scholarly journals Modified Gold Nanoparticles to Overcome the Chemoresistance to Gemcitabine in Mutant p53 Cancer Cells

Pharmaceutics ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2067
Author(s):  
Eduardo García-Garrido ◽  
Marco Cordani ◽  
Álvaro Somoza
Keyword(s):  
Gold Nanoparticles ◽  
Cancer Cells ◽  
Electrostatic Interactions ◽  
Human Cancer ◽  
Tp53 Gene ◽  
Therapeutic Strategies ◽  
Mutant P53 ◽  
Layer By Layer ◽  
Missense Mutations ◽  
Efficient Delivery

Mutant p53 proteins result from missense mutations in the TP53 gene, the most mutated in human cancer, and have been described to contribute to cancer initiation and progression. Therapeutic strategies for targeting mutant p53 proteins in cancer cells are limited and have proved unsuitable for clinical application due to problems related to drug delivery and toxicity to healthy tissues. Therefore, the discovery of efficient and safe therapeutic strategies that specifically target mutant p53 remains challenging. In this study, we generated gold nanoparticles (AuNPs) chemically modified with low molecular branched polyethylenimine (bPEI) for the efficient delivery of gapmers targeting p53 mutant protein. The AuNPs formulation consists of a combination of polymeric mixed layer of polyethylene glycol (PEG) and PEI, and layer-by-layer assembly of bPEI through a sensitive linker. These nanoparticles can bind oligonucleotides through electrostatic interactions and release them in the presence of a reducing agent as glutathione. The nanostructures generated here provide a non-toxic and powerful system for the delivery of gapmers in cancer cells, which significantly downregulated mutant p53 proteins and altered molecular markers related to cell growth and apoptosis, thus overcoming chemoresistance to gemcitabine.

scholarly journals Autophagy induced by SAHA affects mutant P53 degradation and cancer cell survival

2019 ◽  
Vol 39 (2) ◽  
Author(s):  
Giorgia Foggetti ◽  
Laura Ottaggio ◽  
Debora Russo ◽  
Carlotta Mazzitelli ◽  
Paola Monti ◽  
...  
Keyword(s):  
Cell Death ◽  
Human Cancer ◽  
Tp53 Gene ◽  
Mutant P53 ◽  
Strong Impact ◽  
Cancer Therapies ◽  
Missense Mutations ◽  
Reduce Cell Proliferation ◽  
Cancer Cell Survival ◽  
Autophagy Inhibition

Abstract Missense mutations in the TP53 gene produce mutant p53 (mutp53) proteins which may acquire oncogenic properties favoring chemoresistance, cell migration, and metastasis. The exploitation of cellular pathways that promote mutp53 degradation may reduce cell proliferation and invasion as well as increase the sensitivity to anticancer drugs, with a strong impact on current cancer therapies. In the last years, several molecules have been characterized for their ability to induce the degradation of mutp53 through the activation of autophagy. Here, we investigated the correlation between autophagy and mutp53 degradation induced by suberoylanilide hydroxamic acid (SAHA), an FDA-approved histone deacetylase inhibitor. In the human cancer lines MDA-MB-231 (mutp53-R280K) and DLD1 (mutp53-S241F), SAHA induced a significant mutp53 degradation. However, such degradation correlated with autophagy induction only in MDA-MB-231 cells, being counteracted by autophagy inhibition, which also increased SAHA-induced cell death. Conversely, in DLD1 cells SAHA triggered a low level of autophagy despite promoting a strong decrease in mutp53 level, and autophagy inhibition did not change either mutp53 levels or sensitivity to this drug. We conclude that autophagy can be a relevant pathway for mutp53 degradation induced by SAHA, but its contribution to mutp53 destabilization and the consequences on cell death are likely context-dependent.

scholarly journals Functional Inactivation of Endogenous MDM2 and CHIP by HSP90 Causes Aberrant Stabilization of Mutant p53 in Human Cancer Cells

2011 ◽  
Vol 9 (5) ◽  
pp. 577-588 ◽  
Author(s):  
Dun Li ◽  
Natalia D. Marchenko ◽  
Ramona Schulz ◽  
Victoria Fischer ◽  
Talia Velasco-Hernandez ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Human Cancer ◽  
Mutant P53 ◽  
Human Cancer Cells ◽  
Functional Inactivation

scholarly journals Identification of a druggable protein-protein interaction site between mutant p53 and its stabilizing chaperone DNAJA1

2020 ◽  
pp. jbc.RA120.014749
Author(s):  
Xin Tong ◽  
Dandan Xu ◽  
Rama K. Mishra ◽  
Ryan D Jones ◽  
Leyu Sun ◽  
...  
Keyword(s):  
Small Molecule ◽  
Tp53 Gene ◽  
Dominant Negative ◽  
Site Directed Mutagenesis ◽  
Dominant Negative Effect ◽  
Mutant P53 ◽  
Missense Mutations ◽  
Oncogenic Function

The TP53 gene is the most frequently mutated gene in human cancers, and the majority of TP53 mutations are missense mutations. As a result, these mutant p53 (mutp53) either directly lose wild-type p53 (wtp53) tumor suppressor function or exhibit a dominant negative effect over wtp53. In addition, some mutp53 have acquired new oncogenic function (gain of function). Therefore, targeting mutp53 for its degradation, may serve as a promising strategy for cancer prevention and therapy. Based on our previous finding that farnesylated DNAJA1 is a crucial chaperone in maintaining mutp53 stabilization, and by using an in silico approach, we built 3-D homology models of human DNAJA1 and mutp53R175H proteins, identified the interacting pocket in the DNAJA1-mutp53R175H complex, and found one critical druggable small molecule binding  site in the DNAJA1 glycine/phenylalanine rich region. We confirmed that the interacting pocket in the DNAJA1-mutp53R175H complex was crucial for stabilizing mutp53R175H using a site-directed mutagenesis approach. We further screened a drug-like library to identify a promising small molecule hit (GY1-22) against the interacting pocket in DNAJA1-mutp53R175H complex. The GY1-22 compound displayed an effective activity against DNAJA1-mutp53R175H complex. Treatment with GY1-22 significantly reduced mutp53 protein levels, enhanced Waf1p21 expression, suppressed cyclin D1 expression, and inhibited mutp53-driven pancreatic cancer growth both in vitro and in vivo. Together, our results indicate that the interacting pocket in the DNAJA1-mutp53R175H complex is critical for mutp53’s stability and oncogenic function, and DNAJA1 is a robust therapeutic target for developing the efficient small molecule inhibitors against oncogenic mutp53.

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

Biomolecules ◽  
2020 ◽  
Vol 10 (3) ◽  
pp. 361 ◽  
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.

scholarly journals p53’s Extended Reach: The Mutant p53 Secretome

Biomolecules ◽  
2020 ◽  
Vol 10 (2) ◽  
pp. 307 ◽  
Author(s):  
Evangelos Pavlakis ◽  
Thorsten Stiewe
Keyword(s):  
Tumor Cell ◽  
Cancer Cells ◽  
Cell Communication ◽  
Tp53 Gene ◽  
Genetic Alterations ◽  
Dominant Negative ◽  
Mutant P53 ◽  
Matrix Remodeling ◽  
Primary Tumor Site ◽  
Metastatic Colonization

p53 suppresses tumorigenesis by activating a plethora of effector pathways. While most of these operate primarily inside of cells to limit proliferation and survival of incipient cancer cells, many extend to the extracellular space. In particular, p53 controls expression and secretion of numerous extracellular factors that are either soluble or contained within extracellular vesicles such as exosomes. As part of the cellular secretome, they execute key roles in cell-cell communication and extracellular matrix remodeling. Mutations in the p53-encoding TP53 gene are the most frequent genetic alterations in cancer cells, and therefore, have profound impact on the composition of the tumor cell secretome. In this review, we discuss how the loss or dominant-negative inhibition of wild-type p53 in concert with a gain of neomorphic properties observed for many mutant p53 proteins, shapes a tumor cell secretome that creates a supportive microenvironment at the primary tumor site and primes niches in distant organs for future metastatic colonization.

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

Cells ◽  
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.

scholarly journals Protein mimetic amyloid inhibitor potently abrogates cancer-associated mutant p53 aggregation and restores tumor suppressor function

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
L. Palanikumar ◽  
Laura Karpauskaite ◽  
Mohamed Al-Sayegh ◽  
Ibrahim Chehade ◽  
Maheen Alam ◽  
...  
Keyword(s):  
Self Assembly ◽  
Human Cancer ◽  
Mutant P53 ◽  
Amyloid Formation ◽  
Missense Mutations ◽  
Hydrophobic Core ◽  
Tumor Suppressor Function ◽  
Human Cancer Cells ◽  
Cycle Arrest ◽  
Bona Fide

AbstractMissense mutations in p53 are severely deleterious and occur in over 50% of all human cancers. The majority of these mutations are located in the inherently unstable DNA-binding domain (DBD), many of which destabilize the domain further and expose its aggregation-prone hydrophobic core, prompting self-assembly of mutant p53 into inactive cytosolic amyloid-like aggregates. Screening an oligopyridylamide library, previously shown to inhibit amyloid formation associated with Alzheimer’s disease and type II diabetes, identified a tripyridylamide, ADH-6, that abrogates self-assembly of the aggregation-nucleating subdomain of mutant p53 DBD. Moreover, ADH-6 targets and dissociates mutant p53 aggregates in human cancer cells, which restores p53’s transcriptional activity, leading to cell cycle arrest and apoptosis. Notably, ADH-6 treatment effectively shrinks xenografts harboring mutant p53, while exhibiting no toxicity to healthy tissue, thereby substantially prolonging survival. This study demonstrates the successful application of a bona fide small-molecule amyloid inhibitor as a potent anticancer agent.

scholarly journals Induction of apoptosis in human cancer cells by targeting mitochondria with gold nanoparticles

Nanoscale ◽  
2015 ◽  
Vol 7 (24) ◽  
pp. 10634-10640 ◽  
Author(s):  
M. M. Mkandawire ◽  
M. Lakatos ◽  
A. Springer ◽  
A. Clemens ◽  
D. Appelhans ◽  
...  
Keyword(s):  
Gold Nanoparticles ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Human Cancer ◽  
Human Cancer Cell ◽  
Human Cancer Cells ◽  
Induction Of Apoptosis ◽  
Mitochondria Targeting

Gold nanoparticles conjugated with mitochondria-targeting mitoTGFP and coated with 3rd generation dendrimers successfully reached the mitochondrion in a human cancer cell, while both unconjugated and uncoated AuNPs are encapsulated in endosomes and exocytosed.

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