leukemia (5) cells. Several mechanisms have been proposed to explain ATO-induced apoptosis, including the down-regulation of the PML-RARα fusion protein (6), the involvement of a mitochondrial pathway (7)(8)(9), production of superoxides (8,10), triggering of apoptosis-associated factors (3), and signal transduction (4,10). However, the sensitivity of different types of cells to ATO differs, and the low sensitivity of some cells has restricted its clinical application.…”

Section: Introductionmentioning

confidence: 99%

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E3 ubiquitin ligase Cbl-b potentiates the apoptotic action of arsenic trioxide by inhibiting the PI3K/Akt pathway

Li¹,

Qu²,

Qu³

et al. 2011

Braz J Med Biol Res

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Arsenic trioxide (ATO) is a strong inducer of apoptosis in malignant hematological cells. Inducible phosphatidyl inositol 3 kinase (PI3K)-Akt activation promotes resistance to ATO. In the present study, we evaluated whether E3 ubiquitin ligase Cbl-b, a negative regulator of PI3K activation, is involved in the action of ATO. The effect of ATO on cell viability was measured by the Trypan blue exclusion assay or by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Apoptosis was determined by flow cytometry and protein expression was assayed by Western blotting. ATO decreased the viability of HL60 cells and induced cellular apoptosis, which was accompanied by transient activation of Akt. The PI3K/Akt inhibitor, LY294002, significantly increased ATO-induced apoptosis (P < 0.05). In addition, ATO up-regulated the expression of Cbl-b proteins. Furthermore, ATO inhibited cell viability with an IC 50 of 18.54 μM at 24 h in rat basophilic leukemia-2H3 cells. ATO induced cellular apoptosis with transient activation of Akt and Cbl-b was also up-regulated. Rat basophilic leukemia-2H3 cells transfected with a dominant negative (DN) Cbl-b mutation showed overexpression of Cbl-b (DN) and enhanced Akt activation. Compared with cells transfected with vector, ATO-induced apoptosis was decreased and G2/M phase cells were increased at the same concentration (P < 0.05). The PI3K/Akt inhibitor, LY294002, re-sensitized Cbl-b (DN) overexpressing cells to ATO and reversed G2/M arrest (P < 0.05). Taken together, these results suggest that Cbl-b potentiates the apoptotic action of ATO by inhibition of the PI3K/Akt pathway.

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Section: Discussionsupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

E3 ubiquitin ligase Cbl-b potentiates the apoptotic action of arsenic trioxide by inhibiting the PI3K/Akt pathway

Li¹,

Qu²,

Qu³

et al. 2011

Braz J Med Biol Res

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“…On the basis of recent studies that Akt is a client protein of the chaperone Hsp90 and is subjected to proteasomal degradation in cells exposed to 17-AAG, 33,34 we hypothesized that 17-AAG might synergize ATO action through abrogation of the Akt survival pathway, which was activated in ATO-treated cells (Figure 2g). The ability of 17-AAG to reduce Akt phosphorylation and to decrease Akt protein was first tested by Western blot analysis of protein extracts from cells treated with 17-AAG for various times.…”

Section: -Aag Abrogates Ato-induced Akt Activationmentioning

confidence: 99%

Targeting Hsp90 by 17-AAG in leukemia cells: mechanisms for synergistic and antagonistic drug combinations with arsenic trioxide and Ara-C

et al. 2006

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17-Allylamino-17-demethoxygeldanamycin (17-AAG) is a new anticancer agent currently in clinical trials. The ability of 17-AAG to abrogate the function of heat-shock protein Hsp90 and modulate cellular sensitivity to anticancer agents has prompted recent research to use this compound in drug combination therapy. Here we report that 17-AAG has striking opposite effects on the activity of arsenic trioxide (ATO) and ara-C. Combination of 17-AAG with ATO exhibited a synergistic effect in leukemia cells, whereas coincubation of 17-AAG and ara-C showed antagonistic activity. Mechanistic studies revealed that ATO exerted cytotoxic action by reactive oxygen species generation, and activated Akt survival pathway. 17-AAG abrogated Akt activation and enhanced the activity of ATO. In contrast, treatment of leukemia cells with 17-AAG caused a G1 arrest, a decrease in DNA synthesis and reduced ara-C incorporation into DNA, leading to antagonism. The ability of 17-AAG to enhance the antileukemia activity of ATO was further demonstrated in primary leukemia cells isolated from patients with acute myeloid leukemia and chronic lymphocytic leukemia, including cells from refractory patients. Our data suggest that combination of 17-AAG and ATO may be an effective therapeutic regimen. Caution should be exercised in using 17-AAG together with ara-C, as their combination effects are schedule dependent.

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“…Moreover, we noticed that AdcTm C32/35S alone could induce apoptosis in HepG 2 cells. Since it had been well established that cyto c release was a crucial event in As 2 O 3 -induced apoptosis in APL cell lines [27,28], we measured cyto c release and found that TRX1 could prevent cyto c release induced by As 2 O 3 , whereas Tm C32/35S lost its protective effect. Actually, the mutant form of TRX1 enhanced the cyto c release from mitochondria ( Figure 3C).…”

Section: Trx1 Over-expression Inhibits As 2 O 3 -Induced Apoptosis Inmentioning

confidence: 99%

Redox status of thioredoxin-1 (TRX1) determines the sensitivity of human liver carcinoma cells (HepG2) to arsenic trioxide-induced cell death

et al. 2007

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Intracellular redox homeostasis plays a critical role in determining tumor cells' sensitivity to drug-induced apoptosis. Here we investigated the role of thioredoxin-1 (TRX1), a key component of redox regulation, in arsenic trioxide (As 2 O 3 )-induced apoptosis. Over-expression of wild-type TRX1 in HepG 2 cells led to the inhibition of As 2 O 3 -induced cytochrome c (cyto c) release, caspase activation and apoptosis, and down-regulation of TRX1 expression by RNAi sensitized HepG 2 cells to As 2 O 3 -induced apoptosis. Interestingly, mutation of the active site of TRX1 from Cys 32/35 to Ser 32/35 converted this molecule from an apoptotic protector to an apoptotic promoter. In an effort to understand the mechanisms of this conversion, we used isolated mitochondria from mouse liver and found that recombinant wild-type TRX1 could protect mitochondria from the apoptotic changes. In contrast, the mutant form of TRX1 alone elicited mitochondria-related apoptotic changes, including the mitochondrial permeability transition pore (mPTP) opening, loss of mitochondrial membrane potential, and cyto c release from mitochondria. These apoptotic effects were inhibited by cyclosporine A (CsA), indicating that mutant TRX1 targeted to mPTP. Alteration of TRX1 from its reduced form to oxidized form in vivo by 2,4-dinitrochlorobenzene (DNCB), a specific inhibitor of TRX reductase, also sensitized HepG 2 cells to As 2 O 3 -induced apoptosis. These data suggest that TRX1 plays a central role in regulating apoptosis by blocking cyto c release, and inactivation of TRX1 by either mutation or oxidization of the active site cysteines may sensitize tumor cells to As 2 O 3 -induced apoptosis.

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Arsenic trioxide-induced apoptosis in U937 cells involve generation of reactive oxygen species and inhibition of Akt

Cited by 28 publications

References 0 publications

E3 ubiquitin ligase Cbl-b potentiates the apoptotic action of arsenic trioxide by inhibiting the PI3K/Akt pathway

E3 ubiquitin ligase Cbl-b potentiates the apoptotic action of arsenic trioxide by inhibiting the PI3K/Akt pathway

Targeting Hsp90 by 17-AAG in leukemia cells: mechanisms for synergistic and antagonistic drug combinations with arsenic trioxide and Ara-C

Redox status of thioredoxin-1 (TRX1) determines the sensitivity of human liver carcinoma cells (HepG2) to arsenic trioxide-induced cell death

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