Actinomycin D induces p53-independent cell death and prolongs survival in high-risk chronic lymphocytic leukemia

Merkel, Olaf; Wacht, Nathalie; Sifft, Eveline; Melchardt, Thomas; Hamacher, Frank; Köcher, Thomas; Denk, Ursula; Hofbauer, Josefina Piñón; Egle, Alexander; Scheideler, Marcel; Schlederer, Michaela; Steurer, Michael; Kenner, Lukas; Greil, Richard

doi:10.1038/leu.2012.147

Cited by 23 publications

(15 citation statements)

References 46 publications

(71 reference statements)

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“…Low doses of Act D also induce ribosomal stress and the sequestration of MDM2 by free ribosomal proteins, leading to the accumulation of p53 [7]. However, Act D induces p53-independent cell death and prolongs survival in chronic lymphocytic leukemia [8]. These studies indicate a potential for Act D as a therapeutic agent for a variety of cancers, either as monotherapy or in combination with other drugs.…”

Section: Introductionmentioning

confidence: 93%

Upregulation of heat shock protein 27 confers resistance to actinomycin D‐induced apoptosis in cancer cells

Teng

Hua

et al. 2013

The FEBS Journal

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Actinomycin D (Act D) is a general transcriptional inhibitor that is approved for the treatment of sarcomas, and Wilms, germ cell and trophoblastic tumors. Little is known about the molecular mechanisms that dictate the sensitivity of cancer cells to Act D. In this study, we investigated the effects of Act D on heat shock proteins (HSPs) and the expression and roles of HSP27 in Act D-induced cancer cell apoptosis. We show that Act D upregulates HSP27 and HSP70 expression in cancer cells, whereas it inhibits HSP90 expression. The upregulation of HSP27 by Act D is not attributable to changes in HSP27 transcription or HSP27 synthesis. HSP27 knockdown leads to an increase in Act D-induced caspase 3 and caspase 7 cleavage, and sensitizes rhabdosarcoma cells and breast cancer cells to Act D-induced apoptosis. We conclude that upregulation of HSP27 represents an adaptive response that compromises the anticancer activity of Act D.

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Section: Introductionmentioning

confidence: 93%

Upregulation of heat shock protein 27 confers resistance to actinomycin D‐induced apoptosis in cancer cells

Teng

Hua

et al. 2013

The FEBS Journal

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“…Therefore, therapeutics that target the antiapoptotic pathway represent valuable strategies for CLL treatment. Preclinical studies of actinomycin D 108 and silvestrol (a plant-derived cyclopenta[b] benzofuran) 109 that, respectively, inhibit transcription and translation, and of 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) (a derivative of the heat shock protein 90 inhibitor geldanamycin) 94 showed promising results and were indeed associated with a reduction in the levels of antiapoptotic proteins. The studies may provide a rationale for the treatment of CLL cases carrying a deletion of the 17p locus (that are resistant to standard chemotherapy including fludarabine) 110 with actinomycin D or silvestrol, which can induce apoptosis in a P53-independent fashion.…”

Section: Em-tcl1 Transgenic Mouse Model As a Preclinical Model For Nomentioning

confidence: 99%

“…The studies may provide a rationale for the treatment of CLL cases carrying a deletion of the 17p locus (that are resistant to standard chemotherapy including fludarabine) 110 with actinomycin D or silvestrol, which can induce apoptosis in a P53-independent fashion. 108,109 Epigenome targeting. Finally, CLL cells display epigenetic alterations, and evidence suggests that overexpression of histone deacetylase enzymes contributes to CLL pathogenesis.…”

Section: Em-tcl1 Transgenic Mouse Model As a Preclinical Model For Nomentioning

confidence: 99%

Mouse models in the study of chronic lymphocytic leukemia pathogenesis and therapy

Simonetti

Bertilaccio

Ghia

et al. 2014

Blood

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Mouse models that recapitulate human malignancy are valuable tools for the elucidation of the underlying pathogenetic mechanisms and for preclinical studies. Several genetically engineered mouse models have been generated, either mimicking genetic aberrations or deregulated gene expression in chronic lymphocytic leukemia (CLL). The usefulness of such models in the study of the human disease may potentially be hampered by species-specific biological differences in the target cell of the oncogenic transformation. Specifically, do the genetic lesions or the deregulated expression of leukemia-associated genes faithfully recapitulate the spectrum of lymphoproliferations in humans? Do the CLL-like lymphoproliferations in the mouse have the phenotypic, histological, genetic, and clinical features of the human disease? Here we compare the various CLL mouse models with regard to disease phenotype, penetrance, and severity. We discuss similarities and differences of the murine lymphoproliferations compared with human CLL. We propose that the Eμ-TCL1 transgenic and 13q14-deletion models that have been comprehensively studied at the levels of leukemia phenotype, antigen-receptor repertoire, and disease course show close resemblance to the human disease. We conclude that modeling CLL-associated genetic dysregulations in mice can provide important insights into the molecular mechanisms of disease pathogenesis and generate valuable tools for the development of novel therapies.

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“…However, NTSR1 knockdown could significantly downregulate the expression of Bcl-w but not sharply alter the expression of Bcl-2 (Figure 4C). It was reported that actinomycin D and doxorubicin could downregulate Bcl-2 expression (Merkel et al , 2012; Florou et al , 2013). So we added low concentration of actinomycin D and doxorubicin in NTSR1-downregulated cells and the results showed that both Bcl-w and Bcl-2 was inhibited, thus sensitising actinomycin D-induced apoptosis (Figure 3D and F, Supplementary Figures S4A–B).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of neurotensin receptor 1 induces intrinsic apoptosis via let-7a-3p/Bcl-w axis in glioblastoma

et al. 2017

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Backgroud:Glioblastoma is a kind of highly malignant and aggressive tumours in the central nervous system. Previously, we found that neurotensin (NTS) and its high-affinity receptor 1 (NTSR1) had essential roles in cell proliferation and invasiveness of glioblastoma. Unexpectedly, cell death also appeared by inhibition of NTSR1 except for cell cycle arrest. However, the mechanisms were remained to be further explored.Methods:Cells treated with SR48692, a selective antagonist of NTSR1, or NTSR1 shRNA were stained with Annexin V-FITC/PI and the apoptosis was assessed by flow cytometry. Cytochrome c release was detected by using immunofluorescence. Mitochondrial membrane potential (MMP, ΔΨm) loss was stained by JC-1 and detected by immunofluorescence or flow cytometry. Apoptosis antibody array and microRNA microarray were performed to seek the potential regulators of NTSR1 inhibition-induced apoptosis. Interaction between let-7a-3p and Bcl-w 3′UTR was evaluated by using luciferase assay.Results:SR48692 induced massive apoptosis, which was related to mitochondrial cytochrome c release and MMP loss. Knockdown of NTSR1 induced slight apoptosis and significant MMP loss. In addition, NTSR1 inhibition sensitised glioblastoma cells to actinomycin D or doxorubicin-induced apoptosis. Consistently, NTSR1 inhibition-induced mitochondrial apoptosis was accompanied by downregulation of Bcl-w and Bcl-2. Restoration of Bcl-w partly rescued NTSR1 deficiency-induced apoptosis. In addition, NTSR1 deficiency promoted higher let-7a-3p expression and inhibition let-7a-3p partly rescued NTSR1 inhibition-induced apoptosis. In addition, let-7a-3p inhibition promoted 3′UTR activities of Bcl-w and the expression of c-Myc and LIN28, which were the upstream of let-7a-3p, decreased after NTSR1 inhibition.Conclusions:NTSR1 had an important role in protecting glioblastoma from intrinsic apoptosis via c-Myc/LIN28/let-7a-3p/Bcl-w axis.

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Actinomycin D induces p53-independent cell death and prolongs survival in high-risk chronic lymphocytic leukemia

Cited by 23 publications

References 46 publications

Upregulation of heat shock protein 27 confers resistance to actinomycin D‐induced apoptosis in cancer cells

Upregulation of heat shock protein 27 confers resistance to actinomycin D‐induced apoptosis in cancer cells

Mouse models in the study of chronic lymphocytic leukemia pathogenesis and therapy

Inhibition of neurotensin receptor 1 induces intrinsic apoptosis via let-7a-3p/Bcl-w axis in glioblastoma

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