scholarly journals Greensporone C, a Freshwater Fungal Secondary Metabolite Induces Mitochondrial-Mediated Apoptotic Cell Death in Leukemic Cell Lines

2018 ◽  
Vol 9 ◽  
Author(s):  
Kirti S. Prabhu ◽  
Kodappully Sivaraman Siveen ◽  
Shilpa Kuttikrishnan ◽  
Ahmad N. Iskandarani ◽  
Abdul Q. Khan ◽  
...  
Keyword(s):  
Cell Death ◽  
Secondary Metabolite ◽  
Cell Lines ◽  
Apoptotic Cell ◽  
Leukemic Cell ◽  
Apoptotic Cell Death ◽  
Leukemic Cell Lines ◽  
Fungal Secondary Metabolite

scholarly journals Greensporone A, a Fungal Secondary Metabolite Suppressed Constitutively Activated AKT via ROS Generation and Induced Apoptosis in Leukemic Cell Lines

Biomolecules ◽  
2019 ◽  
Vol 9 (4) ◽  
pp. 126 ◽  
Author(s):  
Kirti Prabhu ◽  
Kodappully Siveen ◽  
Shilpa Kuttikrishnan ◽  
Anh Jochebeth ◽  
Tayyiba Ali ◽  
...  
Keyword(s):  
Cell Death ◽  
Cytochrome C ◽  
Cell Lines ◽  
Apoptotic Cell ◽  
Leukemic Cell ◽  
Apoptotic Cell Death ◽  
Leukemic Cells ◽  
Leukemic Cell Lines ◽  
Fungal Secondary Metabolite

Greensporone A is a fungal secondary metabolite that has exhibited potential in vitro for anti-proliferative activity in vitro. We studied the anticancer activity of greensporone A in a panel of leukemic cell lines. Greensporone A-mediated inhibition of proliferation is found to be associated with the induction of apoptotic cell death. Greensporone A treatment of leukemic cells causes inactivation of constitutively activated AKT and its downstream targets, including members GSK3 and FOXO1, and causes downregulation of antiapoptotic genes such as Inhibitor of Apoptosis (IAPs) and Bcl-2. Furthermore, Bax, a proapoptotic member of the Bcl-2 family, was found to be upregulated in leukemic cell lines treated with greensporone A. Interestingly, gene silencing of AKT using AKT specific siRNA suppressed the expression of Bcl-2 with enhanced expression of Bax. Greensporone A-mediated increase in Bax/Bcl-2 ratio causes permeabilization of the mitochondrial membrane leading to the accumulation of cytochrome c in the cytoplasm. Greensporone A-induced cytochrome c accumulation causes the activation of caspase cascade and cleavage of its effector, poly(ADP-ribose) polymerase (PARP), leading to apoptosis. Greensporone A-mediated apoptosis in leukemic cells occurs through the generation of reactive oxygen species (ROS) due to depletion of glutathione (GSH) levels. Finally, greensporone A potentiated the anticancer activity of imatinib in leukemic cells. In summary, our study showed that greensporone A suppressed the growth of leukemic cells via induction of apoptotic cell death. The apoptotic cell death occurs by inhibition of AKT signaling and activation of the intrinsic apoptotic/caspase pathways. These results raise the possibility that greensporone A could be developed as a therapeutic agent for the treatment of leukemia and other hematological malignancies.

Induction of apoptotic cell death by direct-current treatment in human leukemic cell lines

1997 ◽  
Vol 123 (7) ◽  
pp. 370-376 ◽  
Author(s):  
Masatsugu Kurokawa ◽  
Hiroshi Sakagami ◽  
Fumio Kokubu ◽  
Hiromichi Noda ◽  
Minoru Takeda ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Lines ◽  
Direct Current ◽  
Apoptotic Cell ◽  
Leukemic Cell ◽  
Current Treatment ◽  
Apoptotic Cell Death ◽  
Human Leukemic Cell ◽  
Leukemic Cell Lines

Induction of apoptotic cell death by direct-current treatment in human leukemic cell lines

1997 ◽  
Vol 123 (7) ◽  
pp. 370-376 ◽  
Author(s):  
Masatsugu Kurokawa ◽  
Hiroshi Sakagami ◽  
Fumio Kokubu ◽  
Hiromichi Noda ◽  
Minoru Takeda ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Lines ◽  
Direct Current ◽  
Apoptotic Cell ◽  
Leukemic Cell ◽  
Current Treatment ◽  
Apoptotic Cell Death ◽  
Human Leukemic Cell ◽  
Leukemic Cell Lines

scholarly journals Inhibition of Replication Induces Non-Apoptotic Cell Death in Fibroblast Cell Lines Derived from LEC Rats

2003 ◽  
Vol 65 (2) ◽  
pp. 249-254 ◽  
Author(s):  
Masanobu HAYASHI ◽  
Taku HAMASU ◽  
Daiji ENDOH ◽  
Reiko SHIMOJIMA ◽  
Toyo OKUI
Keyword(s):  
Cell Death ◽  
Cell Lines ◽  
Apoptotic Cell ◽  
Fibroblast Cell ◽  
Apoptotic Cell Death ◽  
Lec Rats ◽  
Fibroblast Cell Lines

scholarly journals ADP-Ribosylation of Actin by the Clostridium botulinum C2 Toxin in Mammalian Cells Results in Delayed Caspase-Dependent Apoptotic Cell Death

2008 ◽  
Vol 76 (10) ◽  
pp. 4600-4608 ◽  
Author(s):  
Karin Heine ◽  
Sascha Pust ◽  
Stefanie Enzenmüller ◽  
Holger Barth
Keyword(s):  
Cell Death ◽  
Cell Lines ◽  
Mammalian Cells ◽  
Clostridium Botulinum ◽  
Apoptotic Cell ◽  
Apoptotic Cell Death ◽  
Adp Ribosylation ◽  
Mammalian Cell Lines ◽  
Adp Ribosyltransferase ◽  
C2 Toxin

ABSTRACT The binary C2 toxin from Clostridium botulinum mono-ADP-ribosylates G-actin in the cytosol of eukaryotic cells. This modification leads to depolymerization of actin filaments accompanied by cell rounding within 3 h of incubation but does not immediately induce cell death. Here we investigated the long-term responses of mammalian cell lines (HeLa and Vero) following C2 toxin treatment. Cells stayed round even though the toxin was removed from the medium after its internalization into the cells. No unmodified actin reappeared in the C2 toxin-treated cells within 48 h. Despite actin being completely ADP-ribosylated after about 7 h, no obvious decrease in the overall amount of actin was observed for at least 48 h. Therefore, ADP-ribosylation was not a signal for an accelerated degradation of actin in the tested cell lines. C2 toxin treatment resulted in delayed apoptotic cell death that became detectable about 15 to 24 h after toxin application in a portion of the cells. Poly(ADP)-ribosyltransferase 1 (PARP-1) was cleaved in C2 toxin-treated cells, an indication of caspase 3 activation and a hallmark of apoptosis. Furthermore, specific caspase inhibitors prevented C2 toxin-induced apoptosis, implying that caspases 8 and 9 were activated in C2 toxin-treated cells. C2I, the ADP-ribosyltransferase component of the C2 toxin, remained active in the cytosol for at least 48 h, and no extensive degradation of C2I was observed. From our data, we conclude that the long-lived nature of C2I in the host cell cytosol was essential for the nonreversible cytotoxic effect of C2 toxin, resulting in delayed apoptosis of the tested mammalian cells.

scholarly journals Apoptotic signaling through CD95 (Fas/Apo-1) activates an acidic sphingomyelinase.

1994 ◽  
Vol 180 (4) ◽  
pp. 1547-1552 ◽  
Author(s):  
M G Cifone ◽  
R De Maria ◽  
P Roncaioli ◽  
M R Rippo ◽  
M Azuma ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Lines ◽  
Intracellular Signaling ◽  
Apoptotic Cell ◽  
Human Tumor ◽  
Apoptotic Cell Death ◽  
Cell Surface Receptor ◽  
Cross Linking ◽  
Cell Extracts

Intracellular pathways leading from membrane receptor engagement to apoptotic cell death are still poorly characterized. We investigated the intracellular signaling generated after cross-linking of CD95 (Fas/Apo-1 antigen), a broadly expressed cell surface receptor whose engagement results in triggering of cellular apoptotic programs. DX2, a new functional anti-CD95 monoclonal antibody was produced by immunizing mice with human CD95-transfected L cells. Crosslinking of CD95 with DX2 resulted in the activation of a sphingomyelinase (SMase) in promyelocytic U937 cells, as well as in other human tumor cell lines and in CD95-transfected murine cells, as demonstrated by induction of in vivo sphingomyelin (SM) hydrolysis and generation of ceramide. Direct in vitro measurement of enzymatic activity within CD95-stimulated U937 cell extracts, using labeled SM vesicles as substrates, showed strong SMase activity, which required pH 5.0 for optimal substrate hydrolysis. Finally, all CD95-sensitive cell lines tested could be induced to undergo apoptosis after exposure to cell-permeant C2-ceramide. These data indicate that CD95 cross-linking induces SM breakdown and ceramide production through an acidic SMase, thus providing the first information regarding early signal generation from CD95, and may be relevant in defining the biochemical nature of intracellular messengers leading to apoptotic cell death.

scholarly journals The Bispidinone Derivative 3,7-Bis-[2-(S)-amino-3-(1H-indol-3-yl)-propionyl]-1,5-diphenyl-3,7-diazabicyclo[3.3.1]nonan-9-one Dihydrochloride Induces an Apoptosis-Mediated Cytotoxic Effect on Pancreatic Cancer Cells In Vitro

Molecules ◽  
2019 ◽  
Vol 24 (3) ◽  
pp. 524 ◽  
Author(s):  
Melanie Predebon ◽  
Danielle Bond ◽  
Joshua Brzozowski ◽  
Helen Jankowski ◽  
Fiona Deane ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Flow Cytometry ◽  
Cell Death ◽  
Cell Lines ◽  
Cytotoxic Effect ◽  
Treatment Time ◽  
Apoptotic Cell ◽  
Apoptotic Cell Death ◽  
Cytotoxic Agents ◽  
Cell Counting

Pancreatic cancer (PC) is a complex, heterogeneous disease with a dismal prognosis. Current therapies have failed to improve survival outcomes, urging the need for discovery of novel targeted treatments. Bispidinone derivatives have yet to be investigated as cytotoxic agents against PC cells. The cytotoxic effect of four bispidinone derivatives (BisP1: 1,5-diphenyl-3,7-bis(2-hydroxyethyl)-3,7-diazabicyclo[3.3.1]nonan-9-one; BisP2: 3,7-bis-(2-(S)-amino-4-methylsulfanylbutyryl)-1,5-diphenyl-3,7-diazabicyclo[3.3.1]nonan-9-one dihydrochloride; BisP3: [2-{7-[2-(S)-tert-butoxycarbonylamino-3-(1H-indol-3-yl)-propionyl]-9-oxo-1,5-diphenyl-3,7-diazabicyclo[3.3.1]non-3-yl}-1-(S)-(1H-indol-3-ylmethyl)-2-oxoethyl]-carbamic acid tertbutyl ester; BisP4: 3,7-bis-[2-(S)-amino-3-(1H-indol-3-yl)-propionyl]-1,5-diphenyl-3,7-diazabicyclo[3.3.1]nonan-9-one dihydrochloride) was assessed against PC cell lines (MiaPaca-2, CFPAC-1 and BxPC-3). Cell viability was assessed using a Cell Counting Kit-8 (CCK-8) colorimetric assay, while apoptotic cell death was confirmed using fluorescence microscopy and flow cytometry. Initial viability screening revealed significant cytotoxic activity from BisP4 treatment (1 µM–100 µM) on all three cell lines, with IC50 values for MiaPaca-2, BxPC-3, and CFPAC-1 16.9 µM, 23.7 µM, and 36.3 µM, respectively. Cytotoxic treatment time-response (4 h, 24 h, and 48 h) revealed a 24 h treatment time was sufficient to produce a cytotoxic effect on all cell lines. Light microscopy evaluation (DAPI staining) of BisP4 treated MiaPaca-2 PC cells revealed dose-dependent characteristic apoptotic morphological changes. In addition, flow cytometry confirmed BisP4 induced apoptotic cell death induction of activated caspase-3/-7. The bispidinone derivative BisP4 induced an apoptosis-mediated cytotoxic effect on MiaPaca-2 cell lines and significant cytotoxicity on CFPAC-1 and BxPC-3 cell lines. Further investigations into the precise cellular mechanisms of action of this class of compounds are necessary for potential development into pre-clinical trials.

Ruthenium(II)-arene complexes with dibenzoylmethane induce apoptotic cell death in multiple myeloma cell lines

2017 ◽  
Vol 454 ◽  
pp. 139-148 ◽  
Author(s):  
Riccardo Pettinari ◽  
Fabio Marchetti ◽  
Agnese Petrini ◽  
Claudio Pettinari ◽  
Giulio Lupidi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Death ◽  
Cell Lines ◽  
Apoptotic Cell ◽  
Myeloma Cell ◽  
Apoptotic Cell Death ◽  
Arene Complexes ◽  
Multiple Myeloma Cell

Cannabis-induced cytotoxicity in leukemic cell lines: the role of the cannabinoid receptors and the MAPK pathway

Blood ◽  
2005 ◽  
Vol 105 (3) ◽  
pp. 1214-1221 ◽  
Author(s):  
Thomas Powles ◽  
Robert te Poele ◽  
Jonathan Shamash ◽  
Tracy Chaplin ◽  
David Propper ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Cell Death ◽  
Cell Lines ◽  
Leukemic Cell ◽  
Cytotoxic Agents ◽  
Complex Signal ◽  
Signal Transduction Pathways ◽  
Potent Inducer ◽  
Leukemic Cell Lines

Abstract Δ9-Tetrahydrocannabinol (THC) is the active metabolite of cannabis. THC causes cell death in vitro through the activation of complex signal transduction pathways. However, the role that the cannabinoid 1 and 2 receptors (CB1-R and CB2-R) play in this process is less clear. We therefore investigated the role of the CB-Rs in mediating apoptosis in 3 leukemic cell lines and performed microarray and immunoblot analyses to establish further the mechanism of cell death. We developed a novel flow cytometric technique of measuring the expression of functional receptors and used combinations of selective CB1-R and CB2-R antagonists and agonists to determine their individual roles in this process. We have shown that THC is a potent inducer of apoptosis, even at 1 × IC50 (inhibitory concentration 50%) concentrations and as early as 6 hours after exposure to the drug. These effects were seen in leukemic cell lines (CEM, HEL-92, and HL60) as well as in peripheral blood mononuclear cells. Additionally, THC did not appear to act synergistically with cytotoxic agents such as cisplatin. One of the most intriguing findings was that THC-induced cell death was preceded by significant changes in the expression of genes involved in the mitogen-activated protein kinase (MAPK) signal transduction pathways. Both apoptosis and gene expression changes were altered independent of p53 and the CB-Rs.

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