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Effects of PRIMA‐1 on chronic lymphocytic leukaemia cells with and without hemizygous p53 deletion
Abstract
Summary: The tumour suppressor gene p53 is the most commonly mutated gene in solid tumours. Although less common in haematological malignancies, 10–15% of B‐cell chronic lymphocytic leukaemia (B‐CLL) cases carry a p53 mutation. Recently, the compound P53‐dependent reactivation and induction of massive apoptosis (PRIMA‐1) has been shown to induce cytotoxic effects and apoptosis in human tumour cells by restoration of the transcriptional activity of mutated p53. This is believed to be mediated by a change in the conformation of mutated p53 protein, restoring DNA binding and activation of p53 target genes. We studied the effects of PRIMA‐1 and commonly used anti‐leukaemic drugs on B‐CLL cells from 14 patients with and without hemizygous p53 deletion. Cells obtained from peripheral blood or bone marrow were exposed to PRIMA‐1 and fludarabine alone or in combination. PRIMA‐1 showed cytotoxic effects on B‐CLL cells from samples with and without hemizygous p53 deletion. Furthermore, conventional B‐CLL drugs were less effective in cell samples with hemizygous p53 deletion and the response depended on the size of the p53 deleted clone. Finally, we found evidence for synergistic and additive effects of PRIMA‐1 in combination with fludarabine.
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“Tumor cell lines carrying TP53, TP53 mutations, or TP53 deletions responded to APR-246 treatment.397–400”
From Targeting p53 pathways: mechanisms, structures, and advances in therapy (2023) · cites this paper as [397]
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Restoration of the tumor suppressor function to mutant p53 by a low-molecular-weight compound
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Self-citationDisruption of the ARF-Mdm2-p53 tumor suppressor pathway in Myc-induced lymphomagenesis
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Cited by
Targeting p53 pathways: mechanisms, structures, and advances in therapy
Wang, H., Guo, M., Wei, H., & Chen, Y. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01347-1 · Cited by 1,016
PRIMA-1 reactivates mutant p53 by covalent binding to the core domain
Lambert, J. M. R., Gorzov, P., Veprintsev, D. B., Söderqvist, M., Segerbäck, D., Bergman, J., Fersht, A. R., Hainaut, P., Wiman, K. G., & Bykov, V. J. N. (2009) · Cancer Cell · doi:10.1016/j.ccr.2009.03.003 · Cited by 592
Self-citationThe p53 Pathway in Glioblastoma
Zhang, Y., Dube, C., Gibert, M., Cruickshanks, N., Wang, B., Coughlan, M., Yang, Y., Setiady, I., Deveau, C., Saoud, K., et al. (2018) · Cancers · doi:10.3390/cancers10090297 · Cited by 440
Lehmann, S., Bykov, V. J. N., Ali, D., Andrén, O., Cherif, H., Tidefelt, U., Uggla, B., Yachnin, J., Juliusson, G., Moshfegh, A., et al. (2012) · Journal of Clinical Oncology · doi:10.1200/jco.2011.40.7783 · Cited by 406
Self-citationReactivation of mutant p53: molecular mechanisms and therapeutic potential
Selivanova, G., & Wiman, K. G. (2007) · Oncogene · doi:10.1038/sj.onc.1210295 · Cited by 186
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Metadata
- Authors
- Nahi, H., Lehmann, S., Mollgard, L., Bengtzen, S., Selivanova, G., Wiman, K. G., Paul, C., & Merup, M.
- Venue
- British Journal of Haematology
- Publisher
- Wiley
- Published
- 2004-10-18
- Volume
- 127
- Issue
- 3
- Pages
- 285-291
- ISSN
- 0007-1048
- 1365-2141
- Cited by
- 50
- References
- 2
- Language
- en
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- Nahi, H., Lehmann, S., Mollgard, L., Bengtzen, S., Selivanova, G., Wiman, K. G., Paul, C., & Merup, M. (2004). Effects of PRIMA‐1 on chronic lymphocytic leukaemia cells with and without hemizygous p53 deletion. British Journal of Haematology. https://doi.org/10.1111/j.1365-2141.2004.05210.x
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