Antitumor Effects of PRIMA-1 and PRIMA-1Met (APR246) in Hematological Malignancies: Still a Mutant P53-Dependent Affair?

Because of its role in the regulation of the cell cycle, DNA damage response, apoptosis, DNA repair, cell migration, autophagy, and cell metabolism, the TP53 tumor suppressor gene is a key player for cellular homeostasis. TP53 gene is mutated in more than 50% of human cancers, although its overall dysfunction may be even more frequent. TP53 mutations are detected in a lower percentage of hematological malignancies compared to solid tumors, but their frequency generally increases with disease progression, generating adverse effects such as resistance to chemotherapy. Due to the crucial role of P53 in therapy response, several molecules have been developed to re-establish the wild-type P53 function to mutant P53. PRIMA-1 and its methylated form PRIMA-1Met (also named APR246) are capable of restoring the wild-type conformation to mutant P53 and inducing apoptosis in cancer cells; however, they also possess mutant P53-independent properties. This review presents the activities of PRIMA-1 and PRIMA-1Met/APR246 and describes their potential use in hematological malignancies.

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Dysfunction of the TP53 tumor suppressor gene in lymphoid malignancies

Blood ◽

10.1182/blood-2011-11-366062 ◽

2012 ◽

Vol 119 (16) ◽

pp. 3668-3683 ◽

Cited By ~ 96

Author(s):

Zijun Y. Xu-Monette ◽

L. Jeffrey Medeiros ◽

Yong Li ◽

Robert Z. Orlowski ◽

Michael Andreeff ◽

...

Keyword(s):

Tp53 Gene ◽

Suppressor Gene ◽

Wild Type ◽

Lymphoid Malignancies ◽

The Status ◽

Tp53 Tumor Suppressor Gene ◽

P53 Activation ◽

Apoptotic Pathways ◽

P53 Inactivation ◽

Tp53 Pathway

AbstractMutations of the TP53 gene and dysregulation of the TP53 pathway are important in the pathogenesis of many human cancers, including lymphomas. Tumor suppression by p53 occurs via both transcription-dependent activities in the nucleus by which p53 regulates transcription of genes involved in cell cycle, DNA repair, apoptosis, signaling, transcription, and metabolism; and transcription-independent activities that induces apoptosis and autophagy in the cytoplasm. In lymphoid malignancies, the frequency of TP53 deletions and mutations is lower than in other types of cancer. Nonetheless, the status of TP53 is an independent prognostic factor in most lymphoma types. Dysfunction of TP53 with wild-type coding sequence can result from deregulated gene expression, stability, and activity of p53. To overcome TP53 pathway inactivation, therapeutic delivery of wild-type p53, activation of mutant p53, inhibition of MDM2-mediated degradation of p53, and activation of p53-dependent and -independent apoptotic pathways have been explored experimentally and in clinical trials. We review the mechanisms of TP53 dysfunction, recent advances implicated in lymphomagenesis, and therapeutic approaches to overcoming p53 inactivation.

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Mutant p53-Associated Molecular Mechanisms of ROS Regulation in Cancer Cells

Biomolecules ◽

10.3390/biom10030361 ◽

2020 ◽

Vol 10 (3) ◽

pp. 361 ◽

Cited By ~ 9

Author(s):

Marco Cordani ◽

Giovanna Butera ◽

Raffaella Pacchiana ◽

Francesca Masetto ◽

Nidula Mullappilly ◽

...

Keyword(s):

Cancer Cells ◽

Molecular Mechanisms ◽

Antioxidant Activities ◽

Tp53 Gene ◽

Suppressor Gene ◽

Antioxidant Systems ◽

Mutant P53 ◽

Tp53 Tumor Suppressor Gene ◽

Altered Gene ◽

P53 Isoforms

The TP53 tumor suppressor gene is the most frequently altered gene in tumors and an increasing number of studies highlight that mutant p53 proteins can acquire oncogenic properties, referred to as gain-of-function (GOF). Reactive oxygen species (ROS) play critical roles as intracellular messengers, regulating numerous signaling pathways linked to metabolism and cell growth. Tumor cells frequently display higher ROS levels compared to healthy cells as a result of their increased metabolism as well as serving as an oncogenic agent because of its damaging and mutational properties. Several studies reported that in contrast with the wild type protein, mutant p53 isoforms fail to exert antioxidant activities and rather increase intracellular ROS, driving a pro-tumorigenic survival. These pro-oxidant oncogenic abilities of GOF mutant p53 include signaling and metabolic rewiring, as well as the modulation of critical ROS-related transcription factors and antioxidant systems, which lead ROS unbalance linked to tumor progression. The studies summarized here highlight that GOF mutant p53 isoforms might constitute major targets for selective therapeutic intervention against several types of tumors and that ROS enhancement driven by mutant p53 might represent an “Achilles heel” of cancer cells, suggesting pro-oxidant drugs as a therapeutic approach for cancer patients bearing the mutant TP53 gene.

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Mutant p53 as a Regulator and Target of Autophagy

Frontiers in Oncology ◽

10.3389/fonc.2020.607149 ◽

2021 ◽

Vol 10 ◽

Cited By ~ 1

Author(s):

Yong Shi ◽

Erik Norberg ◽

Helin Vakifahmetoglu-Norberg

Keyword(s):

Tumor Suppressor ◽

High Frequency ◽

Human Cancer ◽

Cell Metabolism ◽

Suppressor Gene ◽

Mutant P53 ◽

Wild Type ◽

Complex Action ◽

Wild Type P53

One of the most notoriously altered genes in human cancer is the tumor-suppressor TP53, which is mutated with high frequency in more cancers than any other tumor suppressor gene. Beyond the loss of wild-type p53 functions, mutations in the TP53 gene often lead to the expression of full-length proteins with new malignant properties. Among the defined oncogenic functions of mutant p53 is its effect on cell metabolism and autophagy. Due to the importance of autophagy as a stress adaptive response, it is frequently dysfunctional in human cancers. However, the role of p53 is enigmatic in autophagy regulation. While the complex action of the wild-type p53 on autophagy has extensively been described in literature, in this review, we focus on the conceivable role of distinct mutant p53 proteins in regulating different autophagic pathways and further discuss the available evidence suggesting a possible autophagy stimulatory role of mutant p53. Moreover, we describe the involvement of different autophagic pathways in targeting and degrading mutant p53 proteins, exploring the potential strategies of targeting mutant p53 in cancer by autophagy.

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The Janus Face of p53-Targeting Ubiquitin Ligases

Cells ◽

10.3390/cells9071656 ◽

2020 ◽

Vol 9 (7) ◽

pp. 1656 ◽

Cited By ~ 3

Author(s):

Qian Hao ◽

Yajie Chen ◽

Xiang Zhou

Keyword(s):

Cancer Progression ◽

Ubiquitin Ligases ◽

Tp53 Gene ◽

Mutant P53 ◽

E3 Ubiquitin Ligases ◽

Tumor Suppressor P53 ◽

Wild Type ◽

Cell Growth Arrest ◽

Cancer Cell Survival ◽

P53 Status

The tumor suppressor p53 prevents tumorigenesis and cancer progression by maintaining genomic stability and inducing cell growth arrest and apoptosis. Because of the extremely detrimental nature of wild-type p53, cancer cells usually mutate the TP53 gene in favor of their survival and propagation. Some of the mutant p53 proteins not only lose the wild-type activity, but also acquire oncogenic function, namely “gain-of-function”, to promote cancer development. Growing evidence has revealed that various E3 ubiquitin ligases are able to target both wild-type and mutant p53 for degradation or inactivation, and thus play divergent roles leading to cancer cell survival or death in the context of different p53 status. In this essay, we reviewed the recent progress in our understanding of the p53-targeting E3 ubiquitin ligases, and discussed the potential clinical implications of these E3 ubiquitin ligases in cancer therapy.

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Mutant p53-reactivating compound APR-246 synergizes with asparaginase in inducing growth suppression in acute lymphoblastic leukemia cells

Cell Death and Disease ◽

10.1038/s41419-021-03988-y ◽

2021 ◽

Vol 12 (7) ◽

Author(s):

Sophia Ceder ◽

Sofi E. Eriksson ◽

Ying Yu Liang ◽

Emarndeena H. Cheteh ◽

Si Min Zhang ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Hematological Malignancies ◽

Lymphoblastic Leukemia ◽

Therapy Response ◽

Growth Suppression ◽

Leukemia Cells ◽

Mutant P53 ◽

Novel Treatment ◽

Phase Ii And Iii ◽

Cellular Thermal Shift Assay

AbstractAsparaginase depletes extracellular asparagine in the blood and is an important treatment for acute lymphoblastic leukemia (ALL) due to asparagine auxotrophy of ALL blasts. Unfortunately, resistance occurs and has been linked to expression of the enzyme asparagine synthetase (ASNS), which generates asparagine from intracellular sources. Although TP53 is the most frequently mutated gene in cancer overall, TP53 mutations are rare in ALL. However, TP53 mutation is associated with poor therapy response and occurs at higher frequency in relapsed ALL. The mutant p53-reactivating compound APR-246 (Eprenetapopt/PRIMA-1Met) is currently being tested in phase II and III clinical trials in several hematological malignancies with mutant TP53. Here we present CEllular Thermal Shift Assay (CETSA) data indicating that ASNS is a direct or indirect target of APR-246 via the active product methylene quinuclidinone (MQ). Furthermore, combination treatment with asparaginase and APR-246 resulted in synergistic growth suppression in ALL cell lines. Our results thus suggest a potential novel treatment strategy for ALL.

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Irradiation induces p53 loss of heterozygosity in breast cancer expressing mutant p53

Communications Biology ◽

10.1038/s42003-019-0669-y ◽

2019 ◽

Vol 2 (1) ◽

Cited By ~ 4

Author(s):

Amr Ghaleb ◽

Alisha Yallowitz ◽

Natalia Marchenko

Keyword(s):

Cell Cycle ◽

Cell Cycle Progression ◽

Tp53 Gene ◽

P53 Mutation ◽

Cell Cycle Checkpoint ◽

Mutant P53 ◽

Wild Type ◽

Γ Irradiation ◽

Cycle Progression ◽

Cycle Checkpoint

AbstractMutations in one allele of the TP53 gene in cancer early stages are frequently followed by the loss of the remaining wild-type allele (LOH) during tumor progression. However, the clinical impact of TP53 mutations and p53LOH, especially in the context of genotoxic modalities, remains unclear. Using MMTV;ErbB2 model carrying a heterozygous R172H p53 mutation, we report a previously unidentified oncogenic activity of mutant p53 (mutp53): the exacerbation of p53LOH after irradiation. We show that wild-type p53 allele is partially transcriptionally competent and enables the maintenance of the genomic integrity under normal conditions in mutp53 heterozygous cells. In heterozygous cells γ-irradiation promotes mutp53 stabilization, which suppresses DNA repair and the cell cycle checkpoint allowing cell cycle progression in the presence of inefficiently repaired DNA, consequently increases genomic instability leading to p53LOH. Hence, in mutp53 heterozygous cells, irradiation facilitates the selective pressure for p53LOH that enhances cancer cell fitness and provides the genetic plasticity for acquiring metastatic properties.

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Tumor-Associated Antigen xCT and Mutant-p53 as Molecular Targets for New Combinatorial Antitumor Strategies

Cells ◽

10.3390/cells10010108 ◽

2021 ◽

Vol 10 (1) ◽

pp. 108

Author(s):

Jolanda Magri ◽

Alessandro Gasparetto ◽

Laura Conti ◽

Enzo Calautti ◽

Chiara Cossu ◽

...

Keyword(s):

Cancer Cells ◽

Current Knowledge ◽

Tp53 Gene ◽

Metabolic Reprogramming ◽

Mutant P53 ◽

Wild Type ◽

Glutathione Biosynthesis ◽

Tumor Associated Antigen ◽

Promising Target ◽

Cancer Types

The cystine/glutamate antiporter xCT is a tumor-associated antigen that has been newly identified in many cancer types. By participating in glutathione biosynthesis, xCT protects cancer cells from oxidative stress conditions and ferroptosis, and contributes to metabolic reprogramming, thus promoting tumor progression and chemoresistance. Moreover, xCT is overexpressed in cancer stem cells. These features render xCT a promising target for cancer therapy, as has been widely reported in the literature and in our work on its immunotargeting. Interestingly, studies on the TP53 gene have revealed that both wild-type and mutant p53 induce the post-transcriptional down modulation of xCT, contributing to ferroptosis. Moreover, APR-246, a small molecule drug that can restore wild-type p53 function in cancer cells, has been described as an indirect modulator of xCT expression in tumors with mutant p53 accumulation, and is thus a promising drug to use in combination with xCT inhibition. This review summarizes the current knowledge of xCT and its regulation by p53, with a focus on the crosstalk of these two molecules in ferroptosis, and also considers some possible combinatorial strategies that can make use of APR-246 treatment in combination with anti-xCT immunotargeting.

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Advanced Strategies for Therapeutic Targeting of Wild-Type and Mutant p53 in Cancer

10.20944/preprints202201.0020.v1 ◽

2022 ◽

Author(s):

Shengliang Zhang ◽

Lindsey Carlsen ◽

Liz Hernandez Borrero ◽

Attila A. Seyhan ◽

Xiaobing Tian ◽

...

Keyword(s):

Cancer Therapy ◽

Target Genes ◽

P53 Protein ◽

Suppressor Gene ◽

Functional Restoration ◽

Mutant P53 ◽

Combination Therapies ◽

Loss Of Function ◽

Wild Type ◽

Promising Target

TP53 is a tumor suppressor gene that encodes a sequence-specific DNA-binding transcription factor activated by stressful stimuli and upregulates target genes involved in growth suppression, cell death, DNA repair, metabolism, among others. P53 is the most frequently mutated gene in tumors with mutations not only leading to loss-of-function (LOF), but also gain-of-function (GOF) which promotes tumor progression, and metastasis. The tumor-specific status of mutant p53 protein has suggested it is a promising target for cancer therapy. We summarize the current progress of targeting wild-type and mutant p53 for cancer therapy through biotherapeutic and biopharmaceutical methods for 1) boosting p53 activity in cancer, 2) p53-dependent and p53-independent strategies for targeting p53 pathway functional restoration in p53-mutated cancer, 3) targeting p53 in immunotherapy, and 4) combination therapies targeting p53, p53 checkpoints, or mutant p53 for cancer therapy.

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In silico investigation of Y220C mutant p53 for lead design

10.1101/820761 ◽

2019 ◽

Author(s):

Mayank Roy Chowdhury ◽

Anamika Tiwari ◽

G.P. Dubey

Keyword(s):

Tumor Suppressor ◽

P53 Protein ◽

Tp53 Gene ◽

Docking Studies ◽

Mutant P53 ◽

Wild Type ◽

Dynamic Simulations ◽

Complex Processes ◽

Cycle Arrest ◽

To Come

Abstractp53 protein coded by the Tp53 gene is considered as one of the most intensively researched protein and mainly due to its role as a tumor suppressor, it acts as a tumor suppressor by carrying out two biologically complex processes namely Cell cycle arrest and apoptosis, In the oncogenic Y220C mutant p53, tyrosine is replaced by cysteine at 220th residue of the DNA binding Domain which causes the formation of a surface crevice, this specific mutation is responsible for approx. 100,000 cancer cases per year due to the destabilization and denaturation of the protein, as a result, the protein degrades at room temperature. In this work we carry out intensive Molecular Dynamic Simulations and Molecular Docking Studies to understand the structural dynamics of wild type p53 and changes the occurs in the mutant protein and also try to design lead against the druggable crevice and at the end of our study we used fragment-based optimization to come up with lead molecules which can act as scaffold for further drug development process

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