Arsenic trioxide induces accumulation of cytotoxic levels of ceramide in acute promyelocytic leukemia and adult T-cell leukemia/lymphoma cells through de novo ceramide synthesis and inhibition of glucosylceramide synthase activity

Dbaibo, Ghassan; Kfoury, Youmna; Darwiche, Nadine; Panjarian, Shoghag; Kozhaya, Lina; Nasr, Rihab; Abdallah, M.; Hermine, Olivier; El-Sabban, Marwan; Bazarbachi, Ali

doi:10.3324/haematol.10968

Cited by 47 publications

(32 citation statements)

References 52 publications

(31 reference statements)

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“…However, given the contrasting functions of SK1 and SK2 in regulating cell survival, future investigation into the differential effects of SK1 and SK2 on autophagy induction and function would be intriguing. In contrast to S1P, the current literature supports the notion that ceramide-induced autophagy functions to promote cell death, either through the induction of autophagic cell death ( 84,88,97,98,102,103 ) or by "switching" off autophagy and inducing apoptosis through the calpain-mediated cleavage of Atg5 ( 109,110 ) and/or iDISC formation ( 30 ). Consistent with the "many ceramides" hypothesis and recent reports demonstrating the chain-length-specifi c properties of ceramides in the induction of apoptosis, it is likely that individual ceramide species may differentially regulate autophagy.…”

Section: Downloaded Frommentioning

confidence: 76%

“…Exogenous C2-ceramide, tamoxifen, and PDMP enhance the expression of Beclin 1 to promote autophagy ( 85 ). Increased expression of Beclin 1 is a contributing factor in the induction of lethal autophagy in human leukemia cell lines treated with arsenic trioxide, an agent that stimulates de novo ceramide synthesis and inhibits ceramide metabolism to glucosylceramide ( 97,98 ). Ceramide is a well-established activator of the stressactivated kinase JNK ( 99,100 ), and the JNK-mediated activation of the transcription factor c-Jun enhances Beclin 1 expression ( 89 ).…”

Section: Ceramidementioning

confidence: 99%

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Sphingolipids: regulators of crosstalk between apoptosis and autophagy

Young

Kester

Wang

2013

Journal of Lipid Research

293

274

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decades ago, pioneering work by Hannun et al. and Kolesnick et al. established the foundation for the bioactive nature of sphingolipids by demonstrating the inhibition of protein kinase C (PKC) by sphingosine and the stimulation of a ceramide-activated protein kinase in response to tumor necrosis factor (TNF)-␣ , respectively ( 1, 2 ). Sphingolipids have since been recognized as critical activators or inhibitors of various protein kinases and phosphatases, receptors, and ion transporters ( 3 ). Moreover, sphingolipids have been identifi ed as key regulators of a vast number of cellular processes, including cell growth, adhesion, migration, senescence, apoptosis, and most recently, autophagy ( 3, 4 ).Much of the investigation into sphingolipid signaling has focused on the disparate nature of ceramide and sphingosine-1-phosphate (S1P). Ceramide is typically associated with growth arrest and apoptosis, while S1P promotes cell proliferation and survival. The opposing nature and dynamic balance of intracellular ceramide and S1P, termed the "sphingolipid rheostat," has been proposed to determine cell fate ( 5 ). However, emerging evidence and extensive characterization of the sphingolipid metabolic network suggests that this two-dimensional model does not adequately refl ect sphingolipid signaling and function within the cell. In addition to ceramide and S1P, other sphingolipid metabolites, such as sphingosine, dihydroceramide, and gangliosides, have been implicated in the regulation of apoptosis and macroautophagy (hereafter referred to as autophagy). Although autophagy is typically considered to be a cytoprotective mechanism for the suppression of apoptosis, recent evidence indicates that autophagy can also promote cell death ( 6 ). Due to the differential regulation of apoptosis and autophagy by sphingolipid metabolites, the sphingolipid network has emerged as a novel molecular switch between the apoptotic and autophagic Abstract Apoptosis and autophagy are two evolutionarily conserved processes that maintain homeostasis during stress. Although the two pathways utilize fundamentally distinct machinery, apoptosis and autophagy are highly interconnected and share many key regulators. The crosstalk between apoptosis and autophagy is complex, as autophagy can function to promote cell survival or cell death under various cellular conditions. The molecular mechanisms of crosstalk are beginning to be elucidated and have critical implications for the treatment of various diseases, such as cancer. Sphingolipids are a class of bioactive lipids that mediate many key cellular processes, including apoptosis and autophagy. By targeting several of the shared regulators, sphingolipid metabolites differentially regulate the induction of apoptosis and autophagy. Importantly, individual sphingolipid species appear to "switch" autophagy toward cell survival (e.g., sphingosine-1-phosphate) or cell death (e.g., ceramide, gangliosides). This review assesses the current understanding of sphingolipid-induced apoptosis and autophagy to addr...

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Section: Downloaded Frommentioning

confidence: 76%

Section: Ceramidementioning

confidence: 99%

Sphingolipids: regulators of crosstalk between apoptosis and autophagy

Young

Kester

Wang

2013

Journal of Lipid Research

293

274

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“…Arsenic trioxide (APL) [188] Resveratrol (APL, CML) [188] ing macrophages and developing embryos which suggests its importance for maintaining homeostasis in healthy cells as well [49,50]. Furthermore, apoptotic induction by ceramides is a known mechanism for stress-induced cell death as shown by numerous studies [51][52][53][54].…”

Section: Dihydrosphingosinementioning

confidence: 99%

“…Radiation and chemotherapy are among the causative factors identified so far [186]. Ceramide appears to be important in the chemotherapeutic cytotoxicity for AML cells as well [187,188]. Studies with AML cells showed that ceramides might be important for heat-shock induced apoptosis [189].…”

Section: Targeting Sphingolipid Metabolism For the Treatment Of Leukementioning

confidence: 99%

Bioactive Sphingolipids in Response to Chemotherapy: A Scope on Leukemias

Ekiz

Baran²

2011

ACAMC

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Sphingolipids are major constituents of the cells with emerging roles in the regulation of cellular processes. Deregulation of sphingolipid metabolism is reflected as various pathophysiological conditions including metabolic disorders and several forms of cancer. Ceramides, ceramide-1-phosphate (C1P), glucosyl ceramide (GluCer), sphingosine and sphingosine-1-phosphate (S1P) are among the bioactive sphingolipid species that have important roles in the regulation of cell death, survival and chemotherapeutic resistance. Some of those species are known to accumulate in the cells upon chemotherapy while some others are known to exhibit an opposite pattern. Even though the length of fatty acid chain has a deterministic effect, in general, upregulation of ceramides and sphingosine is known to induce apoptosis. However, S1P, C1P and GluCer are proliferative for cells and they are involved in the development of chemoresistance. Therefore, sphingolipid metabolism appears as a good target for the development of novel therapeutics or supportive interventions to increase the effectiveness of the chemotherapeutic drugs currently in hand. Some approaches involve manipulation of the synthesis pathways yielding the increased production of apoptotic sphingolipids while the proliferative ones are suppressed. Some others are trying to take advantage of cytotoxic sphingolipids like short chain ceramide analogs by directly delivering them to the malignant cells as a distinct chemotherapeutic intervention. Numerous studies in the literature show the feasibility of those approaches especially in acute and chronic leukemias. This review compiles the current knowledge about sphingolipids and their roles in chemotherapeutic response with the particular attention to leukemias.

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“…Additionally, it is safe to use this compound since, as opposed to arsenic trioxide (As 2 O 3 ), it may be orally administered and the main adverse effects, such as gastrointestinal reactions and hepatic dysfunction, are highly manageable. Although a few studies on the effectiveness of the As 2 O 3 on blood disorders are currently available, the number of studies on the effectiveness of the As 2 S 2 on NHLs is limited (4)(5)(6)(7)(8)(9)(10)(11).…”

Section: Introductionmentioning

confidence: 99%

Effects of arsenic sulfide (As2S2) on B and T lymphoma cell lines and possible underlying mechanisms

Liu

et al. 2013

Biomedical Reports

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Abstract. Lymphoma is a hematological malignancy that originates from lymph nodes and lymphoid tissues and is divided into Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL), based on its histopathological characteristics. The aim of this study was to investigate the effects of arsenic sulfide (As 2 S 2 ), the main ingredient of realgar, on the proliferation and apoptosis of the Raji B-cell lymphoma and Jurkat T-cell lymphoma lines, comparing the sensitivity between the two cell lines and investigating the possible underlying mechanisms. The two lymphoma cell lines were cultured in vitro, using different concentrations of As 2 S 2 for different time periods. The cell proliferation was detected using the Cell Counting kit-8 (CCK-8). Apoptosis was assessed via flow cytometry. Expression levels of the apoptosis-associated genes [Homo sapiens Bcl-2-associated X protein (BAX), Homo sapiens B-cell CLL/lymphoma 2 (Bcl-2), Homo sapiens Bcl-2-like protein 1 (BCL2L1, Bcl-xL), Homo sapiens v-myc myelocytomatosis viral oncogene homolog (avian) (MYC, c-Myc) and Homo sapiens pim-1 oncogene (PIM)] were measured via the reverse transcription polymerase chain reaction (RT-PCR) method. The results demonstrated that As 2 S 2 inhibited proliferation and induced apoptosis in the two lymphoma cell lines in a time-and concentration-dependent manner, with the Raji cells being more sensitive to As 2 S 2 compared to Jurkat cells. As 2 S 2 may also alter the expression levels of different apoptosis-associated genes, with the alterations of the mRNA expression levels being different between Raji and Jurkat cells. These findings indicated that As 2 S 2 may inhibit the proliferation and promote the apoptosis of non-Hodgkin lymphoma (NHL) cell lines and that B-cell lymphoma cell lines are more sensitive compared to T-cell lymphoma cell lines. The possible underlying mechanism is that As 2 S 2 alters the expression levels of the apoptosis-associated genes and activates apoptosis-associated signaling pathways.

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Arsenic trioxide induces accumulation of cytotoxic levels of ceramide in acute promyelocytic leukemia and adult T-cell leukemia/lymphoma cells through de novo ceramide synthesis and inhibition of glucosylceramide synthase activity

Cited by 47 publications

References 52 publications

Sphingolipids: regulators of crosstalk between apoptosis and autophagy

Sphingolipids: regulators of crosstalk between apoptosis and autophagy

Bioactive Sphingolipids in Response to Chemotherapy: A Scope on Leukemias

Effects of arsenic sulfide (As2S2) on B and T lymphoma cell lines and possible underlying mechanisms

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