Arsenic Trioxide and Melarsoprol Induce Programmed Cell Death in Myeloid Leukemia Cell Lines and Function in a PML and PML-RAR Independent Manner

Blood ◽  
1998 ◽  
Vol 92 (5) ◽  
pp. 1497-1504 ◽  
Author(s):  
Zhu-Gang Wang ◽  
Roberta Rivi ◽  
Laurent Delva ◽  
Andrea König ◽  
David A. Scheinberg ◽  
...  
Keyword(s):  
Cell Line ◽  
Arsenic Trioxide ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Leukemia Cell ◽  
Nuclear Bodies ◽  
Independent Manner ◽  
Leukemia Cell Lines ◽  
Induced Apoptosis ◽  
Myeloid Leukemia Cell

Inorganic arsenic trioxide (As2O3) and the organic arsenical, melarsoprol, were recently shown to inhibit growth and induce apoptosis in NB4 acute promyelocytic leukemia (APL) and chronic B-cell leukemia cell lines, respectively. As2O3 has been proposed to principally target PML and PML-RAR proteins in APL cells. We investigated the activity of As2O3 and melarsoprol in a broader context encompassing various myeloid leukemia cell lines, including the APL cell line NB4-306 (a retinoic acid–resistant cell line derived from NB4 that no longer expresses the intact PML-RAR fusion protein), HL60, KG-1, and the myelomonocytic cell line U937. To examine the role of PML in mediating arsenical activity, we also tested these agents using murine embryonic fibroblasts (MEFs) and bone marrow (BM) progenitors in which the PML gene had been inactivated by homologous recombination. Unexpectedly, we found that both compounds inhibited cell growth, induced apoptosis, and downregulated bcl-2 protein in all cell lines tested. Melarsoprol was more potent than As2O3 at equimolar concentrations ranging from 10−7 to 10−5 mol/L. As2O3 relocalized PML and PML-RAR onto nuclear bodies, which was followed by PML degradation in NB4 as well as in HL60 and U937 cell lines. Although melarsoprol was more potent in inhibiting growth and inducing apoptosis, it did not affect PML and/or PML-RAR nuclear localization. Moreover, both As2O3 and melarsoprol comparably inhibited growth and induced apoptosis of PML+/+ and PML−/− MEFs, and inhibited colony-forming unit erythroid (CFU-E) and CFU granulocyte-monocyte formation in BM cultures of PML+/+ and PML−/− progenitors. Together, these results show that As2O3 and melarsoprol inhibit growth and induce apoptosis independent of both PML and PML-RAR expression in a variety of myeloid leukemia cell lines, and suggest that these agents may be more broadly used for treatment of leukemias other than APL. © 1998 by The American Society of Hematology.

Arsenic Trioxide and Melarsoprol Induce Programmed Cell Death in Myeloid Leukemia Cell Lines and Function in a PML and PML-RAR Independent Manner

Blood ◽  
1998 ◽  
Vol 92 (5) ◽  
pp. 1497-1504 ◽  
Author(s):  
Zhu-Gang Wang ◽  
Roberta Rivi ◽  
Laurent Delva ◽  
Andrea König ◽  
David A. Scheinberg ◽  
...  
Keyword(s):  
Cell Line ◽  
Arsenic Trioxide ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Leukemia Cell ◽  
Nuclear Bodies ◽  
Independent Manner ◽  
Leukemia Cell Lines ◽  
Induced Apoptosis ◽  
Myeloid Leukemia Cell

Abstract Inorganic arsenic trioxide (As2O3) and the organic arsenical, melarsoprol, were recently shown to inhibit growth and induce apoptosis in NB4 acute promyelocytic leukemia (APL) and chronic B-cell leukemia cell lines, respectively. As2O3 has been proposed to principally target PML and PML-RAR proteins in APL cells. We investigated the activity of As2O3 and melarsoprol in a broader context encompassing various myeloid leukemia cell lines, including the APL cell line NB4-306 (a retinoic acid–resistant cell line derived from NB4 that no longer expresses the intact PML-RAR fusion protein), HL60, KG-1, and the myelomonocytic cell line U937. To examine the role of PML in mediating arsenical activity, we also tested these agents using murine embryonic fibroblasts (MEFs) and bone marrow (BM) progenitors in which the PML gene had been inactivated by homologous recombination. Unexpectedly, we found that both compounds inhibited cell growth, induced apoptosis, and downregulated bcl-2 protein in all cell lines tested. Melarsoprol was more potent than As2O3 at equimolar concentrations ranging from 10−7 to 10−5 mol/L. As2O3 relocalized PML and PML-RAR onto nuclear bodies, which was followed by PML degradation in NB4 as well as in HL60 and U937 cell lines. Although melarsoprol was more potent in inhibiting growth and inducing apoptosis, it did not affect PML and/or PML-RAR nuclear localization. Moreover, both As2O3 and melarsoprol comparably inhibited growth and induced apoptosis of PML+/+ and PML−/− MEFs, and inhibited colony-forming unit erythroid (CFU-E) and CFU granulocyte-monocyte formation in BM cultures of PML+/+ and PML−/− progenitors. Together, these results show that As2O3 and melarsoprol inhibit growth and induce apoptosis independent of both PML and PML-RAR expression in a variety of myeloid leukemia cell lines, and suggest that these agents may be more broadly used for treatment of leukemias other than APL. © 1998 by The American Society of Hematology.

Sodium Salicylate Activates Caspases and Induces Apoptosis of Myeloid Leukemia Cell Lines

Blood ◽  
1999 ◽  
Vol 93 (7) ◽  
pp. 2386-2394 ◽  
Author(s):  
Lidija Klampfer ◽  
Jörg Cammenga ◽  
Hans-Georg Wisniewski ◽  
Stephen D. Nimer
Keyword(s):  
Cell Death ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Sodium Salicylate ◽  
Leukemia Cell ◽  
Human Leukemia ◽  
Leukemia Cell Lines ◽  
Induced Apoptosis ◽  
Chemopreventive Activity ◽  
Myeloid Leukemia Cell

Abstract Nonsteroidal antiinflammatory agents (NSAIA) have been shown to exert potent chemopreventive activity against colon, lung, and breast cancers. In this study, we show that at pharmacological concentrations (1 to 3 mmol/L) sodium salicylate (Na-Sal) can potently induce programmed cell death in several human myeloid leukemia cell lines, including TF-1, U937, CMK-1, HL-60, and Mo7e. TF-1 cells undergo rapid apoptosis on treatment with Na-Sal, as indicated by increased annexin V binding capacity, cpp-32 (caspase-3) activation, and cleavage of poly (ADP-ribose) polymerase (PARP) and gelsolin. In addition, the expression of MCL-1, an antiapoptotic member of the BCL-2 family, is downregulated during Na-Sal–induced cell death, whereas the expression of BCL-2, BAX, and BCL-XL is unchanged. Z-VAD, a potent caspase inhibitor, prevents the cleavage of PARP and gelsolin and rescues cells from Na-Sal–induced apoptosis. In addition, we show that Na-Sal accelerates growth factor withdrawal-induced apoptosis and synergizes with daunorubicin to induce apoptosis in TF-1 cells. Thus, our data provide a potential mechanism for the chemopreventive activity of NSAIA and suggest that salicylates may have therapeutic potential for the treatment of human leukemia.

Wilm's Tumor 1 Protein Confers TRAIL Resistance in Myeloid Leukemia Cells Through Bcl-Xl

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2557-2557
Author(s):  
Hima Bansal ◽  
Theresea Siefert ◽  
Divya Chakravarthy ◽  
Manjeet Rao ◽  
Gail E Tomlinson ◽  
...  
Keyword(s):  
Cell Lines ◽  
Myeloid Leukemia ◽  
Leukemia Cell ◽  
Leukemia Cells ◽  
Hsp90 Inhibitors ◽  
Leukemia Cell Lines ◽  
Myeloid Leukemias ◽  
Trail Resistance ◽  
Induced Apoptosis ◽  
Myeloid Leukemia Cell

Abstract Abstract 2557 INTRODUCTION: Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is an attractive therapeutic agent because of its selective potential to induce apoptosis in variety of tumors but not in normal cells. However, many cancers including myeloid leukemias exhibit resistance to TRAIL and the underlying mechanisms are not fully understood. Wilms' tumor 1 (WT1) protein is an aberrantly overexpressed protein that is associated with leukemia blast survival, chemoresistance and shortened disease-free survival in acute myeloid leukemia (AML). Here, we report a previously unknown protective role of WT1 against TRAIL-induced apoptosis in leukemia cells. METHODS: Various myeloid leukemia cell lines with variable WT1 expression levels were tested for TRAIL sensitivity. The effect of pharmacological or short hairpin RNA (shRNA)-mediated inhibition of WT1 on TRAIL-induced apoptosis was evaluated by AnnexinV/PI staining method. The mRNA levels of WT1 and Bcl-xL were measured by reverse transcription-PCR (RT-PCR) and the expression of apoptosis regulators were analyzed by western blotting. RESULTS: We observed a strong correlation between higher levels of WT1 and increased TRAIL resistance in myeloid leukemia cell lines. WT1 downregulation by shRNA significantly sensitized leukemia cells to TRAIL-induced apoptosis and importantly, ectopic expression of shRNA resistant WT1 (WT1SR) in WT1-knockdown cells restored the TRAIL resistance. WT1 influences apoptosis through transcriptional regulation of Bcl-2 family members such as Bcl-2 and Bak. We found for the first time, a positive correlation between WT1 and Bcl-xL expression in leukemia cell lines and primary AML samples. Furthermore, using chromatin immunoprecipitation (ChIP) analysis, we show that Bcl-xL is a bonafide WT1-target gene as WT1 transctivates Bcl-xL by binding to its promoter. We have (Bansal et al., Blood 2010) recently shown that the expression and oncogenic functions of WT1 could be abrogated by heat shock protein 90 (Hsp90) inhibitors in myeloid leukemia cells. In order to establish whether Hsp90- mediated regulation of WT1 has any functional significance in TRAIL-resistance we treated leukemia cell with the Hsp90 inhibitor, 17-allylamino-17-demethoxygeldanamycin (17-AAG). The results confirm that Hsp90 inhibition was able to overcome TRAIL resistance, by reducing levels of WT1 and Bcl-xL and by increasing the levels of the proapoptotic protein Bak. Taken together, our results reveal that increased expression of Bcl-xL, along with low Bak, confer WT1-mediated TRAIL resistance. CONCLUSION: Our data indicate that TRAIL resistance in myeloid leukemia cells is mediated by overexpression of the panleukemic marker WT1 and this can be overcome by either silencing WT1 or by pharmacologic inhibitors such as 17-AAG. of Hsp90. Our study highlights the potential therapeutic benefit of the combining TRAIL and Hsp90 inhibitors for the treatment of myeloid leukemias. Disclosures: No relevant conflicts of interest to declare.

Differential effects of bexarotene on intrinsic and extrinsic pathways in TRAIL-induced apoptosis in two myeloid leukemia cell lines

2007 ◽  
Vol 48 (5) ◽  
pp. 1003-1014 ◽  
Author(s):  
Shao Xu Ying ◽  
Sudeshna Seal ◽  
Nissa Abbassi ◽  
David M. Hockenbery ◽  
Hans-Peter Kiem ◽  
...  
Keyword(s):  
Cell Lines ◽  
Myeloid Leukemia ◽  
Leukemia Cell ◽  
Differential Effects ◽  
Leukemia Cell Lines ◽  
Induced Apoptosis ◽  
Myeloid Leukemia Cell

Induced apoptosis by mild hyperthermia occurs via telomerase inhibition on the three human myeloid leukemia cell lines: TF-1, K562, and HL-60

2009 ◽  
Vol 50 (9) ◽  
pp. 1519-1527 ◽  
Author(s):  
Abdolkhaleg Deezagi ◽  
Sanaz Manteghi ◽  
Pardis Khosravani ◽  
Neda Vaseli-Hagh ◽  
Zahra-Soheila Soheili
Keyword(s):  
Cell Lines ◽  
Myeloid Leukemia ◽  
Leukemia Cell ◽  
Mild Hyperthermia ◽  
Telomerase Inhibition ◽  
Leukemia Cell Lines ◽  
Induced Apoptosis ◽  
Myeloid Leukemia Cell

Sodium Salicylate Activates Caspases and Induces Apoptosis of Myeloid Leukemia Cell Lines

Blood ◽  
1999 ◽  
Vol 93 (7) ◽  
pp. 2386-2394 ◽  
Author(s):  
Lidija Klampfer ◽  
Jörg Cammenga ◽  
Hans-Georg Wisniewski ◽  
Stephen D. Nimer
Keyword(s):  
Cell Death ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Sodium Salicylate ◽  
Leukemia Cell ◽  
Human Leukemia ◽  
Leukemia Cell Lines ◽  
Induced Apoptosis ◽  
Chemopreventive Activity ◽  
Myeloid Leukemia Cell

Nonsteroidal antiinflammatory agents (NSAIA) have been shown to exert potent chemopreventive activity against colon, lung, and breast cancers. In this study, we show that at pharmacological concentrations (1 to 3 mmol/L) sodium salicylate (Na-Sal) can potently induce programmed cell death in several human myeloid leukemia cell lines, including TF-1, U937, CMK-1, HL-60, and Mo7e. TF-1 cells undergo rapid apoptosis on treatment with Na-Sal, as indicated by increased annexin V binding capacity, cpp-32 (caspase-3) activation, and cleavage of poly (ADP-ribose) polymerase (PARP) and gelsolin. In addition, the expression of MCL-1, an antiapoptotic member of the BCL-2 family, is downregulated during Na-Sal–induced cell death, whereas the expression of BCL-2, BAX, and BCL-XL is unchanged. Z-VAD, a potent caspase inhibitor, prevents the cleavage of PARP and gelsolin and rescues cells from Na-Sal–induced apoptosis. In addition, we show that Na-Sal accelerates growth factor withdrawal-induced apoptosis and synergizes with daunorubicin to induce apoptosis in TF-1 cells. Thus, our data provide a potential mechanism for the chemopreventive activity of NSAIA and suggest that salicylates may have therapeutic potential for the treatment of human leukemia.

Wnt signaling inhibitor FH535 selectively inhibits cell proliferation and potentiates imatinib-induced apoptosis in myeloid leukemia cell lines

2016 ◽  
Vol 105 (2) ◽  
pp. 196-205 ◽  
Author(s):  
Kran Suknuntha ◽  
Thanyatip Thita ◽  
Padma Priya Togarrati ◽  
Piyanee Ratanachamnong ◽  
Patompon Wongtrakoongate ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Wnt Signaling ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Leukemia Cell ◽  
Leukemia Cell Lines ◽  
Induced Apoptosis ◽  
Myeloid Leukemia Cell

Use of different human myeloid leukemia cell lines to determine the specificity of 3,3’-diaminobenzidine cytochemistry for the ultrastructural localization of myeloperoxidase and catalase

1995 ◽  
Vol 53 ◽  
pp. 1060-1061
Author(s):  
J. E. Boyd ◽  
C. S. Gilbert ◽  
B. Pinnix ◽  
C. A. Ballinger ◽  
J. M. Kinkade ◽  
...  
Keyword(s):  
Cell Line ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Leukemia Cell ◽  
Myeloid Cell ◽  
Ultrastructural Localization ◽  
Ultrastructural Cytochemistry ◽  
Leukemia Cell Lines ◽  
Biochemical Assays ◽  
Myeloid Leukemia Cell

Myeloid cells are known to contain myeloperoxidase (MPO) and catalase. This study has used MPO and catalase replete and deficient myeloid cell lines to clarify the localization of these components using 3,3’-diaminobenzidine (DAB) ultrastructural cytochemistry. Conditions of DAB incubation can be modified to preferentially stain catalase (alkaline at pH 9.7) or MPO (neutral at pH 7.0-7.6), but crossreactivity persists, preventing the discrimination between catalase and peroxidase. Biochemical assays demonstrated both MPO and catalase in HL60 cells; similar amounts of catalase but no MPO activity in the A7 cell line; increased amounts of catalase but no MPO activity in the HP50 and HP100 cell lines; and neither MPO nor catalase in the KG1 cell line. Neutral DAB stained MPO (pH 7.4; [DAB] 5 or 20 mg/10 mL 0.05 M Tris; 30 min or 120 min; 24° or 37°C; 0.01% H2O2) in HL60 (Fig. 1), but not in A7. Alkaline DAB intensely stained catalase (pH 9.7; 20 mg/10 mL; 120 min; 37°C; 0.01% or 0.03%) in A7.

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