Albendazole-Induced SIRT3 Upregulation Protects Human Leukemia K562 Cells from the Cytotoxicity of MCL1 Suppression

Previous studies have shown that MCL1 stabilization confers cancer cells resistance to microtubule targeting agents (MTAs) and functionally extends the lifespan of MTA-triggered mitotically arrested cells. Albendazole (ABZ), a benzimidazole anthelmintic, shows microtubule-destabilizing activity and has been repositioned for cancer therapies. To clarify the role of MCL1 in ABZ-induced apoptosis, we investigated the cytotoxicity of ABZ on human leukemia K562 cells. Treatment with ABZ for 24 h did not appreciably induce apoptosis or mitochondrial depolarization in K562 cells, though it caused the mitotic arrest of K562 cells. ABZ-evoked p38 MAPK activation concurrently suppressed Sp1-mediated MCL1 expression and increased SIRT3 mRNA stability and protein expression. ABZ and A-1210477 (an MCL1 inhibitor) enhanced the cytotoxicity of ABT-263 (a BCL2/BCL2L1 inhibitor) to their effect on MCL1 suppression. Unlike ABZ, A-1210477 did not affect SIRT3 expression and reduced the survival of K562 cells. Overexpression of SIRT3 attenuated the A-1210477 cytotoxicity on K562 cells. ABZ treatment elicited marked apoptosis and ΔΨm loss in ABT-263-resistant K562 (K562/R) cells, but did not alter SIRT3 expression. Ectopic expression of SIRT3 alleviated the cytotoxicity of ABZ on K562/R cells. Collectively, our data demonstrate that ABZ-induced SIRT3 upregulation delays the apoptosis-inducing effect of MCL1 suppression on apoptosis induction in K562 cells.

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Mitomycin Induced Apoptosis in Human Leukemia K562 Cells

Advanced Materials Research ◽

10.4028/www.scientific.net/amr.599.71 ◽

2012 ◽

Vol 599 ◽

pp. 71-75

Author(s):

Shu Li Shao ◽

Bin Zhao ◽

Wei Wei Zhang ◽

Wei Zhao ◽

Guang Hui Wu ◽

...

Keyword(s):

Flow Cytometry ◽

Gel Electrophoresis ◽

Light Microscope ◽

Previous Experiment ◽

K562 Cells ◽

S Phase ◽

Fluorescence Microscope ◽

Human Leukemia ◽

Induced Apoptosis ◽

Human Leukemia K562 Cells

Objective: The research aimed to study the effects of mitomycin on human leukemic K562 cells, and to explore the mechanism of mitomycin induced apoptosis．In order to provide previous experiment basis for mitomycin applying clinical treatments Methods: The multiplication and apoptosis status of K562 cells treated different time by different concentration mitomycin were observed by light microscope, fluorescence microscope, TEM, agrose gel electrophoresis of DNA and flow cytometry. Results: The results showed that mitomycin could induce K562 cells apoptosis, and the best concentration was 12.5μg/ml for 48 h. The optimal concentration of apoptosis induced by apoptosis rate is （28.8±1.04）% （P<0.01）. Mitomycin could affect the S phase among cellular multiplication, cell could be blocked by mitomycin and then apoptosis in this phase. Conclusions: Mitomycin can induce the apoptosis of human leukemic K562 cells. It is of great significance to guide clinical medication.

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CGP57148B (STI-571) induces differentiation and apoptosis and sensitizes Bcr-Abl–positive human leukemia cells to apoptosis due to antileukemic drugs

Blood ◽

10.1182/blood.v96.6.2246 ◽

2000 ◽

Vol 96 (6) ◽

pp. 2246-2253 ◽

Cited By ~ 192

Author(s):

Guofu Fang ◽

Caryn Naekyung Kim ◽

Charles L. Perkins ◽

Nimmanapalli Ramadevi ◽

Elliott Winton ◽

...

Keyword(s):

Myeloid Leukemia ◽

Fas Ligand ◽

Ectopic Expression ◽

K562 Cells ◽

Parp Cleavage ◽

Human Leukemia ◽

Sti 571 ◽

Tnf Α ◽

Cyt C ◽

Induced Apoptosis

Abstract The differentiation and apoptosis-sensitizing effects of the Bcr-Abl–specific tyrosine kinase inhibitor CGP57148B, also known as STI-571, were determined in human Bcr-Abl–positive HL-60/Bcr-Abl and K562 cells. First, the results demonstrate that the ectopic expression of the p185 Bcr-Abl fusion protein induced hemoglobin in the acute myeloid leukemia (AML) HL-60 cells. Exposure to low-dose cytosine arabinoside (Ara-C; 10 nmol/L) increased hemoglobin levels in HL-60/Bcr-Abl and in the chronic myeloid leukemia (CML) blast crisis K562 cells, which express the p210 Bcr-Abl protein. As compared with HL-60/neo, HL-60/Bcr-Abl and K562 cells were resistant to apoptosis induced by Ara-C, doxorubicin, or tumor necrosis factor-α (TNF-α), which was associated with reduced processing of caspase-8 and Bid protein and decreased cytosolic accumulation of cytochrome c (cyt c). Exposure to CGP57148B alone increased hemoglobin levels and CD11b expression and induced apoptosis of HL-60/Bcr-Abl and K562 cells. CGP57148B treatment down-regulated antiapoptotic XIAP, cIAP1, and Bcl-xL, without affecting Bcl-2, Bax, Apaf-1, Fas (CD95), Fas ligand, Abl, and Bcr-Abl levels. CGP57148B also inhibited constitutively active Akt kinase and NFκB in Bcr-Abl–positive cells. Attenuation of NFκB activity by ectopic expression of transdominant repressor of IκB sensitized HL-60/Bcr-Abl and K562 cells to TNF-α but not to apoptosis induced by Ara-C or doxorubicin. Importantly, cotreatment with CGP57148B significantly increased Ara-C– or doxorubicin-induced apoptosis of HL-60/Bcr-Abl and K562 cells. This was associated with greater cytosolic accumulation of cyt c and PARP cleavage activity of caspase-3. These in vitro data indicate that combinations of CGP57148B and antileukemic drugs such as Ara-C may have improved in vivo efficacy against Bcr-Abl–positive acute leukemia.

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Low-dose radiation-induced apoptosis in human leukemia K562 cells through mitochondrial pathways

Molecular Medicine Reports ◽

10.3892/mmr.2014.2381 ◽

2014 ◽

Vol 10 (3) ◽

pp. 1569-1575 ◽

Cited By ~ 3

Author(s):

YONG XIN ◽

HAI-BIN ZHANG ◽

TIAN-YOU TANG ◽

GUI-HONG LIU ◽

JIAN-SHE WANG ◽

...

Keyword(s):

Low Dose ◽

K562 Cells ◽

Human Leukemia ◽

Low Dose Radiation ◽

Radiation Induced ◽

Induced Apoptosis ◽

Dose Radiation ◽

Human Leukemia K562 Cells

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CGP57148B (STI-571) induces differentiation and apoptosis and sensitizes Bcr-Abl–positive human leukemia cells to apoptosis due to antileukemic drugs

Blood ◽

10.1182/blood.v96.6.2246.h8002246_2246_2253 ◽

2000 ◽

Vol 96 (6) ◽

pp. 2246-2253 ◽

Cited By ~ 10

Author(s):

Guofu Fang ◽

Caryn Naekyung Kim ◽

Charles L. Perkins ◽

Nimmanapalli Ramadevi ◽

Elliott Winton ◽

...

Keyword(s):

Myeloid Leukemia ◽

Fas Ligand ◽

Ectopic Expression ◽

K562 Cells ◽

Parp Cleavage ◽

Human Leukemia ◽

Sti 571 ◽

Tnf Α ◽

Cyt C ◽

Induced Apoptosis

The differentiation and apoptosis-sensitizing effects of the Bcr-Abl–specific tyrosine kinase inhibitor CGP57148B, also known as STI-571, were determined in human Bcr-Abl–positive HL-60/Bcr-Abl and K562 cells. First, the results demonstrate that the ectopic expression of the p185 Bcr-Abl fusion protein induced hemoglobin in the acute myeloid leukemia (AML) HL-60 cells. Exposure to low-dose cytosine arabinoside (Ara-C; 10 nmol/L) increased hemoglobin levels in HL-60/Bcr-Abl and in the chronic myeloid leukemia (CML) blast crisis K562 cells, which express the p210 Bcr-Abl protein. As compared with HL-60/neo, HL-60/Bcr-Abl and K562 cells were resistant to apoptosis induced by Ara-C, doxorubicin, or tumor necrosis factor-α (TNF-α), which was associated with reduced processing of caspase-8 and Bid protein and decreased cytosolic accumulation of cytochrome c (cyt c). Exposure to CGP57148B alone increased hemoglobin levels and CD11b expression and induced apoptosis of HL-60/Bcr-Abl and K562 cells. CGP57148B treatment down-regulated antiapoptotic XIAP, cIAP1, and Bcl-xL, without affecting Bcl-2, Bax, Apaf-1, Fas (CD95), Fas ligand, Abl, and Bcr-Abl levels. CGP57148B also inhibited constitutively active Akt kinase and NFκB in Bcr-Abl–positive cells. Attenuation of NFκB activity by ectopic expression of transdominant repressor of IκB sensitized HL-60/Bcr-Abl and K562 cells to TNF-α but not to apoptosis induced by Ara-C or doxorubicin. Importantly, cotreatment with CGP57148B significantly increased Ara-C– or doxorubicin-induced apoptosis of HL-60/Bcr-Abl and K562 cells. This was associated with greater cytosolic accumulation of cyt c and PARP cleavage activity of caspase-3. These in vitro data indicate that combinations of CGP57148B and antileukemic drugs such as Ara-C may have improved in vivo efficacy against Bcr-Abl–positive acute leukemia.

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