Wnt-expressing rat embryonic fibroblasts suppress Apo2L/TRAIL-induced apoptosis of human leukemia cells

Acute myeloid leukemia (AML) is an aggressive type of human leukemia with a low survival rate, and its complete remission remains challenging. Although chemotherapy is the first-line treatment of AML, it exerts toxicity in noncancerous cells when used in high doses, thus necessitating the development of novel compounds with a high therapeutic window. This study aimed to investigate the anticancer effects of several compounds derived from the fruits of Melia azedarach (a tree with medicinal properties). Among them, 1-cinnamoyltrichilinin (CT) was found to strongly suppress the viability of HL-60 human leukemia cells. CT treatment induced apoptosis and increased nuclear fragmentation and fractional DNA content in HL-60 cells in a dose-dependent manner. CT induced phosphorylation of p38 mitogen-activated protein kinases (p38), though not of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK), and activated Bcl-2 family proteins towards the proapoptosis and cleavage of caspase-3 and poly (ADP-ribose) polymerase. Both CT-mediated apoptosis and apoptotic protein expression were reversed by treatment with the p38 inhibitor, thereby indicating the p38 pathway to be critical in CT-stimulated apoptosis. The results collectively indicated CT to suppress HL-60 survival by activating the p38 pathway and inducing apoptosis, hence being a novel potential therapeutic agent for AML.

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Naja atra Cardiotoxin 3 Elicits Autophagy and Apoptosis in U937 Human Leukemia Cells through the Ca2+/PP2A/AMPK Axis

Toxins ◽

10.3390/toxins11090527 ◽

2019 ◽

Vol 11 (9) ◽

pp. 527 ◽

Cited By ~ 6

Author(s):

Jing-Ting Chiou ◽

Yi-Jun Shi ◽

Liang-Jun Wang ◽

Chia-Hui Huang ◽

Yuan-Chin Lee ◽

...

Keyword(s):

Cell Death ◽

Membrane Damage ◽

Leukemia Cells ◽

Human Leukemia ◽

U937 Cells ◽

Cell Membrane Damage ◽

Human Leukemia Cells ◽

Phosphatase 2A ◽

Induced Apoptosis ◽

Naja Atra

Cardiotoxins (CTXs) are suggested to exert their cytotoxicity through cell membrane damage. Other studies show that penetration of CTXs into cells elicits mitochondrial fragmentation or lysosome disruption, leading to cell death. Considering the role of AMPK-activated protein kinase (AMPK) in mitochondrial biogenesis and lysosomal biogenesis, we aimed to investigate whether the AMPK-mediated pathway modulated Naja atra (Taiwan cobra) CTX3 cytotoxicity in U937 human leukemia cells. Our results showed that CTX3 induced autophagy and apoptosis in U937 cells, whereas autophagic inhibitors suppressed CTX3-induced apoptosis. CTX3 treatment elicited Ca2+-dependent degradation of the protein phosphatase 2A (PP2A) catalytic subunit (PP2Acα) and phosphorylation of AMPKα. Overexpression of PP2Acα mitigated the CTX3-induced AMPKα phosphorylation. CTX3-induced autophagy was via AMPK-mediated suppression of the Akt/mTOR pathway. Removal of Ca2+ or suppression of AMPKα phosphorylation inhibited the CTX3-induced cell death. CTX3 was unable to induce autophagy and apoptosis in U937 cells expressing constitutively active Akt. Met-modified CTX3 retained its membrane-perturbing activity, however, it did not induce AMPK activation and death of U937 cells. These results conclusively indicate that CTX3 induces autophagy and apoptosis in U937 cells via the Ca2+/PP2A/AMPK axis, and suggest that the membrane-perturbing activity of CTX3 is not crucial for the cell death signaling pathway induction.

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Mechanism of UV-Induced Apoptosis in Human Leukemia Cells: Roles of Ca2+/Mg2+-Dependent Endonuclease, Caspase-3, and Stress-Activated Protein Kinases

Experimental Cell Research ◽

10.1006/excr.1997.3912 ◽

1998 ◽

Vol 239 (2) ◽

pp. 411-422 ◽

Cited By ~ 51

Author(s):

Chika Kimura ◽

Qing-Li Zhao ◽

Takashi Kondo ◽

Mutsuo Amatsu ◽

Yoshisada Fujiwara

Keyword(s):

Protein Kinases ◽

Caspase 3 ◽

Leukemia Cells ◽

Human Leukemia ◽

Human Leukemia Cells ◽

Dependent Endonuclease ◽

Induced Apoptosis

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Enforced expression of the tumor suppressor p53 renders human leukemia cells (U937) more sensitive to 1-[β-d-arabinofuranosyl]cytosine (ara-C)-induced apoptosis

Biochemical Pharmacology ◽

10.1016/s0006-2952(03)00149-7 ◽

2003 ◽

Vol 65 (12) ◽

pp. 1997-2008 ◽

Cited By ~ 4

Author(s):

Roy H. Decker ◽

Jay Levin ◽

Lora B. Kramer ◽

Yun Dai ◽

Steven Grant

Keyword(s):

Tumor Suppressor ◽

Leukemia Cells ◽

Human Leukemia ◽

Tumor Suppressor P53 ◽

Human Leukemia Cells ◽

Induced Apoptosis

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Modulation of the expression of Bcl-2 and related proteins in human leukemia cells by protein kinase C activators: relationship to effects on 1-[β-D-arabinofuranosyl]cytosine-induced apoptosis

Cell Death and Differentiation ◽

10.1038/sj.cdd.4400242 ◽

1997 ◽

Vol 4 (4) ◽

pp. 294-303 ◽

Cited By ~ 6

Author(s):

Tina M Bartimole ◽

Julie A Vrana ◽

Alex J Freemerman ◽

W David Jarvis ◽

John C Reed ◽

...

Keyword(s):

Protein Kinase C ◽

Protein Kinase ◽

Leukemia Cells ◽

Human Leukemia ◽

Kinase C ◽

Human Leukemia Cells ◽

Protein Kinase C Activators ◽

Induced Apoptosis ◽

Related Proteins

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Aspirin Induces Apoptosis in Human Leukemia Cells Independently of NF-κB and MAPKs through Alteration of the Mcl-1/Noxa Balance.

Blood ◽

10.1182/blood.v114.22.4825.4825 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4825-4825

Author(s):

Ana M Cosialls ◽

Daniel Iglesias-Serret ◽

Maria Piqué ◽

Montserrat Barragán ◽

Antonio F Santidrián ◽

...

Keyword(s):

Conflicts Of Interest ◽

Leukemia Cell ◽

Cell Types ◽

Lymphocytic Leukemia ◽

Leukemia Cells ◽

Human Leukemia ◽

Mrna Levels ◽

Protein Levels ◽

Human Leukemia Cells ◽

Induced Apoptosis

Abstract Abstract 4825 Aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) induce apoptosis in most cell types. We examined the mechanism of aspirin-induced apoptosis in human leukemia cells. Our results show that aspirin induced apoptosis in leukemia Jurkat T cells independently of NF-κB. Although aspirin induced p38 MAPK and c-Jun N-terminal kinase (JNK) activation, selective inhibitors of these kinases did not inhibit aspirin-induced apoptosis. We studied the regulation of Bcl-2 family members in aspirin-induced apoptosis. The mRNA levels of some pro-apoptotic members, such as BIM, NOXA, BMF or PUMA, were induced by aspirin. However, none of these pro-apoptotic proteins increased and the levels of Mcl-1 protein were reduced. Interestingly, in the presence of aspirin the protein levels of Noxa remained high. This alteration of the Mcl-1/Noxa balance was also found in other leukemia cell lines and primary chronic lymphocytic leukemia cells (CLL). Furthermore, in CLL cells aspirin induced an increase in the protein levels of Noxa. Knockdown of Noxa or Puma significantly attenuated aspirin-induced apoptosis. These results indicate that aspirin induces apoptosis through alteration of the Mcl-1/Noxa balance. Disclosures No relevant conflicts of interest to declare.

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