Wild type p53 reactivation: From lab bench to clinic

Selivanova, Galina

doi:10.1016/j.febslet.2014.03.049

Cited by 64 publications

(54 citation statements)

References 153 publications

(223 reference statements)

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“…For instance, many potential treatments aim to inhibit the negative regulation of p53 by MDM2. In cases in which WT p53 is expressed, small molecules or peptides that interfere with the p53 -MDM2 interaction either directly or via secondary pathways can prevent p53 degradation, restoring its functions (Selivanova 2014;Stindt et al 2014;Yu et al 2014). Although this approach has yielded promising results, the p53 interactome is highly complex, and any therapy that targets a specific protein or interaction may produce unexpected side effects.…”

Section: New Approaches For Cancer Therapy Involving P53 Aggregation mentioning

confidence: 99%

Aggregation and Prion-Like Properties of Misfolded Tumor Suppressors: Is Cancer a Prion Disease?

Costa

Oliveira

Cino

et al. 2016

Cold Spring Harb Perspect Biol

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Prion diseases are disorders that share several characteristics that are typical of many neurodegenerative diseases. Recently, several studies have extended the prion concept to pathological aggregation in malignant tumors involving misfolded p53, a tumor-suppressor protein. The aggregation of p53 and its coaggregation with p53 family members, p63 and p73, have been shown. Certain p53 mutants exert a dominant-negative regulatory effect on wild-type (WT) p53. The basis for this dominant-negative effect is that amyloid-like mutant p53 converts WT p53 into an aggregated species, leading to a gain-of-function (GoF) phenotype and the loss of its tumor-suppressor function. Recently, it was shown that p53 aggregates can be internalized by cells and can coaggregate with endogenous p53, corroborating the prion-like properties of p53 aggregates. The prion-like behavior of oncogenic p53 mutants provides an explanation for its dominant-negative and GoF properties, including the high metastatic potential of cancer cells carrying p53 mutations. The inhibition of p53 aggregation appears to represent a promising target for therapeutic intervention in patients with malignant tumors.

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Section: New Approaches For Cancer Therapy Involving P53 Aggregation mentioning

confidence: 99%

Aggregation and Prion-Like Properties of Misfolded Tumor Suppressors: Is Cancer a Prion Disease?

Costa

Oliveira

Cino

et al. 2016

Cold Spring Harb Perspect Biol

View full text Add to dashboard Cite

show abstract

“…The p53 pathway is an attractive target because of its well-documented oncosuppressive function (1,2). Since the discovery of MDM2 as crucial p53 inhibitor (3,4), there have been numerous attempts to pharmacologically disrupt the interaction between these two proteins to reactivate p53 in human wild-type TP53 tumors (2).…”

Section: Introductionmentioning

confidence: 99%

Targeting the MDM2/MDM4 Interaction Interface as a Promising Approach for p53 Reactivation Therapy

et al. 2015

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Restoration of wild-type p53 tumor suppressor function has emerged as an attractive anticancer strategy. Therapeutics targeting the two p53-negative regulators, MDM2 and MDM4, have been developed, but most agents selectively target the ability of only one of these molecules to interact with p53, leaving the other free to operate. Therefore, we developed a method that targets the activity of MDM2 and MDM4 simultaneously based on recent studies indicating that formation of MDM2/MDM4 heterodimer complexes are required for efficient inactivation of p53 function. Using computational and mutagenesis analyses of the heterodimer binding interface, we identified a peptide that mimics the MDM4 C-terminus, competes with endogenous MDM4 for MDM2 binding, and activates p53 function. This peptide induces p53-dependent apoptosis in vitro and reduces tumor growth in vivo. Interestingly, interfering with the MDM2/ MDM4 heterodimer specifically activates a p53-dependent oxidative stress response. Consistently, distinct subcellular pools of MDM2/MDM4 complexes were differentially sensitive to the peptide; nuclear MDM2/MDM4 complexes were particularly highly susceptible to the peptide-displacement activity. Taken together, these data identify the MDM2/MDM4 interaction interface as a valuable molecular target for therapeutic reactivation of p53 oncosuppressive function.

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“…However, the efficacy of chemotherapy is influenced by the resistance to platinum in the tumor tissue, leading to variations in efficacy between individuals (4). Several mechanisms have been proposed to explain the resistance of cancer cells to chemotherapy (5)(6)(7). It has been demonstrated in previous studies that resistance to platinum in lung cancer cells could be enhanced by P-glycoprotein (P-gP) expression, which is upregulated by the multi-drug resistance-1 gene (8,9).…”

Section: Introductionmentioning

confidence: 99%

Role of gambogic acid and NaI131 in A549/DDP cells

et al. 2016

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Abstract. Resistance to platinum in tumor tissue is a considerable barrier against effective lung cancer treatment. Radionuclide therapy is the primary adjuvant treatment, however, the toxic side effects limit its dosage in the clinical setting. Therefore, the present study aimed to determine whether an NaI 131 radiosensitizer could help reduce the toxic side effects of radionuclide therapy. In vitro experiments were conducted to determine whether NaI 131 can inhibit platinum resistance in A549/DDP cells, which are cisplatin-resistant non-small cell lung cancer cells, and whether gambogic acid (GA) is an effective NaI 131 radiosensitizer. Cell proliferation following drug intervention was analyzed using MTT and isobolographic analysis. Apoptosis was assessed by flow cytometry. In addition, the mechanisms of drug intervention were analyzed by measuring the expression of P-glycoprotein (P-gP), B cell lymphoma 2 (Bcl-2), Bcl2-associated X protein (Bax) and P53 using western blot analysis and immunocytochemistry. According to isobolographic analysis, a low concentration of NaI 131 combined with GA had a synergistic effect on the inhibition of A549/DDP cell proliferation, which was consistent with an increased rate of apoptosis. Furthermore, the overexpression of Bax, and the downregulation of P-gP, P53 and Bcl-2 observed demonstrated the potential mechanism(s) of NaI 131 and GA intervention. NaI 131 may induce apoptosis in A549/DDP cells by regulating apoptosis-related proteins. A low concentration combination of NaI 131 and GA was able to significantly inhibit A549/DDP cell proliferation and induce cell apoptosis. Thus, the two drugs appear to have a synergistic effect on apoptosis of A549/DDP cells.

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Wild type p53 reactivation: From lab bench to clinic

Cited by 64 publications

References 153 publications

Aggregation and Prion-Like Properties of Misfolded Tumor Suppressors: Is Cancer a Prion Disease?

Aggregation and Prion-Like Properties of Misfolded Tumor Suppressors: Is Cancer a Prion Disease?

Targeting the MDM2/MDM4 Interaction Interface as a Promising Approach for p53 Reactivation Therapy

Role of gambogic acid and NaI131 in A549/DDP cells

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