Enhanced ceramide generation and induction of apoptosis in human leukemia cells exposed to DT388–granulocyte-macrophage colony-stimulating factor (GM-CSF), a truncated diphtheria toxin fused to human GM-CSF

Senchenkov, Alex; Han, Tian; Wang, Hongtao; Frankel, Arthur E.; Kottke, Timothy; Kaufmann, Scott H.; Cabot, Myles C.

doi:10.1182/blood.v98.6.1927

Cited by 17 publications

(8 citation statements)

References 58 publications

(70 reference statements)

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“…Diphtheria toxin conjugated to granulocytemacrophage colony-stimulating factor (DT(388)-GM-CSF) elevated ceramide levels significantly and decreased the viability in vincristine resistant HL60 cells. Similar results were obtained for parental sensitive counterparts [137]. Treatment of HL60 cells with cytosine arabinoside increased ceramide levels in a time-and dosedependent manner.…”

Section: Sphingolipids In the Perspective Of Chemo-therapeutic Responsesupporting

confidence: 76%

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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Section: Sphingolipids In the Perspective Of Chemo-therapeutic Responsesupporting

confidence: 76%

Bioactive Sphingolipids in Response to Chemotherapy: A Scope on Leukemias

Ekiz

Baran²

2011

ACAMC

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“…7,8 We have previously shown that the 425.3-PE IT is active against breast cancer in experimental animal models, 12 and these findings prompted us to investigate the mechanism involved in 425.3PE-induced effects.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of the antiapoptotic MCL‐1 protein and apoptosis in MA‐11 breast cancer cells induced by an anti‐epidermal growth factor receptor–Pseudomonas exotoxin a immunotoxin

Andersson

Juell

Fodstad

2004

Intl Journal of Cancer

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Pseudomonas exotoxin (PE)-containing immunotoxins (ITs) act by arresting protein synthesis and promoting apoptosis, but the mechanisms of the induced apoptosis and the relationship to protein synthesis inhibition is not well elucidated. We studied these effects in MA Key words: immunotoxin; apoptosis; Mcl-1; breast cancerITs represent one group of targeted therapeutics that have shown promising efficacy in patients for whom standard treatment is no longer an option. 1,2 ITs are dimeric proteins consisting of a targeting moiety linked to a toxin (ricin, PE, DT), which induce arrest of protein synthesis and result in cell death. 1 The targeting moiety binds to molecules expressed on cancer cells, theoretically leaving normal cells unaffected.The mechanism of action of such toxins and ITs is not, as previously believed, merely inhibition of protein synthesis in the cell. Thus, ricin, PE and DT may also induce apoptosis, a feature of major importance in cancer therapy. 3,4 Two common features of apoptotic cell death are activation of a group of cysteine proteases called caspases and caspase-catalyzed cleavage of so-called death substrates, such as the nuclear repair enzyme PARP. 5 Caspases are present in cells as inactive precursors, which are proteolytically activated upon induction of apoptosis. The protein substrates of caspases include proteins of regulatory or structural function in cell life. Caspases play a central role in the apoptotic program, functioning as initiators and executors of the apoptotic pathway. Caspase-3, e.g., is directly involved in apoptosis induced by both toxins and ITs in several human tumor cell lines. 6 -8 The Bcl-2 protein family is a major molecular modulator of apoptosis. 9,10 These proteins can be divided into 2 groups, including antiapoptotic (Bcl-2, Mcl-1, Bcl-X L ) and proapoptotic (Bax, Bak, Bad) molecules that regulate cellular sensitivity to drugs at the mitochondrial level. Pro-and antiapoptotic family members can heterodimerize and titrate each other's function, implying that their relative concentration may act as a balance in the suicide program. 11 Therapeutic drugs can modulate the expression of Bcl-2 family members, their activity and their subcellular localization.We have previously shown that the 425.3PE IT increased symptom-free survival in a human breast cancer model in nude rats 12 and wanted to investigate the mechanisms underlying the ITinduced cell death. This IT consists of the 425.3 MAb, which targets the EGFr and covalently links to the bacterial toxin PE. 12 It is well known that PE-containing ITs induce protein synthesis arrest by inactivation of EF-2, but it remains to be elucidated how this is linked to apoptosis.In the present study, we demonstrate simultaneous induction of apoptosis and protein synthesis inhibition by the holo-PE-containing IT in MA-11 breast cancer cells. Thus, upon IT treatment, expression of the antiapoptotic protein Mcl-1 was quickly and markedly reduced. The IT also induced loss of ⌬⌿ mito and activation of the caspase cascade, f...

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“…Several recent in vitro studies have explored the immune effects of GM‐CSF fused to a diphtheria toxin (DT) carrier protein. Senchenkov et al have demonstrated that DT(388)‐GM‐CSF stimulates ceramide formation, which, in turn, induces the apoptosis of human leukemia cells 108. Other preliminary work by Kim et al resulted in similar findings, suggesting a synergistic apoptotic response of DT(388)‐GM‐CSF combined with cytosine arabinoside 109…”

Section: Future Directions For Antitumor Studies Using Cytokinesmentioning

confidence: 86%

Modulation of antitumor immune responses by hematopoietic cytokines

Waller¹,

Ernstoff²

2003

Cancer

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BACKGROUNDAdvances in immunotherapy for the treatment of patients with malignant disease have led to increasingly successful use of these methods in the clinical setting. This review presents findings from recent studies that have explored improved methods for the presentation of tumor‐associated antigens and for the restoration of tumor specific immune responses using cytokine therapy.METHODSA review of human clinical trial research on immune cytokines from 1995 (MEDLINE) to the present was conducted. Particular attention was focused on articles that reported results from Phase II or later clinical studies in patients with malignant disease.RESULTSThe defects in cellular immunity commonly seen in patients with malignancies often are expressed as tumor specific anergy. Reversing patient tolerance to tumor antigens may be accomplished by treatment with immunoregulatory cytokines, such as Flt‐3 and granulocyte‐macrophage–colony stimulating factor, that mature and activate dendritic cells. Published clinical studies indicate that granulocyte‐macrophage–colony stimulating factor stimulates antigen‐presenting cells and has promising antitumor activity as an adjunct or as stand‐alone therapy for patients with malignant disease, including leukemia, melanoma, breast carcinoma, prostate carcinoma, and renal cell carcinoma.CONCLUSIONSImmune‐modulating cytokines may be used alone or in combination with other treatments to help restore immune function, improve response to tumor‐associated antigens, and reduce the toxic effects of standard antitumor therapies. The evolving understanding of how dendritic cells regulate immune responses and promising results from published studies of immune‐enhancing cytokines in the treatment of patients with malignant disease support the conduct of randomized clinical trials to confirm the clinical benefit of these immunotherapeutic strategies. Cancer 2003;97:1797–809. © 2003 American Cancer Society.DOI 10.1002/cncr.11247

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Enhanced ceramide generation and induction of apoptosis in human leukemia cells exposed to DT388–granulocyte-macrophage colony-stimulating factor (GM-CSF), a truncated diphtheria toxin fused to human GM-CSF

Cited by 17 publications

References 58 publications

Bioactive Sphingolipids in Response to Chemotherapy: A Scope on Leukemias

Bioactive Sphingolipids in Response to Chemotherapy: A Scope on Leukemias

Downregulation of the antiapoptotic MCL‐1 protein and apoptosis in MA‐11 breast cancer cells induced by an anti‐epidermal growth factor receptor–Pseudomonas exotoxin a immunotoxin

Modulation of antitumor immune responses by hematopoietic cytokines

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