| The novel tryptamine derivative JNJ-26854165 induces wild-type p53- and E2F1-mediated apoptosis in acute myeloid and lymphoid leukemias. | |
| | |
MedLine Citation:
|
PMID: 20736344 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
|
The development of small-molecule activators of p53 is currently focused on malignancies containing a wild-type p53 genotype, which is present in most leukemias. JNJ-26854165 is one such p53-activating agent, but its mechanism of action remains to be elucidated. Here, we report the effects of JNJ-26854165 in acute leukemias. JNJ-26854165 treatment induced p53-mediated apoptosis in acute leukemia cells with wild-type p53, in which p53 rapidly drives transcription-independent apoptosis followed by activation of a transcription-dependent pathway. JNJ-26854165 accelerated the proteasome-mediated degradation of p21 and antagonized the transcriptional induction of p21 by p53. Interestingly, JNJ-26854165 induced S-phase delay and upregulated E2F1 expression in p53 mutant cells, resulting in apoptosis preferentially of S-phase cells. E2F1 knockdown blocked apoptosis induced by JNJ-26854165 in p53 mutant cells. Apoptotic activity of JNJ-26854165 against primary acute leukemia cells was maintained in leukemia/stroma cocultures, unlike doxorubicin, which has reduced cytrotoxicity in coculture systems. JNJ-26854165 synergizes with 1-β-arabinofuranosylcytosine or doxorubicin to induce p53-mediated apoptosis. Our data suggest that JNJ-26854165 may provide a novel therapeutic approach for the treatment of acute leukemias. The presence of p53-independent apoptotic activity in addition to p53-mediated apoptosis induction, if operational in vivo, may prevent the selection of p53 mutant subclones during therapy. |
| | |
Authors:
|
Kensuke Kojima; Jared K Burks; Janine Arts; Michael Andreeff |
Related Documents
:
|
15255934 - Inhibition of the e2f-1/p53/bax pathway by tauroursodeoxycholic acid in amyloid beta-pe... 20423464 - Deregulation of apoptosis mediators' p53 and bcl2 in lung tissue of copd patients. 20840854 - Non-dioxin-like pcbs interact with benzo[a]pyrene-induced p53-responses and inhibit apo... 15064714 - Progesterone prevents radiation-induced apoptosis in breast cancer cells. 18309904 - Pharmacological intervention to the inflammatory response from decompression sickness i... 17996064 - The role of ifn-gamma in regulation of ifn-gamma-inducible protein 10 (ip-10) expressio... |
Publication Detail:
|
Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2010-08-24 |
Journal Detail:
|
Title: Molecular cancer therapeutics Volume: 9 ISSN: 1538-8514 ISO Abbreviation: Mol. Cancer Ther. Publication Date: 2010 Sep |
Date Detail:
|
Created Date: 2010-09-10 Completed Date: 2011-02-17 Revised Date: 2011-09-26 |
Medline Journal Info:
|
Nlm Unique ID: 101132535 Medline TA: Mol Cancer Ther Country: United States |
Other Details:
|
Languages: eng Pagination: 2545-57 Citation Subset: IM |
Affiliation:
|
Section of Molecular Hematology and Therapy, Department of Stem Cell Transplantation and Cellular Therapy, M.D. Anderson Cancer Center, The University of Texas, Houston, Texas 77030, USA. |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
Apoptosis
/
drug effects*,
genetics Cell Line, Tumor E2F1 Transcription Factor / genetics, metabolism* Genes, p53* Humans Leukemia, Myeloid, Acute / drug therapy*, genetics, metabolism, pathology Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy, genetics, metabolism, pathology Transfection Tryptamines / pharmacology* |
| Grant Support | |
ID/Acronym/Agency:
|
CA16672/CA/NCI NIH HHS; CA49639/CA/NCI NIH HHS; CA55164/CA/NCI NIH HHS; CA89346/CA/NCI NIH HHS; P01 CA049639-09A19007/CA/NCI NIH HHS; P01 CA055164-08/CA/NCI NIH HHS; P01 CA055164-09/CA/NCI NIH HHS; P30 CA016672-22S29015/CA/NCI NIH HHS; R01 CA089346-03/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
|
0/E2F1 Transcription Factor; 0/Tryptamines |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Detecting two-locus associations allowing for interactions in genome-wide association studies.
Next Document: Substitution of adenovirus serotype 3 hexon onto a serotype 5 oncolytic adenovirus reduces factor X ...