Involvement of the CD95 (APO–1/Fas) receptor/ligand system in drug–induced apoptosis in leukemia cells

Friesen, Claudia; Herr, Ingrid; Krammer, Peter H.; Debatin, Klaus‐Michael

doi:10.1038/nm0596-574

Cited by 907 publications

(668 citation statements)

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“…For this purpose, a number of di erent cell clones were employed, which were either devoid of individual caspases or which expressed proteins interfering with discrete steps of the apoptotic cascade. It has been proposed that the CD95 system is involved in anticancer drug-induced cell death (Friesen et al, 1996;Fulda et al, 1997aFulda et al, ,1998MuÈ ller et al, 1997;Herr et al, 1998). However, we and others have recently demonstrated that anticancer drugs induce apoptosis by a mitochondrial pathway that is independent of death receptors.…”

Section: Discussionmentioning

confidence: 83%

“…It has been demonstrated that chemotherapeutic drugs induce the expression of CD95 and CD95L. Therefore, it was proposed that drug-induced apoptosis is mediated in a paracrine or autocrine loop via CD95/CD95L interaction, analogously to T cell receptor-mediated cell death (Friesen et al, 1996;Fulda et al, 1997aFulda et al, , 1998MuÈ ller et al, 1997;Herr et al, 1998;Dhein et al, 1995). However, there are also reports indicating that anticancer drugs induce apoptosis independently of death receptors Wesselborg et al, 1999;Eischen et al, 1997;Gamen et al, 1997;Villunger et al, 1997;Fulda et al, 1997b;Tolomeo et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

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Caspase-8/FLICE functions as an executioner caspase in anticancer drug-induced apoptosis

et al. 2000

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Caspase-8 plays an essential role in apoptosis triggered by death receptors. Through the cleavage of Bid, a proapoptotic Bcl-2 member, it further activates the mitochondrial cytochrome c/Apaf-1 pathway. Because caspase-8 can be processed also by anticancer drugs independently of death receptors, we investigated its exact role and order in the caspase cascade. We show that in Jurkat cells either de®cient for caspase-8 or overexpressing its inhibitor c-FLIP apoptosis mediated by CD95, but not by anticancer drugs was inhibited. In the absence of active caspase-8, anticancer drugs still induced the processing of caspase-9, -3 and Bid, indicating that Bid cleavage does not require caspase-8. Overexpression of Bcl-x L prevented the processing of caspase-8 as well as caspase-9, -6 and Bid in response to drugs, but was less e ective in CD95-induced apoptosis. Similar responses were observed by overexpression of a dominant-negative caspase-9 mutant. To further determine the order of caspase-8 activation, we employed MCF7 cells lacking caspase-3. In contrast to caspase-9 that was cleaved in these cells, anticancer drugs induced caspase-8 activation only in caspase-3 transfected MCF7 cells. Thus, our data indicate that, unlike its proximal role in receptor signaling, in the mitochondrial pathway caspase-8 rather functions as an amplifying executioner caspase.

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Section: Discussionmentioning

confidence: 83%

Section: Introductionmentioning

confidence: 99%

Caspase-8/FLICE functions as an executioner caspase in anticancer drug-induced apoptosis

et al. 2000

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“…Injection of anti-Fas MAb into mice carrying lymphoma xenotransplants can induce tumour regression (Coney et al, 1994;Durandy et al, 1997). The Fas/FasL apoptotic pathway may also play a role in the action of chemotherapeutic drugs (Friesen et al, 1996;Landowski et al, 1997). Taken together, these observations suggest that Fas may be involved in the regulation of in vivo lymphoma growth and that Fas triggering may be a promising strategy for treatment of NHLs.…”

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confidence: 99%

Sensitivity to Fas-mediated apoptosis is null or weak in B-cell non-Hodgkin's lymphomas and is moderately increased by CD40 ligation

Xerri

Bouabdallah²,

Devilard³

et al. 1998

Br J Cancer

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Summary The Fas receptor (APO-1/CD95) is capable of inducing apoptosis of lymphoid cells and is expressed in some non-Hodgkin's lymphomas (NHLs). Fas expression is up-regulated at the surface of normal B cells upon triggering of the CD40 receptor. In this report, we investigated the sensitivity of NHLs to Fas-mediated apoptosis induced by anti-Fas monoclonal antibodies (MAbs) and its possible modulation by CD40 ligation in 18 NHL biopsy samples of various histological subtypes. Flow cytometric analysis showed that the fraction of Fas-expressing lymphoma cells was highly variable from sample to sample (from 1% to 93%, mean value 46%). The frequency of apoptotic cells was not significantly increased upon treatment with an anti-Fas MAb compared with control MAb in the 18 NHL cases analysed. The sensitivity of lymphoma cells to Fas-mediated apoptosis was correlated neither with the histological subtypes nor with the level of Fas expression. Activation of neoplastic B cells by CD40 ligation resulted in significant increases in Fas expression and Fas-induced apoptosis among the five B-NHL cases tested. The overall increase in apoptotic rates was moderate and remained lower in tumour samples than in control CD40-activated normal tonsil B cells. Altogether, our results indicate that the sensitivity to Fas-induced apoptosis is null or weak in NHL cells, irrespective of their histological subtype, and that it can be increased to a moderate and variable degree by CD40 ligation on neoplastic B cells. This may be an impediment to the development of Fas-based therapies for NHLs.Keywords: Fas; CD95; apoptosis; CD40; non-Hodgkin's lymphoma; Apo2.7 antibody; 7A6 antigen Dysregulation of programmed cell death, or apoptosis, can lead to aberrant cell accumulation and is recognized as a possible cause of neoplasia (Korsmeyer, 1992). The contribution of apoptosis is crucial in the pathogenesis of some non-Hodgkin's lymphomas (NHLs), such as follicular B-cell NHLs. In this particular NHL type, expression of the Bcl-2 antiapoptotic protein is increased in up to 85% of cases, because of a rearrangement of the BCL-2 gene (Bakhshi et al, 1985).The possible influence of apoptosis abnormalities on the growth of other NHL types is still debated. One of the major pathways regulating apoptosis in lymphoid cells appears to be mediated by the Fas antigen (APO-l/CD95), a 45-kDa membrane protein belonging to the tumour necrosis factor receptor (TNFR) superfamily (Itoh et al, 1991;Oehm et al, 1992;Armitage, 1994). Mice deficient in Fas or its ligand (FasL) are known as Ipr and gld mice respectively (Watanabe-Fukunaga et al, 1992;Lynch et al, 1994). They develop massive lymphadenopathy, splenomegaly, B-cell activation and autoimmunity owing to unscheduled lymphocyte accumulation (Watanabe-Fukunaga et al, 1992;Lynch et al, 1994). In addition, Fas has also been demonstrated to act as a tumoursuppressor gene in some particular conditions (Peng et al, 1996).Fas is expressed in various human lymphoproliferations (M6ller et al, 1993; Xerri et al, 1995a)...

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“…Several studies demonstrated that a variety of widely used anticancer drugs kill cancer cells through induction of apoptosis (Walker et al, 1991;Vial et al, 1997), and some authors observed that antineoplastic agents can induce apoptosis through a Fas/ Fas-ligand-dependent pathway (Friesen et al, 1996;Fulda et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

“…Many mechanisms for caspase activation probably exist, but the best documented is that involving several members of the tumour necrosis factor (TNF) family of cytokine receptors including TNF-R1 and Fas (CD95/APO-1) (Nagata & Golstein, 1995). Although, it has been observed that antineoplastic agents can induce apoptosis through a Fas/Fas-ligand-dependent pathway (Friesen et al, 1996;Fulda et al, 1997) currently there are many controversial and diverging opinions about its implication in drug-induced apoptosis and many studies, including our previous observations, indicate that antineoplastic treatments trigger apoptosis through a Fas-independent pathway (Villunger et al, 1997;Eischen et al, 1997;Tolomeo et al, 1998). It is possible that these divergent results could depend on the di erent experimental models used.…”

Section: Introductionmentioning

confidence: 99%

Effects of chemically modified tetracyclines (CMTs) in sensitive, multidrug resistant and apoptosis resistant leukaemia cell lines

Tolomeo

Grimaudo

Milano

et al. 2001

British J Pharmacology

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1 Recently discovered chemically modi®ed tetracyclines (CMTs) have shown in vitro and in vivo anti-proliferative and anti-tumour activities. Here, we evaluated in vitro the anti-proliferative and apoptotic activity of six di erent dedimethylamino chemically modi®ed tetracyclines (CMT-1, CMT-3, CMT-5, CMT-6, CMT-7 and CMT-8) in sensitive and multidrug resistant myeloid leukaemia cells (HL60 and HL60R) in vitro. 2 Three of these compounds (CMT-5, CMT-6, CMT-7) showed low cytotoxic activity both in sensitive and in resistant cells, CMT-3 was endowed with a high anti-proliferative activity only in sensitive cells and was moderately e ective as apoptosis inducing agent, with an activity similar to that shown by doxycycline. On the contrary, CMT-1 and CMT-8 were very e ective as programmed cell death inducing agents. 3 The apoptotic pathway activated by these compounds involved the activation of caspases, especially caspase-9 and, for CMT-1, also the activation of Fas. 4 Interestingly CMT-8, but not CMT-1, was able to induce apoptosis in multidrug resistant HL60R and in Fas-ligand resistant HUT78B1 cell lines. These properties, together with others previously described (e.g. anti-metastatic and anti-osteolytic activities), suggest that CMT-8 may have important applications in the clinical management of cancer. 5 The comparative analysis of structure-activity relationship of CMT-8 and doxycycline suggests that the C-5 hydroxy moiety may play an important role in conferring activity in multidrug resistant cells. These ®ndings appear to support the hypothesis that CMT-8 may represent an interesting lead for the development of a new class of potent apoptosis inducer agents active in multidrug resistant and Fas-ligand resistant malignancies.

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Involvement of the CD95 (APO–1/Fas) receptor/ligand system in drug–induced apoptosis in leukemia cells

Cited by 907 publications

References 22 publications

Caspase-8/FLICE functions as an executioner caspase in anticancer drug-induced apoptosis

Caspase-8/FLICE functions as an executioner caspase in anticancer drug-induced apoptosis

Sensitivity to Fas-mediated apoptosis is null or weak in B-cell non-Hodgkin's lymphomas and is moderately increased by CD40 ligation

Effects of chemically modified tetracyclines (CMTs) in sensitive, multidrug resistant and apoptosis resistant leukaemia cell lines

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