Cited by 80Cancer-related Molecular PathwaysAcute Myeloid Leukemia ResearchCell death mechanisms and regulation

The Novel Tryptamine Derivative JNJ-26854165 Induces Wild-Type p53- and E2F1-Mediated Apoptosis in Acute Myeloid and Lymphoid Leukemias

Open access
Kojima, Kensuke, Burks, Jared K., Arts, Janine, Andreeff, Michael·2010·Molecular Cancer Therapeutics

Published version of a preprint

Abstract

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. Mol Cancer Ther; 9(9); 2545–57. ©2010 AACR.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1158/1535-7163.mct-10-0337

Cites

40 of 40 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

2 of the 42 references couldn’t be matched to a known paper.

Research works printed but not linked: 3

  1. [30]Vassilev LT Vu BT Graves B In vivo activation of the p53 pathway by small-molecule antagonists of MDM2 Science 2004 303 844 8 14704432
  2. [31]Enge M Bao W Hedström E Jackson SP Moumen A Selivanova G MDM2-dependent downregulation of p21 and hnRNP K provides a switch between apoptosis and growth arrest induced by pharmacologically activated p53 Cancer Cell 2009 15 171 83 19249676
  3. [32]Gu L Zhu N Findley HW Zhou M MDM2 antagonist nutlin-3 is a potent inducer of apoptosis in pediatric acute lymphoblastic leukemia cells with wild-type p53 and overexpression of MDM2 Leukemia 2008 22 730 9 18273046 PMC3477706

Cited by

Sorted by citations

Authors
Kojima, K., Burks, J. K., Arts, J., & Andreeff, M.
Affiliations
The University of Texas MD Anderson Cancer Center (US)
Corresponding author
Andreeff, Michael
Venue
Molecular Cancer Therapeutics
Published
2010-09-01
Volume
9
Issue
9
Pages
2545-2557
ISSN
  • 1535-7163 (ISSN-L)
  • 1538-8514
OpenAlex
W2101396048
Cited by
78
References
42
Citations by year
2024: 2 · 2023: 3 · 2022: 1 · 2021: 2 · 2020: 3 · 2019: 4 · 2018: 7 · 2017: 5 · 2016: 4 · 2015: 8 · 2014: 15 · 2013: 9 · 2012: 6
FWCI
3.79
Type
journal article
Language
en
Open access
Locations
  • Molecular Cancer Therapeutics (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Cancer Institute (CA-16672, CA-55164, P01CA049639, P01CA055164, CA89346, R01CA089346, P30CA016672, CA 49639)
Topics
  • Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
  • Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
Keywords
tryptamine derivatives, p53 activators, wild-type p53, E2F1, apoptosis, acute myeloid leukemia, acute lymphoblastic leukemia, proteasomal degradation, S phase delay, p53 mutant cells, doxorubicin, drug synergy, p53-independent apoptosis
MeSH terms
Humans, Transfection, Tryptamines, Leukemia, Myeloid, Acute, Genes, p53, Apoptosis, Cell Line, Tumor, E2F1 Transcription Factor, Precursor Cell Lymphoblastic Leukemia-Lymphoma

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review