The triterpenoid CDDO induces apoptosis in refractory CLL B cells

Blood ◽  
2002 ◽  
Vol 100 (8) ◽  
pp. 2965-2972 ◽  
Author(s):  
Irene M. Pedersen ◽  
Shinichi Kitada ◽  
Aaron Schimmer ◽  
Youngsoo Kim ◽  
Juan M. Zapata ◽  
...  
Keyword(s):  
B Cells ◽  
Anticancer Agents ◽  
Fas Ligand ◽  
Proteolytic Processing ◽  
Caspase 8 ◽  
Dependent Manner ◽  
Caspase 9 ◽  
Apoptosis Pathway ◽  
Apoptosis Protein ◽  
Induced Apoptosis

Chronic lymphocytic leukemia (CLL) cells develop chemo-resistance over time. Most anticancer agents function through induction of apoptosis, and therefore resistance against these agents is likely to be caused by selection for CLL cells with defects in the particular apoptosis pathway that is triggered by these drugs. Anticancer agents that function through alternative apoptotic pathways might therefore be useful in treating chemo-resistant CLL. Triterpenoids represent a class of naturally occurring and synthetic compounds with demonstrated antitumor activity. We examined the effects of CDDO (triterpenoid 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid) on CLL B cells in vitro. CDDO induced apoptosis in a dose-dependent manner in all (n = 30) CLL samples tested, including previously untreated and chemo-resistant CLL specimens. CDDO induced rapid proteolytic processing of caspase-8, but not caspase-9, in CLL B cells, suggesting activation of a mitochondria-independent pathway. CDDO-induced apoptosis of CLL B cells was blocked by cytokine response modifier A (CrmA), a suppressor of caspase-8, but not by X-linked inhibitor of apoptosis protein–baculovirus IAP repeat–3 (XIAP-BIR3), a fragment of XIAP, which selectively inhibits caspase-9. Examination of CDDO effects on expression of several apoptosis-relevant genes demonstrated significant reductions in the levels of caspase-8 homolog Fas-ligand interleukin-1–converting enzyme (FLICE)–inhibitory protein (c-FLIP), an endogenous antagonist of caspase-8. However, reductions of FLIP achieved by FLIP antisense oligonucleotides were insufficient for triggering apoptosis, indicating that CDDO has other targets in CLL B cells besides FLIP. These data suggest that the synthetic triterpenoid CDDO should be further explored as a possible therapeutic agent for treatment of chemo-resistant CLL.

Antileukemic drugs increase death receptor 5 levels and enhance Apo-2L–induced apoptosis of human acute leukemia cells

Blood ◽  
2000 ◽  
Vol 96 (12) ◽  
pp. 3900-3906 ◽  
Author(s):  
Jinghai Wen ◽  
Nimmanapalli Ramadevi ◽  
Diep Nguyen ◽  
Charles Perkins ◽  
Elizabeth Worthington ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Fas Ligand ◽  
Leukemia Cell ◽  
Jurkat Cells ◽  
Leukemia Cells ◽  
Maximum Effect ◽  
Caspase 8 ◽  
Dependent Manner ◽  
Caspase 9 ◽  
Induced Apoptosis

Abstract In present studies, treatment with tumor necrosis factor (TNF)–related apoptosis inducing ligand (TRAIL, also known as Apo-2 ligand [Apo-2L]) is shown to induce apoptosis of the human acute leukemia HL-60, U937, and Jurkat cells in a dose-dependent manner, with the maximum effect seen following treatment of Jurkat cells with 0.25 μg/mL of Apo-2L (95.0% ± 3.5% of apoptotic cells). Susceptibility of these acute leukemia cell types, which are known to lack p53wt function, did not appear to correlate with the levels of the apoptosis-signaling death receptors (DRs) of Apo-2L, ie, DR4 and DR5; decoy receptors (DcR1 and 2); FLAME-1 (cFLIP); or proteins in the inhibitors of apoptosis proteins (IAP) family. Apo-2L–induced apoptosis was associated with the processing of caspase-8, Bid, and the cytosolic accumulation of cytochrome c as well as the processing of caspase-9 and caspase-3. Apo-2L–induced apoptosis was significantly inhibited in HL-60 cells that overexpressed Bcl-2 or Bcl-xL. Cotreatment with either a caspase-8 or a caspase-9 inhibitor suppressed Apo-2L–induced apoptosis. Treatment of human leukemic cells with etoposide, Ara-C, or doxorubicin increased DR5 but not DR4, Fas, DcR1, DcR2, Fas ligand, or Apo-2L levels. Importantly, sequential treatment of HL-60 cells with etoposide, Ara-C, or doxorubicin followed by Apo-2L induced significantly more apoptosis than treatment with Apo-2L, etoposide, doxorubicin, or Ara-C alone, or cotreatment with Apo-2L and the antileukemic drugs, or treatment with the reverse sequence of Apo-2L followed by one of the antileukemic drugs. These findings indicate that treatment with etoposide, Ara-C, or doxorubicin up-regulates DR5 levels in a p53-independent manner and sensitizes human acute leukemia cells to Apo-2L–induced apoptosis.

Antileukemic drugs increase death receptor 5 levels and enhance Apo-2L–induced apoptosis of human acute leukemia cells

Blood ◽  
2000 ◽  
Vol 96 (12) ◽  
pp. 3900-3906 ◽  
Author(s):  
Jinghai Wen ◽  
Nimmanapalli Ramadevi ◽  
Diep Nguyen ◽  
Charles Perkins ◽  
Elizabeth Worthington ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Fas Ligand ◽  
Leukemia Cell ◽  
Jurkat Cells ◽  
Leukemia Cells ◽  
Maximum Effect ◽  
Caspase 8 ◽  
Dependent Manner ◽  
Caspase 9 ◽  
Induced Apoptosis

In present studies, treatment with tumor necrosis factor (TNF)–related apoptosis inducing ligand (TRAIL, also known as Apo-2 ligand [Apo-2L]) is shown to induce apoptosis of the human acute leukemia HL-60, U937, and Jurkat cells in a dose-dependent manner, with the maximum effect seen following treatment of Jurkat cells with 0.25 μg/mL of Apo-2L (95.0% ± 3.5% of apoptotic cells). Susceptibility of these acute leukemia cell types, which are known to lack p53wt function, did not appear to correlate with the levels of the apoptosis-signaling death receptors (DRs) of Apo-2L, ie, DR4 and DR5; decoy receptors (DcR1 and 2); FLAME-1 (cFLIP); or proteins in the inhibitors of apoptosis proteins (IAP) family. Apo-2L–induced apoptosis was associated with the processing of caspase-8, Bid, and the cytosolic accumulation of cytochrome c as well as the processing of caspase-9 and caspase-3. Apo-2L–induced apoptosis was significantly inhibited in HL-60 cells that overexpressed Bcl-2 or Bcl-xL. Cotreatment with either a caspase-8 or a caspase-9 inhibitor suppressed Apo-2L–induced apoptosis. Treatment of human leukemic cells with etoposide, Ara-C, or doxorubicin increased DR5 but not DR4, Fas, DcR1, DcR2, Fas ligand, or Apo-2L levels. Importantly, sequential treatment of HL-60 cells with etoposide, Ara-C, or doxorubicin followed by Apo-2L induced significantly more apoptosis than treatment with Apo-2L, etoposide, doxorubicin, or Ara-C alone, or cotreatment with Apo-2L and the antileukemic drugs, or treatment with the reverse sequence of Apo-2L followed by one of the antileukemic drugs. These findings indicate that treatment with etoposide, Ara-C, or doxorubicin up-regulates DR5 levels in a p53-independent manner and sensitizes human acute leukemia cells to Apo-2L–induced apoptosis.

Arsenic trioxide–induced apoptosis in myeloma cells: p53-dependent G1 or G2/M cell cycle arrest, activation of caspase-8 or caspase-9, and synergy with APO2/TRAIL

Blood ◽  
2003 ◽  
Vol 101 (10) ◽  
pp. 4078-4087 ◽  
Author(s):  
Qun Liu ◽  
Susan Hilsenbeck ◽  
Yair Gazitt
Keyword(s):  
Cell Cycle ◽  
Arsenic Trioxide ◽  
Cell Lines ◽  
Myeloma Cell ◽  
Caspase 8 ◽  
Dependent Manner ◽  
Caspase 9 ◽  
Myeloma Cells ◽  
Induced Apoptosis ◽  
In Cells

Abstract Arsenic trioxide (ATO) has been shown to induce differentiation and apoptosis in acute promyelocytic leukemia (APL) cells concomitant with down-regulation of the PML-RARα fusion protein, a product of the t(15:17) translocation characteristic of APL leukemic cells. However, ATO is also a potent inducer of apoptosis in a number of other cancer cells lacking the t(15:17) translocation. The exact mechanism of ATO-induced apoptosis in these cells is not yet clear. We tested the effect of ATO on 7 myeloma cell lines with varying p53 status and report that in cells with mutated p53, ATO induced rapid and extensive (more than 90%) apoptosis in a time- and dose-dependent manner concomitant with arrest of cells in G2/M phase of the cell cycle. Myeloma cells with wild-type (wt) p53 were relatively resistant to ATO with maximal apoptosis of about 40% concomitant with partial arrest of cells in G1 and up-regulation of p21. The use of caspase blocking peptides, fluorescence-tagged caspase-specific substrate peptides, and Western immunoblotting confirmed the involvement of primarily caspase-8 and -3 in ATO-induced apoptosis in myeloma cells with mutated p53 and primarily caspase-9 and -3 in cells expressing wt p53. We also observed up-regulation by ATO of R1 and R2 APO2/TRAIL (tumor necrosis factor–related apoptosis-inducing ligand) receptors. Most important, however, we observed a synergy between ATO and APO2/TRAIL in the induction of apoptosis in the partially resistant myeloma cell lines and in myeloma cells freshly isolated from myeloma patients. Our results justify the use of the combination of these 2 drugs in clinical setting in myeloma patients.

Role of mitochondria in aspirin-induced apoptosis in human gastric epithelial cells

2005 ◽  
Vol 289 (4) ◽  
pp. G731-G738 ◽  
Author(s):  
Maria J. Redlak ◽  
Jacinda J. Power ◽  
Thomas A. Miller
Keyword(s):  
Epithelial Cells ◽  
Complex Formation ◽  
Oxidative Phosphorylation ◽  
Caspase 8 ◽  
Mucosal Cell ◽  
Dependent Manner ◽  
Gastric Epithelial Cells ◽  
Caspase 9 ◽  
Mitochondrial Fractions ◽  
Induced Apoptosis

This study was undertaken to determine whether the Bcl-2 family proteins and Smac are regulators of aspirin-mediated apoptosis in a gastric mucosal cell line known as AGS cells. Cells were incubated with varying concentrations of acetylsalicylic acid (ASA; 2–40 mM), with or without preincubation of caspase inhibitors. Apoptosis was characterized by Hoechst staining and DNA-histone-associated complex formation. Antiapoptotic Bcl-2, proapoptotic Bax and Bid, Smac, and cytochrome- c oxidase (COX IV) were analyzed by Western blot analyses from cytosol and mitochondrial fractions. ASA downregulated Bcl-2 protein expression and induced Bax translocation into the mitochondria and cleavage of Bid. In contrast, expression of Smac was significantly decreased in mitochondrial fractions of ASA-treated cells. Bax and Bid involvement in apoptosis regulation was dependent on caspase activation, because caspase-8 inhibition suppressed Bax translocation and Bid processing. Caspase-9 inhibition prevented Smac release from mitochondria. Additionally, increased expression of the oxidative phosphorylation enzyme COX IV was observed in mitochondrial fractions exposed to ASA at concentrations >5 mM. Although caspase-8 inhibition had no effect on aspirin-induced apoptosis and DNA-histone complex formation, caspase-9 inhibition significantly decreased both of these events. We conclude that Bcl-2 protein family members and Smac regulate the apoptotic pathway in a caspase-dependent manner. Our results indicate also that mitochondrial integration and oxidative phosphorylation play a critical role in the pathogenesis of apoptosis in human gastric epithelial cells.

scholarly journals Bullatacin Triggered ABCB1-Overexpressing Cell Apoptosis via the Mitochondrial-Dependent Pathway

2009 ◽  
Vol 2009 ◽  
pp. 1-9 ◽  
Author(s):  
Yong-Ju Liang ◽  
Xu Zhang ◽  
Chun-Ling Dai ◽  
Jian-Ye Zhang ◽  
Yan-Yan Yan ◽  
...  
Keyword(s):  
Cell Apoptosis ◽  
Multidrug Resistant ◽  
Resistant Cell ◽  
Ros Generation ◽  
Caspase 8 ◽  
Dependent Manner ◽  
Caspase 9 ◽  
Concentration Dependent Manner ◽  
Induced Apoptosis ◽  
Dependent Pathway

This paper was to explore bullatacin-mediated multidrug-resistant cell apoptosis at extremely low concentration. To investigate its precise mechanisms, the pathway of cell apoptosis induced by bullatacin was examined. Bullatacin causes an upregulation of ROS and a downregulation ofΔΨmin a concentration-dependent manner in ABCB1-overexpressing KBv200 cells. In addition, cleavers of caspase-9, caspase-3, and PARP were observed following the release of cytochrome c from mitochondria after bullatacin treatment. However, neither cleavage of caspase-8 nor change of expression level of bcl-2, bax and Fas was observed by the same treatment. Pretreating KBv200 cells with N-acetylcysteine, an antioxidant modulator, resulted in a significant reduction of ROS generation and cell apoptosis induced by bullatacin. Bullatacin-induced apoptosis was antagonized by z-LEHD-fmk, a caspase-9 inhibitor, but not by z-IETD-fmk, a caspase-8 inhibitor. These implied that apoptosis of KBv200 cells induced by bullatacin was associated with the mitochondria-dependent pathway that was limited to activation of apical caspase-9.

scholarly journals NeosedumosideIII induced Apoptosis of Human Hepatocellular Carcinoma HepG2 cells and SMMC-7721 Cells and Related Mechanism

2021 ◽  
Author(s):  
Xin-Yu Li ◽  
Xin Zhou ◽  
Yu- Liu ◽  
Feng Qiu ◽  
Qing-Qing Zhao
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Cycle ◽  
Hepg2 Cells ◽  
Caspase 3 ◽  
Human Hepatocellular Carcinoma ◽  
Caspase 8 ◽  
Dependent Manner ◽  
Caspase 9 ◽  
Induced Apoptosis

Abstract Purpose: NeosedumosideIII (Neo) is a megastigmanes and belongs to monocyclic sesquiterpenoids compound with antioxidant, anti-inflammatory and other pharmacological activities. In order to explore the anti-cancer effect and possible mechanism of Neo, the study examined the anti-proliferation and apoptosis effect of Neo against human hepatocellular carcinoma HepG2 cells and SMMC-772 cells and related mechanism in vitro. Methods ：The anti-proliferation effect of Neo was detected on HepG2 cells and SMMC-772 cells by MTT assay and IC50 with increasing dose and time. Cell cycle and apoptosis were detected by flow cytometer. The changes of Bcl-2, Bax, Caspase-3, Caspase-8 and Caspase-9 proteins were detected by western blotting.Results ：The results indicated that Neo could inhibited proliferation of HepG2 cells and SMMC-772 cells in vitro and promoted apoptosis, it significantly induced apoptosis of HepG2 cells and SMMC-772 cells arrested cell cycle at G0/G1 phase in a dose-dependent manner, reduce the expression of Bcl-2 protein, and increase the expression of Bax and Caspase-3, Caspase-8 and Caspase-9 proteins. Conclusion：Neo could inhibit proliferation and induce apoptosis of HepG2 cells and SMMC-7721 cells in vivo which suggested that it might be served as a promising candidate for the treatment of liver cancer.

Requirement of Caspase-8 Versus Caspase-9 during Apoptosis in Multiple Myeloma Cells Induced by Bortezomib- or a Novel Proteasome Inhibitor NPI-0052.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3378-3378 ◽  
Author(s):  
Dharminder Chauhan ◽  
Laurence Catley ◽  
Mugdha Velankar ◽  
Anthony Letai ◽  
Teru Hideshima ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Proteasome Inhibitor ◽  
Proteasome Inhibition ◽  
Proteolytic Processing ◽  
Caspase 8 ◽  
Caspase 9 ◽  
Transfected Cells ◽  
Viable Cells ◽  
Vector Versus ◽  
Induced Apoptosis

Abstract Proteasome inhibition is an effective therapy for the treatment of relapsed/refractory multiple myeloma (MM); however, the sequence of events leading to apoptosis following proteasome inhibition is unclear. Here we defined the requirement for caspase-8 versus caspase-9 during Bortezomib (VelcadeTM)- or novel proteasome inhibitor NPI-0052-induced apoptosis in MM cells. Incubation of MM.1S cells with pan-caspase inhibitor (Z-VAD-FMK) markedly abrogates both NPI-0052- and Bortezomib-induced apoptosis. Inhibition of caspase-8 (IETD-FMK) led to a significant decrease in NPI-0052-triggered cell death, whereas inhibition of caspase-9 (LEHD-FMK) only moderately blocked NPI-0052-triggered decreased viability in MM.1S cells (P < 0.005). In contrast, Bortezomib-induced decrease in viability is equally blocked by either caspase-8 or caspase-9 inhibitors (P < 0.005). These biochemical data were further examined by genetic studies using dominant-negative (DN) strategies. Treatment of DN-caspase-8-transfected MM cells with NPI-0052 (IC50: 7 nM) markedly increases survival compared to cells transfected with DN-caspase-9. In contrast, treatment of either DN-caspase-8 or DN caspase-9-tranfected MM.1S cells with Bortezomib (IC50: 5 nM) increases survival to a similar extent. The proteolytic processing of pro-caspase-8 is mediated by Fas Associated Death-Domain (FADD) protein, and we next examined blockade of FADD with DN-FADD to further confirm the role of caspase-8. DN-FADD significantly attenuated NPI-0052-induced cytotoxicity compared to empty vector-transfected MM.1S cells (42 ± 2.0% viable cells in vector- versus 76 ± 5.1% viable cells in DN-FADD-transfected cells; P < 0.05). Importantly, treatment of DN-FADD-transfected MM.1S cells with Bortezomib results in only 16% increase in survival compared to vector-transfected cells (39 ± 2.4% viable cells in vector- versus 55 ± 4.1% viable cells in DN-FADD-transfected cells; P < 0.05). These data, coupled with caspase-8 or caspase-9 inhibition studies, suggest that NPI-0052 relies more on FADD-caspase-8 signaling than does Bortezomib, confirming a differential mechanism of action of NPI-0052 versus Bortezomib in MM cells. To further address this issue, we examined alterations in Bax, a proapoptotic protein which translocates from cytosol to mitochondria during apoptosis, inhibits Bcl-2, and facilitates release of cyto-c and activation of caspase-9. NPI-0052 induces little, if any, increase in Bax levels in mitochondria, whereas Bortezomib triggers a significant accumulation of Bax in mitochondria. Experiments using Bax wild type (WT) or knockout mouse embryonic fibroblast (MEFs) show that NPI-0052 decreases viability in both Bax (WT) and Bax (knock-out) MEFs, whereas deletion of Bax confers significant resistance to Bortezomib. These findings suggest a differential requirement for Bax during NPI-0052- versus Bortezomib-induced apoptosis. Collectively, our data suggest that 1) NPI-0052-induced MM cell apoptosis is predominantly mediated by caspase-8; and 2) Bortezomib-induced apoptosis requires both caspase-8 and caspase-9 activation. These data provide rationale for combining agents based on differential signaling cascades to amplify apoptosis and enhance anti-tumor activity.

scholarly journals Rapid Apoptosis Induced by Shiga Toxin in HeLa Cells

2003 ◽  
Vol 71 (5) ◽  
pp. 2724-2735 ◽  
Author(s):  
Jun Fujii ◽  
Takashi Matsui ◽  
Daniel P. Heatherly ◽  
Kailo H. Schlegel ◽  
Peter I. Lobo ◽  
...  
Keyword(s):  
Dna Fragmentation ◽  
Hela Cells ◽  
Shiga Toxin ◽  
Specific Inhibitor ◽  
Mitochondrial Pathway ◽  
Caspase 8 ◽  
Dependent Manner ◽  
Mitochondrial Membranes ◽  
Caspase 9 ◽  
Induced Apoptosis

ABSTRACT Apoptosis was induced rapidly in HeLa cells after exposure to bacterial Shiga toxin (Stx1 and Stx2; 10 ng/ml). Approximately 60% of HeLa cells became apoptotic within 4 h as detected by DNA fragmentation, terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL) assay, and electron microscopy. Stx1-induced apoptosis required enzymatic activity of the Stx1A subunit, and apoptosis was not induced by the Stx2B subunit alone or by the anti-globotriaosylceramide antibody. This activity was also inhibited by brefeldin A, indicating the need for toxin processing through the Golgi apparatus. The intracellular pathway leading to apoptosis was further defined. Exposure of HeLa cells to Stx1 activated caspases 3, 6, 8, and 9, as measured both by an enzymatic assay with synthetic substrates and by detection of proteolytically activated forms of these caspases by Western immunoblotting. Preincubation of HeLa cells with substrate inhibitors of caspases 3, 6, and 8 protected the cells against Stx1-dependent apoptosis. These results led to a more detailed examination of the mitochondrial pathway of apoptosis. Apoptosis induced by Stx1 was accompanied by damage to mitochondrial membranes, measured as a reduced mitochondrial membrane potential, and increased release of cytochrome c from mitochondria at 3 to 4 h. Bid, an endogenous protein known to permeabilize mitochondrial membranes, was activated in a Stx1-dependent manner. Caspase-8 is known to activate Bid, and a specific inhibitor of caspase-8 prevented the mitochondrial damage. Although these data suggested that caspase-8-mediated cleavage of Bid with release of cytochrome c from mitochondria and activation of caspase-9 were responsible for the apoptosis, preincubation of HeLa cells with a specific inhibitor of caspase-9 did not protect against apoptosis. These results were explained by the discovery of a simultaneous Stx1-dependent increase in endogenous XIAP, a direct inhibitor of caspase-9. We conclude that the primary pathway of Stx1-induced apoptosis and DNA fragmentation in HeLa cells is unique and includes caspases 8, 6, and 3 but is independent of events in the mitochondrial pathway.

scholarly journals Japanese encephalitis virus infection activates caspase-8 and -9 in a FADD-independent and mitochondrion-dependent manner

2008 ◽  
Vol 89 (8) ◽  
pp. 1930-1941 ◽  
Author(s):  
Chang-Huei Tsao ◽  
Hong-Lin Su ◽  
Yi-Ling Lin ◽  
Han-Pang Yu ◽  
Shu-Ming Kuo ◽  
...  
Keyword(s):  
Japanese Encephalitis Virus ◽  
Japanese Encephalitis ◽  
Caspase 3 ◽  
Encephalitis Virus ◽  
Dominant Negative Mutant ◽  
Caspase 8 ◽  
Dependent Manner ◽  
Caspase 9 ◽  
Effector Caspase ◽  
Induced Apoptosis

Japanese encephalitis virus (JEV), a mosquito-borne flavivirus, replicates primarily at the endoplasmic reticulum and thereby triggers apoptosis of infected cells. This study investigated the hierarchical activation of the caspase network induced by JEV infection. It was found that JEV activated the initiators caspase-8 and -9, as well as effector caspase-3, in infected baby hamster kidney and mouse neuroblastoma (N18) cells. In neuronal N18 cells, JEV infection triggered cytochrome c release from mitochondria, which in turn activated caspase-9 and -3. Treatment of JEV-infected N18 cells with cyclosporin A or ruthenium red, which attenuate mitochondrial injuries, blocked activation of caspase-9 or -3, typifying that, in neuronal cells, this apoptosis involves the mitochondrial pathway. Alternatively, in caspase-3-deficient MCF-7 cells, JEV persisted and readily triggered a typical apoptotic response, including cytochrome c release and full activation of caspase-9 and -8 along with caspase-6, indicating that JEV did not require caspase-3 to manifest caspase-8 activation and apoptosis. Interestingly, a Fas-associated death-domain-containing protein (FADD) dominant-negative mutant, which interfered with transmission of the extracellular death signals into cells through the Fas/tumour necrosis factor (TNF) receptor, failed to block JEV-induced apoptosis and caspase-8 activation, implying that receptor oligomerization of the Fas/TNF pathway might not participate in JEV-induced apoptosis. Taken together, these results illustrate that JEV infection triggers caspase cascades involving the initiators caspase-8 and -9, probably through FADD-independent but mitochondrion-dependent pathways.

Smac Mimetic-Mediated Sensitization Of Childhood ALL Cells For Drug-Induced Apoptosis Independent Of TNFα and NFκB Signaling Pathways

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2911-2911
Author(s):  
Karin Schmelz ◽  
Nina Weichert ◽  
Jutta Proba ◽  
Marie-Sophie Erdmann ◽  
Patrick Hundsdoerfer
Keyword(s):  
Signaling Pathways ◽  
Tumor Cells ◽  
Caspase 3 ◽  
Caspase 8 ◽  
Apoptosis Induction ◽  
Caspase 9 ◽  
Drug Induced ◽  
Childhood All ◽  
Apoptosis Pathway ◽  
Induced Apoptosis

Abstract Targeting inhibitor of apoptosis proteins (IAPs) using small molecular Smac mimetics (SM) has been shown to offer a novel promising treatment strategy for resistant malignant diseases including childhood acute lymphoblastic leukemia (ALL). The effect of SM alone has been shown to be associated with endogenous TNFα expression, therefore tumor cells can be classified into sensitive or resistant against apoptosis induction by SM alone. In SM sensitive tumor cells the effect of SM has been shown to be mediated mainly by degradation of cellular IAP (cIAP) and activation of TNFα and NFκB signaling pathways but not inhibition of XIAP. We show here, that sensitivity of ALL cells to SM alone (as well as TNFα expression) is highly variable. Nevertheless even in ALL cells resistant against SM alone, treatment with SM resulted in significant sensitization for drugs used within standard induction therapy for childhood ALL. Sensitization for drug-induced apoptosis by SM was not only mediated by activation of the intrinsic (cleavage of caspase 9) but also extrinsic apoptosis pathway (cleavage of caspase 8). Surprisingly, SM-induced cIAP degradation alone was not sufficient for caspase 8 activation and apoptosis induction. Consistently, SM-mediated sensitization for drug-induced apoptosis was independent of TNFα and NFκB signaling pathways. We demonstrate that caspase 8 activation by combined treatment with SM and cytostatic drugs is blocked by inhibition of caspase 3 and caspase 9 and therefore occurs downstream of intrinsic apoptosis pathway activation. In conclusion, our data argue for a model comprising inhibition of XIAP-mediated blockade of caspase 3/9 as the central effect of SM in chemo-sensitization of childhood ALL cells resistant against SM-alone. Disclosures: No relevant conflicts of interest to declare.

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