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

Menichini, Paola; Speciale, Andrea; Cutrona, Giovanna; Matis, Serena; Fais, Franco; Taìana, Elisa; Neri, Antonino; Bomben, Riccardo; Gentile, Massimo; Gattei, Valter; Ferrarini, Manlio; Morabito, Fortunato; Fronza, Gilberto

doi:10.3390/cells10010098

Cited by 32 publications

(29 citation statements)

References 96 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“… 8–10 wtp53 promotes cell cycle arrest and apoptosis, and also inhibits VEGF-dependent angiogenesis, thereby countering rapid tumor growth, metastasis, and possible drug resistance. 6 , 11 , 12 Upon induction of apoptosis, wtp53 may be rapidly localized to the mitochondria in order to induce mitochondrial outer membrane permeabilization (MOMP), leading to the release of pro-apoptotic factors from the intermembrane space. 10 wtp53 also plays an important role in the DNA damage response, senescence, DNA repair, cell migration and autophagy.…”

Section: P53 Tumor Suppressor: Structure and Functionmentioning

confidence: 99%

“… 11 Furthermore, mtp53 protein is not recognized and is therefore no longer regulated by the MDM2 negative feedback loop, leading to mtp53 protein accumulation. 12 Studies show that the mtp53 protein conformation is stabilized through interactions with proteins such as heat shock protein 90 (HSP90), or as a result of post-translational modifications, such as phosphorylation at the Ser20 and Thr180 residues. In addition, its failure to induce MDM2 activation may also play a role in the stabilization of mtp53 protein.…”

Section: P53 Tumor Suppressor: Structure and Functionmentioning

confidence: 99%

See 1 more Smart Citation

Role of Reactivating Mutant p53 Protein in Suppressing Growth and Metastasis of Triple-Negative Breast Cancer

Berke¹,

Slight²,

Hyder³

2022

OTT

View full text Add to dashboard Cite

Tumor suppressor p53 protein (p53) plays a vital role throughout the body to conserve DNA stability and prevent cancer. Normally, wild-type p53 protein (wtp53) is either degraded or bound to a negative regulator and is inactive. When damage to DNA occurs within a cell, p53 protein is induced and causes cell cycle arrest. This gives cells a chance to repair, but if damage is too severe, cells undergo apoptosis and are rejected. Mutations in the p53 gene ( mtp53 ) are associated with a variety of cancers and occur in 70–80% of cases of triple-negative breast cancer (TNBC). Importantly, many mutations occur in the DNA binding domain of p53 gene and the altered mutant p53 protein (mtp53) is subsequently not degraded. High levels of mtp53 protein accumulate within the cell, leading to the development of tumors. Therefore, converting mtp53 protein back into its functional wild-type conformation is a promising means by which to prevent or reverse tumor development. Herein we will briefly examine how tumor suppressor wtp53 exerts its effects, the mechanisms involved in protecting cells that undergo DNA damage and ways in which wtp53 prevents tumorigenesis. Using TNBC as an example, we will describe the use of specific compounds to reactivate mtp53 protein function by reconfiguring its structure and outline the potential benefits of mtp53 protein reactivation. We will also briefly discuss current clinical trials aimed at reactivating mtp53 protein in order to cure certain cancers. Finally, we make the recommendation that greater emphasis should be placed on testing naturally occurring compounds that are generally non-toxic to re-activate mtp53 protein and control progression of TNBC.

show abstract

Section: P53 Tumor Suppressor: Structure and Functionmentioning

confidence: 99%

Section: P53 Tumor Suppressor: Structure and Functionmentioning

confidence: 99%

Role of Reactivating Mutant p53 Protein in Suppressing Growth and Metastasis of Triple-Negative Breast Cancer

Berke¹,

Slight²,

Hyder³

2022

OTT

View full text Add to dashboard Cite

show abstract

“…APR-246, which is clinically effective in prostate and hematological cancers [ 37 ], was also shown to inhibit growth and metastatic potential of TNBCs by several studies [ 38 , 39 ]. Although APR-246 has been well studied in the context of mutant p53, more recent data suggests that it has an independent role in both wild-type and p53 null contexts [ 22 , 40 ]. Notably, both inhibitors as single agents, under our study conditions, failed to show either a mutant P53- or subtype-specific association.…”

Section: Discussionmentioning

confidence: 99%

CX-5461 Enhances the Efficacy of APR-246 via Induction of DNA Damage and Replication Stress in Triple-Negative Breast Cancer

Makhale

Nanayakkara

Raninga

et al. 2021

IJMS

View full text Add to dashboard Cite

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer lacking targeted therapy. Here, we evaluated the anti-cancer activity of APR-246, a P53 activator, and CX-5461, a RNA polymerase I inhibitor, in the treatment of TNBC cells. We tested the efficacy of individual and combination therapy of CX-5461 and APR-246 in vitro, using a panel of breast cancer cell lines. Using publicly available breast cancer datasets, we found that components of RNA Pol I are predominately upregulated in basal-like breast cancer, compared to other subtypes, and this upregulation is associated with poor overall and relapse-free survival. Notably, we found that the treatment of breast cancer cells lines with CX-5461 significantly hampered cell proliferation and synergistically enhanced the efficacy of APR-246. The combination treatment significantly induced apoptosis that is associated with cleaved PARP and Caspase 3 along with Annexin V positivity. Likewise, we also found that combination treatment significantly induced DNA damage and replication stress in these cells. Our data provide a novel combination strategy by utilizing APR-246 in combination CX-5461 in killing TNBC cells that can be further developed into more effective therapy in TNBC therapeutic armamentarium.

show abstract

“…Interestingly, it was found that the compound PRIMA-1 (MET) can restore transcriptional activity of some mutant forms of TP53, a homolog of TP63 (Bykov et al, 2002). In fact, PRIMA-1 (MET) is currently being tested in a phase III clinical trial for the treatment of certain myelodysplastic syndromes in which patients carry TP53 mutations, and is being explored for therapeutic use in other malignancies (Menichini et al, 2021). Based on structural similarities between TP53 and TP63, studies to investigate the potential for PRIMA-1 (MET) to restore the function of mutant TP63 proteins were conducted.…”

Section: Potential Therapies For Aec and Eecmentioning

confidence: 99%

Rare Genetic Disorders: Novel Treatment Strategies and Insights Into Human Biology

Koch

Koster

2021

Front. Genet.

View full text Add to dashboard Cite

The last decade has seen a dramatic increase in innovative ideas for the treatment of genetic disorders for which no curative therapies exist. Gene and protein replacement therapies stand out as novel approaches to treat a select group of these diseases, such as certain tissue fragility disorders. Further, the advent of stem cell approaches, such as induced pluripotent stem cells (iPSC) technology, has led to the development of new methods of creating replacement tissues for regenerative medicine. This coincided with the discovery of genome editing techniques, which allow for the correction of disease-causing mutations. The culmination of these discoveries suggests that new and innovative therapies for monogenetic disorders affecting single organs or tissues are on the horizon. Challenges remain, however, especially with diseases that simultaneously affect several tissues and organs during development. Examples of this group of diseases include ectodermal dysplasias, genetic disorders affecting the development of tissues and organs such as the skin, cornea, and epithelial appendages. Gene or protein replacement strategies are unlikely to be successful in addressing the multiorgan phenotype of these diseases. Instead, we believe that a more effective approach will be to focus on correcting phenotypes in the most severely affected tissues. This could include the generation of replacement tissues or the identification of pharmaceutical compounds that correct disease pathways in specific tissues.

show abstract

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

Cited by 32 publications

References 96 publications

Role of Reactivating Mutant p53 Protein in Suppressing Growth and Metastasis of Triple-Negative Breast Cancer

Role of Reactivating Mutant p53 Protein in Suppressing Growth and Metastasis of Triple-Negative Breast Cancer

CX-5461 Enhances the Efficacy of APR-246 via Induction of DNA Damage and Replication Stress in Triple-Negative Breast Cancer

Rare Genetic Disorders: Novel Treatment Strategies and Insights Into Human Biology

Contact Info

Product

Resources

About