APR-246—The Mutant TP53 Reactivator—Increases the Effectiveness of Berberine and Modified Berberines to Inhibit the Proliferation of Pancreatic Cancer Cells

McCubrey, James A.; Abrams, Stephen L.; Steelman, Linda S.; Cocco, Lucio; Ratti, Stefano; Martelli, Alberto M.; Lombardi, Paolo; Gizak, Agnieszka; Duda, Przemysław

doi:10.3390/biom12020276

Cited by 6 publications

(4 citation statements)

References 85 publications

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“…The combination treatment with the NAMPT inhibitor could reduce the p53 R175H aggregative signal to refine the p73 activator effect. A similar combination treatment idea was also used recently to add APR-246 to reactive GoF p53 mutants, to refine the anti-cancer effect of berberine and modified berberine compounds in pancreatic cancer, according to the second approach as mentioned above [53].…”

Section: Discussionmentioning

confidence: 99%

NAMPT Inhibitor and P73 Activator Represses P53 R175H Mutated HNSCC Cell Proliferation in a Synergistic Manner

et al. 2022

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The p53 family has the following three members: p53, p63 and p73. p53 is a tumor suppressor gene that frequently exhibits mutation in head and neck cancer. Most p53 mutants are loss-of-function (LoF) mutants, but some acquire some oncogenic function, such as gain of function (GoF). It is known that the aggregation of mutant p53 can induce p53 GoF. The p73 activators RETRA and NSC59984 have an anti-cancer effect in p53 mutation cells, but we found that p73 activators were not effective in all head and neck squamous cell carcinoma (HNSCC) cell lines, with different p53 mutants. A comparison of the gene expression profiles of several regulator(s) in mutant HNSCC cells with or without aggregation of p53 revealed that nicotinamide phosphoribosyltransferase (NAMPT) is a key regulator of mutant p53 aggregation. An NAMPT inhibitor, to reduce abnormal aggregation of mutant p53, used in combination with a p73 activator, was able to effectively repress growth in HNSCC cells with p53 GoF mutants. This study, therefore, suggests a potential combination therapy approach for HNSCC with a p53 GoF mutation.

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Section: Discussionmentioning

confidence: 99%

NAMPT Inhibitor and P73 Activator Represses P53 R175H Mutated HNSCC Cell Proliferation in a Synergistic Manner

et al. 2022

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“…The role of this drug was investigated in pancreatic cancer cell lines. It was found that APR-246 sensitized MIA-PACA-2 cells to berberine compounds [112]. Further, APR-246 has been investigated in several clinical trials.…”

Section: Targeting Mutant P53mentioning

confidence: 99%

Driver Mutations in Pancreatic Cancer and Opportunities for Targeted Therapy

Olaoba,

Adelusi,

Yang

et al. 2024

Cancers

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Pancreatic cancer is the sixth leading cause of cancer-related mortality globally. As the most common form of pancreatic cancer, pancreatic ductal adenocarcinoma (PDAC) represents up to 95% of all pancreatic cancer cases, accounting for more than 300,000 deaths annually. Due to the lack of early diagnoses and the high refractory response to the currently available treatments, PDAC has a very poor prognosis, with a 5-year overall survival rate of less than 10%. Targeted therapy and immunotherapy are highly effective and have been used for the treatment of many types of cancer; however, they offer limited benefits in pancreatic cancer patients due to tumor-intrinsic and extrinsic factors that culminate in drug resistance. The identification of key factors responsible for PDAC growth and resistance to different treatments is highly valuable in developing new effective therapeutic strategies. In this review, we discuss some molecules which promote PDAC initiation and progression, and their potential as targets for PDAC treatment. We also evaluate the challenges associated with patient outcomes in clinical trials and implications for future research.

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“…Low doses of APR-246 reduced the IC 50 concentrations of chemotherapeutic drugs, signal transduction inhibitors, BBR, or certain NAX compounds [ 203 , 204 ]. The ability of APR-246 to lower the IC 50 s of chemotherapeutic drugs, signal transduction inhibitors, BBR and modified NAX compounds was dependent on the presence of WT-TP53 or GOF mut-TP53 as APR-246 did not lower the IC 50 s of chemotherapeutic drugs, signal transduction inhibitors, berberine or certain NAX compounds in PDAC cells which were TP53-null.…”

Section: Possibility Of Treatment Of Pdac With Small Molecule Signal ...mentioning

confidence: 99%

Effects of TP53 Mutations and miRs on Immune Responses in the Tumor Microenvironment Important in Pancreatic Cancer Progression

McCubrey

Yang

Abrams

et al. 2022

Cells

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Approximately 90% of pancreatic cancers are pancreatic ductal adenocarcinomas (PDAC). PDAC is the fourth leading cause of cancer death world-wide. Therapies for PDAC are largely ineffective due to the dense desmoplastic tumor microenvironment which prevents chemotherapeutic drugs and small molecule inhibitors from exerting effective anti-cancer effects. In this review, we will discuss the roles of TP53 and miRs on the PDAC tumor microenvironment and how loss of the normal functions of TP53 promote tumor progression. The TP53 gene is mutated in approximately 50% of pancreatic cancers. Often, these TP53 mutations are point mutations which confer additional functions for the TP53 proteins. These are called gain of function (GOF) mutations (mut). Another class of TP53 mutations are deletions which result in loss of the TP53 protein; these are referred to TP53-null mutations. We have organized this review into various components/properties of the PDAC microenvironment and how they may be altered in the presence of mutant TP53 and loss of certain miR expression.

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APR-246—The Mutant TP53 Reactivator—Increases the Effectiveness of Berberine and Modified Berberines to Inhibit the Proliferation of Pancreatic Cancer Cells

Cited by 6 publications

References 85 publications

NAMPT Inhibitor and P73 Activator Represses P53 R175H Mutated HNSCC Cell Proliferation in a Synergistic Manner

NAMPT Inhibitor and P73 Activator Represses P53 R175H Mutated HNSCC Cell Proliferation in a Synergistic Manner

Driver Mutations in Pancreatic Cancer and Opportunities for Targeted Therapy

Effects of TP53 Mutations and miRs on Immune Responses in the Tumor Microenvironment Important in Pancreatic Cancer Progression

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