Methods to Screen Compounds Against Mutant p53 Misfolding and Aggregation for Cancer Therapeutics

Ferretti, Giulia Diniz da Silva; Costa, David G.; Silva, Jerson L.; Rangel, Luciana P.

doi:10.1007/978-1-4939-8820-4_17

Cited by 2 publications

(2 citation statements)

References 28 publications

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“…The same procedures described in the Western blotting section were performed. In the membrane containing the samples immunoprecipitated with A11, antibody DO-1 (mouse) and secondary anti-mouse antibody IRDye® 800CW (LI-COR, USA) were used ( Ferretti et al, 2019 ). For the dot-blot assay (IP.DB), 17 µL of 0.2 M glycine buffer pH 2.6 (in distilled water) was added to the samples and they were incubated for 10 min under agitation and centrifuged at 800 × g for 2 min at 4°C.…”

Section: Methodsmentioning

confidence: 99%

PRIMA-1 inhibits Y220C p53 amyloid aggregation and synergizes with cisplatin in hepatocellular carcinoma

Paz

Ferretti

Martins-Dinis

et al. 2023

Front. Mol. Biosci.

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Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. Although many therapeutic options are available, several factors, including the presence of p53 mutations, impact tumor development and therapeutic resistance. TP53 is the second most frequently mutated gene in HCC, comprising more than 30% of cases. Mutations in p53 result in the formation of amyloid aggregates that promote tumor progression. The use of PRIMA-1, a small molecule capable of restoring p53, is a therapeutic strategy to pharmacologically target the amyloid state mutant p53. In this study, we characterize an HCC mutant p53 model for the study of p53 amyloid aggregation in HCC cell lines, from in silico analysis of p53 mutants to a 3D-cell culture model and demonstrate the unprecedented inhibition of Y220C mutant p53 aggregation by PRIMA-1. In addition, our data show beneficial effects of PRIMA-1 in several “gain of function” properties of mutant-p53 cancer cells, including migration, adhesion, proliferation, and drug resistance. We also demonstrate that the combination of PRIMA-1 and cisplatin is a promising approach for HCC therapy. Taken together, our data support the premise that targeting the amyloid-state of mutant p53 may be an attractive therapeutic approach for HCC, and highlight PRIMA-1 as a new candidate for combination therapy with cisplatin.

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Section: Methodsmentioning

confidence: 99%

PRIMA-1 inhibits Y220C p53 amyloid aggregation and synergizes with cisplatin in hepatocellular carcinoma

Paz

Ferretti

Martins-Dinis

et al. 2023

Front. Mol. Biosci.

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“…To determine the effect of GTE on cell migration capability, wound-healing assay was performed as previously described [ 32 ]. Cells were cultured as described before until reaching 50–60% confluence.…”

Section: Methodsmentioning

confidence: 99%

Green Tea (Camellia sinensis) Extract Induces p53-Mediated Cytotoxicity and Inhibits Migration of Breast Cancer Cells

Santos

Andrade

Monteiro

et al. 2021

Foods

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Green tea (GT) has been shown to play an important role in cancer chemoprevention. However, the related molecular mechanisms need to be further explored, especially regarding the use of GT extract (GTE) from the food matrix. For this study, epigallocatechin gallate (EGCG) and epigallocatechin (EGC) were identified in GTE, representing 42 and 40% of the total polyphenols, respectively. MDA-MB-231 (p53-p.R280K mutant) and MCF-7 (wild-type p53) breast tumor cells and MCF-10A non-tumoral cells were exposed to GTE for 24–48 h and cell viability was assessed in the presence of p53 inhibitor pifithrin-α. GTE selectively targeted breast tumor cells without cytotoxic effect on non-tumoral cells and p53 inhibition led to an increase in viable cells, especially in MCF-7, suggesting the involvement of p53 in GTE-induced cytotoxicity. GTE was also effective in reducing MCF-7 and MDA-MD-231 cell migration by 30 and 50%, respectively. An increment in p53 and p21 expression stimulated by GTE was observed in MCF-7, and the opposite phenomenon was found in MDA-MB-231 cells, with a redistribution of mutant-p53 from the nucleus and no differences in p21 levels. All these findings provide insights into the action of GTE and support its anticarcinogenic potential on breast tumor cells.

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Methods to Screen Compounds Against Mutant p53 Misfolding and Aggregation for Cancer Therapeutics

Cited by 2 publications

References 28 publications

PRIMA-1 inhibits Y220C p53 amyloid aggregation and synergizes with cisplatin in hepatocellular carcinoma

PRIMA-1 inhibits Y220C p53 amyloid aggregation and synergizes with cisplatin in hepatocellular carcinoma

Green Tea (Camellia sinensis) Extract Induces p53-Mediated Cytotoxicity and Inhibits Migration of Breast Cancer Cells

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