ArticleOncotarget2016
PRIMA-1 targets the vulnerability of multiple myeloma of deregulated protein homeostasis through the perturbation of ER stress via p73 demethylation.
Article in Oncotarget, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers, 1 of them a synthesis that pooled it.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
21 citing papers in PubMed, 1 synthesis or guideline pooled it, 28 citations in OpenAlex.
- Targeting p53 pathways: mechanisms, structures, and advances in therapy.Signal transduction and targeted therapy · 2023Pooled it
- TP53-mutated myelodysplastic syndromes and acute myeloid leukemia: a comprehensive overview of targeted approaches.Frontiers in oncology · 2026Review
- Hotspot gene mutations and treatment response in myelodysplastic syndromes (MDS): predictive biomarkers and targeted strategies.Frontiers in medicine · 2025Review
- Eprenetapopt in the Post-Transplant Setting: Mechanisms and Future Directions.Journal of clinical oncology : official journal of the American Society of Clinical Oncology · 2022Article
- TP53-Mutated Myelodysplastic Syndrome and Acute Myeloid Leukemia: Biology, Current Therapy, and Future Directions.Cancer discovery · 2022Review
- Should mutant TP53 be targeted for cancer therapy?Cell death and differentiation · 2022Review
- Review
- Pathway-Directed Therapy in Multiple Myeloma.Cancers · 2021Review
- Tumor-Associated Antigen xCT and Mutant-p53 as Molecular Targets for New Combinatorial Antitumor Strategies.Cells · 2021Review
- Antitumor Effects of PRIMA-1 and PRIMA-1Cells · 2021Review
- RITA requires eIF2α-dependent modulation of mRNA translation for its anti-cancer activity.Cell death & disease · 2019Article
- Article
- Potent anti-tumor activity of a syringolin analog in multiple myeloma: a dual inhibitor of proteasome activity targeting β2 and β5 subunits.Oncotarget · 2018Article
- Integrin-β4 is a novel transcriptional target of TAp73.Cell cycle (Georgetown, Tex.) · 2018Article
- Deregulation and Targeting of TP53 Pathway in Multiple Myeloma.Frontiers in oncology · 2018Review
- Decitabine and Melphalan Fail to Reactivate p73 in p53 Deficient Myeloma Cells.International journal of molecular sciences · 2017Article
- PRIMA-1 and PRIMA-1Cancers · 2017Review
- Reviving the guardian of the genome: Small molecule activators of p53.Pharmacology & therapeutics · 2017Review
- Association ofOncotarget · 2017Article
- TFDP3 confers chemoresistance in minimal residual disease within childhood T-cell acute lymphoblastic leukemia.Oncotarget · 2017Article
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
Abstract
Despite therapeutic advancement, multiple myeloma (MM) remains incurable with drug resistance being one of the main challenges in the clinic. Myeloma cells possess high protein secretory load, leading to increased intracellular endoplasmic reticulum (ER) stress. Hence, they are vulnerable to further perturbation to its protein homeostasis. In studying the therapeutic mechanism of PRIMA-1 (mutant-p53-reactivating-agent), we uncovered its novel p53-independent-mechanism that can be exploited for myeloma. Despite its inability in restoring the wild type-p53 protein conformation and transcriptional function in the mutant-p53-human-myeloma-cells, PRIMA-1 was efficacious against myeloma cells with differential p53 genotypes. Strikingly, cells without p53 expression demonstrated highest drug sensitivity. Genome-wide gene-expression analysis revealed the involvement of ER stress/UPR-pathway in inducing PRIMA-1-toxicity. UPR markers, HSP70, CHOP and GADD34, were significantly up-regulated, concomitantly with the induction of apoptosis. Furthermore, there was a global attenuation of protein synthesis, correlated with phospho-eIF2a up-regulation. Mechanistically, we identified that PRIMA-1 could cause the demethylation of TP73, through DNMT1 depletion, to subsequently enhance UPR. Of clinical significance, we observed that PRIMA-1 had additive therapeutic effects with another UPR-inducing-agent, bortezomib. Importantly, it can partially re-sensitize bortezomib-resistant cells to bortezomib. Given that MM is already stressed at the baseline in the ER, our results implicated that PRIMA-1 is a potential therapeutic option in MM by targeting its Achilles heel.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.