PRIMA-1 and PRIMA-1Met (APR-246): From Mutant/Wild Type p53 Reactivation to Unexpected Mechanisms Underlying Their Potent Anti-Tumor Effect in Combinatorial Therapies

Perdrix, A.; Najem, Ahmad; Saussez, Sven; Awada, Ahmad; Journé, Fabrice; Ghanem, Ghanem Elias; Krayem, Mohammad

doi:10.3390/cancers9120172

Cited by 94 publications

(86 citation statements)

References 75 publications

(465 reference statements)

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“…In this study, in vitro drug sensitivity analysis identified APR‐246 as an effective agent for TP53 mutant CK/MK AML. APR‐246 has shown multiple anti‐cancer mechanisms including restoration of mutant p53 function, induction of reactive oxygen species and unfold protein response . The myriad of therapeutic effects in addition to p53 restoration might account for its effect on some cases of CK/MK AML carrying wildtype TP53 and those AML with TP53 deletion .…”

Section: Discussionmentioning

confidence: 93%

Distinct mutation spectrum, clinical outcome and therapeutic responses of typical complex/monosomy karyotype acute myeloid leukemia carrying TP53 mutations

Leung

Zhang

et al. 2019

American J Hematol

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The present study aimed to define a subtype of complex/monosomal karyotype (CK/MK) acute myeloid leukemia (AML) by its distinct clinical features, p53 signaling and responses to p53 targeting agents. Ninety‐eight young adults (range: 21‐60 years; median: 49 years) with CK/MK AML were studied. They received standard induction, consolidation and allogeneic hematopoietic stem cell transplantation from siblings or matched unrelated donors if available. Chromosomal abnormalities most commonly affected chromosome 5 (30%), 7 (22%) and 17 (21%). Next generation sequencing of a 54‐myeloid gene panel were available in 76 patients. Tumor protein 53 (TP53) mutations were most common (49%) and associated with the presence of −5/5q‐ (P < .001) and −17/17p‐ (P < .001), but not −7/7q‐ (P = .370). This “typical” CK/MK AML subtype was associated with significantly lower presenting white cell counts, higher number of karyotypic abnormalities, and inferior leukemia‐free and overall survivals, compared with CK/MK AML without the typical features. Blood or bone marrow samples from typical CK/MK AML patients showed defective p53 signaling upon induction by etoposide. In vitro drug sensitivity analysis showed that they were sensitive to APR‐246 that targeted mutant p53, but resistant to MDM2 antagonist MI‐77301. Novel therapeutic strategies targeting TP53 mutations in CK/MK AML should be developed and tested in clinical trials.

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Section: Discussionmentioning

confidence: 93%

Distinct mutation spectrum, clinical outcome and therapeutic responses of typical complex/monosomy karyotype acute myeloid leukemia carrying TP53 mutations

Leung

Zhang

et al. 2019

American J Hematol

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“…p53 is a well‐known tumor suppressor gene, however, mutated p53 plays a role of oncogene, as in this case of our CRC cells. PRIMA‐1 is a mutant p53 reactivating compound that has been progressed to clinical trials . PRIMA‐1 was found to induce apoptosis and increase the expression level of p53 target genes (Puma, Noxa, Bax) .…”

Section: Discussionmentioning

confidence: 99%

“…PRIMA-1 is a mutant p53 reactivating compound that has been progressed to clinical trials. [34] PRIMA-1 was found to induce apoptosis and increase the expression level of p53 target genes (Puma, Noxa, Bax). [35] Similarly, our results demonstrated that natural compound OA suppressed mutated p53 to induce apoptosis by caspase activation through cytochrome c release ( Figure 5).…”

Section: Discussionmentioning

confidence: 99%

Proteomic Analysis Reveals that Odoroside A Triggers G2/M Arrest and Apoptosis in Colorectal Carcinoma Through ROS‐p53 Pathway

et al. 2019

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Odoroside A (OA) is an active ingredient extracted from the leaves of Nerium oleander Linn. (Apocynaceae). This study aims to examine the anticancer bioactivity of OA against CRC cells and to investigate the action mechanisms involved. As a result, OA can significantly inhibit cellular ability and induce apoptosis of CRC cells in a concentration‐dependent manner without any obvious cytotoxicity in normal colorectal epithelial cells. Then, quantitative proteomics combined with bioinformatics is adopted to investigate the alterations of proteins and signaling pathways in response to OA treatment. As suggested by the proteomic analysis, flow cytometry and Western blotting analyses validate that exposure of CRC cells to OA causes cell cycle arrest and apoptosis, accompanied with the activation of the ROS/p53 signaling pathway. This observation demonstrates that OA, as a natural product, can induce oxidative stress to suppress tumor cell growth, implicating a novel therapeutic agent against CRC without obvious side effects.

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“…Furthermore, several compounds were identified to restore p53 functions. Prominently, p53 reactivation and induction of massive apoptosis (PRIMA-1) and PRIMA-1Met are currently evaluated in several clinical trials (67). In the liver, application of the compounds is currently restricted to preclinical data and shows promising anti-tumor effects when mutant p53 is silenced by siRNA.…”

Section: Targeting Of Cell Death As a Therapeutic Strategy For Hccmentioning

confidence: 99%

Predisposition to Apoptosis in Hepatocellular Carcinoma: From Mechanistic Insights to Therapeutic Strategies

Marquardt

Edlich

2019

Front. Oncol.

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Hepatocellular carcinoma (HCC) ranks among the most rapidly evolving cancers in the Western world. The majority of HCCs develop on the basis of a chronic inflammatory liver damage that predisposes liver cancer development and leads to deregulation of multiple cellular signaling pathways. The resulting dysbalance between uncontrolled proliferation and impaired predisposition to cell death with consecutive failure to clear inflammatory damage is a key driver of malignant transformation. Therefore, resistance to death signaling accompanied by metabolic changes as well as failed immunological clearance of damaged pre-neoplastic hepatocytes are considered hallmarks of hepatocarcinogenesis. Hereby, the underlying liver disease, the type of liver damage and individual predisposition to apoptosis determines the natural course of the disease as well as the therapeutic response. Here, we will review common and individual aspects of cell death pathways in hepatocarcinogenesis with a particular emphasis on regulatory networks and key molecular alterations. We will further delineate the potential of targeting cell death-related signaling as a viable therapeutic strategy to improve the outcome of HCC patients.

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PRIMA-1 and PRIMA-1Met (APR-246): From Mutant/Wild Type p53 Reactivation to Unexpected Mechanisms Underlying Their Potent Anti-Tumor Effect in Combinatorial Therapies

Cited by 94 publications

References 75 publications

Distinct mutation spectrum, clinical outcome and therapeutic responses of typical complex/monosomy karyotype acute myeloid leukemia carrying TP53 mutations

Distinct mutation spectrum, clinical outcome and therapeutic responses of typical complex/monosomy karyotype acute myeloid leukemia carrying TP53 mutations

Proteomic Analysis Reveals that Odoroside A Triggers G2/M Arrest and Apoptosis in Colorectal Carcinoma Through ROS‐p53 Pathway

Predisposition to Apoptosis in Hepatocellular Carcinoma: From Mechanistic Insights to Therapeutic Strategies

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