Daunorubicin- and Mitoxantrone-Triggered Phosphatidylcholine Hydrolysis: Implication in Drug-Induced Ceramide Generation and Apoptosis

Bettaieb, Ali; Plo, Isabelle; Mas, Véronique Mansat‐De; Quillet‐Mary, Anne; Levade, Thierry; Laurent, Guy; Jaffrézou, Jean‐Pierre

doi:10.1124/mol.55.1.118

Cited by 39 publications

(26 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This result suggests that DNR may trigger in parallel both cell death (CER) and survival (DAG and phosphorylcholine) mediators and that, in sensitive leukemic cells, CER overrides the protective function of DAG and phosphorylcholine. 91 These results support the notion that reciprocal regulation through DAG and CER may be implicated in the regulation of apoptosis. 92 The mechanism by which phosphatidylcholine-derived DAG influenced intracellular CER concentration in DNR-treated cells is not yet characterized; however, because phosphatidylcholinederived DAG did not appear to influence N-SMase stimulation, it is conceivable that DAG enhanced CER metabolism by facilitating sphingomyelin synthesis.…”

Section: Implication Of Phosphatidylcholine Metabolism In Dnr-inducedsupporting

confidence: 80%

Signaling pathways activated by daunorubicin

Laurent

Jaffrézou

2001

Blood

Self Cite

160

117

View full text Add to dashboard Cite

The anthracycline daunorubicin is widely used in the treatment of acute nonlymphocytic leukemia. The drug has, of course, been the object of intense basic research, as well as preclinical and clinical study. As reviewed in this article, evidence stemming from this research clearly demonstrates that cell response to daunorubicin is highly regulated by multiple signaling events, including a sphingomyelinase-initiated sphingomyelin-ceramide pathway, mitogen-activated kinase and stress-activated protein/c-Jun Nterminal kinase activation, transcription factors such as nuclear factor B, as well as the Fas/Fas-ligand system. These pathways are themselves influenced by a number of lipid products (diacylglycerol, sphingosine-1 phosphate, and glucosyl ceramide), reactive oxygen species, oncogenes (such as the tumor suppressor gene p53), protein kinases (protein kinase C and phosphoinositide-3 kinase), and external stimuli (hematopoietic growth factors and the extracellular matrix). In light of the complexity and diversity of these observations, a comprehensive review has been attempted toward the understanding of their individual implication (and regulation) in daunorubicin-induced signaling. IntroductionThe anthracycline daunorubicin (DNR) is one of the major antitumor agents widely used in the treatment of acute myeloid leukemias (AMLs). Cytotoxicity mediated by DNR is generally thought to be the result of drug-induced damage to DNA. This damage is mediated by quinone-generated redox activity, intercalation-induced distortion of the double helix, or stabilization of the cleavable complex formed between DNA and topoisomerase II. 1 However, how and why such events should bring about cell death remains unclear, especially when one considers that DNA interaction may not be a prerequisite for anthracycline cytotoxicity. [2][3][4][5] Hence, the exploration and understanding of the process of apoptosis has forced a reconsideration of the mechanisms whereby myeloid leukemia cells respond to DNR. In this context, we have shown that, within a narrow concentration range (0.2-1 M), DNR can trigger apoptosis in the monocytic U937 or the myelocytic HL-60 AML cells but not in the immature (CD 34 ϩ ) KG1a, KG1, or HEL cells, 6 the latter being more resistant to DNR than the former. 7 These results suggested that DNR triggers apoptotic signals in drug-sensitive AML cells and that inhibition of these signals may contribute to drug resistance and, for example, to the inherent resistance of immature AML cells. For this reason, others and we have investigated the mechanism by which DNR activates apoptosis in DNR-sensitive AML cells. Implication of sphingomyelin metabolism in DNR-induced apoptosis DNR activates the sphingomyelin cycle in sensitive leukemic cellsIn the early 1990s, a number of studies provided growing evidence that sphingomyelin breakdown products (ie, ceramide [CER] and phosphorylcholine) could play an important role in mediating the action of cytokines, including tumor necrosis factor ␣ (TNF␣) and interferon. For example,...

show abstract

Section: Implication Of Phosphatidylcholine Metabolism In Dnr-inducedsupporting

confidence: 80%

Signaling pathways activated by daunorubicin

Laurent

Jaffrézou

2001

Blood

Self Cite

160

117

View full text Add to dashboard Cite

show abstract

“…DNR stimulated N-SMase activity with a maximum of 129 ± 177% increase within 4 ± 15 min in Ba/F3-wt and Ba/F3-Kit cells but not in Ba/F3-KitD27 and Ba/F3-Kit+SCF cells (Figure 3). These results showed that DNR triggered N-SMase activity in Ba/F3 cells with a similar magnitude and kinetics than previously documented in other leukemic cellular models (Allouche et al, 1997(Allouche et al, , 2000BettaõÈ eb et al, 1999;CoÃ me et al, 1999;JareÂ zou et al, 1996;Mansat et al, 1997a,b), and that Kit activation blocked DNRinduced SMase stimulation.…”

Section: Influence Of Kit Activation On Dnr-induced N-smase Stimulationsupporting

confidence: 86%

“…In further studies, we showed that, at least in some leukemic cellular models, DNR activates the sphingomyelin (SM)-ceramide (CER) cycle leading to apoptosis. Indeed, DNR stimulated neutral sphingomyelinase (N-SMase) activity responsible for SM hydrolysis and subsequent CER generation in leukemic cells (Allouche et al, 1997(Allouche et al, , 2000BettaõÈ eb et al, 1999;CoÃ me et al, 1999;JareÂ zou et al, 1996;Mansat et al, 1997a,b). The fact that cell-permeant CER as well as natural CER (generated by exposure of the cells to bacterial SMase) induce apoptosis in these cells strongly suggests that CER plays an important role in DNR-induced apoptosis.…”

Section: Introductionmentioning

confidence: 99%

Kit signaling and negative regulation of daunorubicin-induced apoptosis: role of phospholipase Cγ

et al. 2001

Self Cite

View full text Add to dashboard Cite

Previous studies have demonstrated that activation of Kit by stem cell factor (SCF), its natural ligand, or by gainof-function point mutation in its intracellular domain, confers signi®cant protection against apoptosis induced by growth factor deprivation or radiation. However, the eects of Kit activation on the cellular response to antitumor agents have not been so extensively documented. This study shows that daunorubicin-induced apoptosis and cytotoxicity were reduced in the murine Ba/F3 cells transfected with Kit (Ba/F3-Kit) in the presence of SCF and in Ba/F3 cells transfected with a constitutively active Kit variant (Ba/F3-KitD27), compared to either parental Ba/F3 (Ba/F3-wt) or unstimulated Ba/F3-Kit cells. In Ba/F3-wt and in Ba/F3-Kit cells, daunorubicin stimulated within 8 ± 15 min neutral sphingomyelinase and ceramide production but not in SCF-stimulated Ba/F3-Kit or in Ba/F3-KitD27 whereas all Ba/F3 cells were equally sensitive to exogenous cell-permeant C6-ceramide. In Ba/F3-Kit, SCF-induced Kit activation resulted in a rapid phospholipase Cg (PLCg) tyrosine phosphorylation followed by diacylglycerol release and protein kinase C (PKC) stimulation. U-73122, a PLCg inhibitor, not only blocked diacylglycerol production and PKC stimulation but also restored daunorubicin-induced sphingomyelinase stimulation, ceramide production, and apoptosis. These results suggest that Kit activation results in PLCg-mediated PKC-dependent sphingomyelinase inhibition which contributes to drug resistance in Kit-related malignancies. Oncogene (2001) 20, 6752 ± 6763.

show abstract

“…Several chemotherapeutic drugs were shown to activate a sphingomyelinase in leukemic cells, including daunorubicin, mitoxantrone, etoposide, vincristine, dexamethasone, ara-C and cis-platinum. [206][207][208][209] …”

Section: Lipid-dependent Signaling Pathwaysmentioning

confidence: 99%

Positive and negative regulation of apoptotic pathways by cytotoxic agents in hematological malignancies

et al. 2000

View full text Add to dashboard Cite

Most chemotherapeutic drugs can induce tumor cell death by apoptosis. Analysis of the molecular mechanisms that regulate apoptosis has indicated that anticancer agents simultaneously activate several pathways that either positively or negatively regulate the death process. The main pathway from specific damage induced by the drug to apoptosis involves activation of caspases in the cytosol by pro-apoptotic molecules such as cytochrome c released from the mitochondrial intermembrane space. At least in some cell types, anticancer drugs also upregulate the expression of death receptors and sensitize tumor cells to their cognate ligands. The Fas-mediated pathway could contribute to the early steps of drug-induced apoptosis while sensitization to the cytokine TRAIL could be used to amplify the response to cytotoxic drugs. The Bcl-2 family of proteins, that includes anti-and pro-apoptotic molecules, regulates cell sensitivity mainly at the mitochondrial level. Anticancer drugs modulate their expression (eg through p53-dependent gene transcription), their activity (eg by phosphorylating Bcl-2) and their subcellular localization (eg by inducing the translocation of specific BH3-only pro-apoptotic proteins). Very early after interacting with tumor cells, anticancer drugs also activate lipid-dependent signaling pathways that either increase or decrease cell ability to die by apoptosis. In addition, cytotoxic agents can activate protective pathways that involve activation of NF B transcription factor, accumulation of heat shock proteins such as Hsp27 and activation of proteins involved in cell cycle regulation. This review discusses how modulation of the balance between noxious and protective signals that regulate drug-induced apoptosis could be used to improve the efficacy of current therapeutic regimens in hematological malignancies.

show abstract

Daunorubicin- and Mitoxantrone-Triggered Phosphatidylcholine Hydrolysis: Implication in Drug-Induced Ceramide Generation and Apoptosis

Cited by 39 publications

References 39 publications

Signaling pathways activated by daunorubicin

Signaling pathways activated by daunorubicin

Kit signaling and negative regulation of daunorubicin-induced apoptosis: role of phospholipase Cγ

Positive and negative regulation of apoptotic pathways by cytotoxic agents in hematological malignancies

Contact Info

Product

Resources

About