The Novel Tryptamine Derivative JNJ-26854165 Induces Wild-Type p53- and E2F1-Mediated Apoptosis in Acute Myeloid and Lymphoid Leukemias
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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.
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More preclinical studies reported that JNJ-26854165 increased p53 levels in U87 glioblastoma grafts, accompanied by apoptotic stimulation.
“More preclinical studies reported that JNJ-26854165 increased p53 levels in U87 glioblastoma grafts, accompanied by apoptotic stimulation.373–376”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [376]
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Self-citation
- 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
- PMC
- PMC2949269
- 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
- green
- www.ncbi.nlm.nih.gov
- 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
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