PRIMA-1 increases cisplatin sensitivity in chemoresistant ovarian cancer cells with p53 mutation: a requirement for Akt down-regulation

Kobayashi, Noriko; Abedini, Mohammadreza; Sakuragi, Noriaki; Tsang, Benjamin K.

doi:10.1186/1757-2215-6-7

Cited by 19 publications

(22 citation statements)

References 37 publications

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“…The combination of drugs directly targeting mutant p53 with drugs inhibiting mutant p53-related pathways is surprisingly avoided (Figure 1 ), although it might favor the decrease of compensatory responses and dosage toxicity, and thus an increase in the therapeutic efficacy. This notion is supported by a number of experiments showing that the combination of PRIMA-1 and PRIMA1-MET/APR-246 with cisplatin (CDDP) results in synergistic effects in cancer cells and xenografts ( 79 – 81 ). Taking into account that mutant p53 is known to increase chemoresistance to cisplatin ( 49 ), it is not surprising that targeting the cause of this chemoresistance opens the window to more effective treatments.…”

Section: Targeting Mutant P53 In Cancermentioning

confidence: 89%

Mutant p53: One, No One, and One Hundred Thousand

2015

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Encoded by the mutated variants of the TP53 tumor suppressor gene, mutant p53 proteins are getting an increased experimental support as active oncoproteins promoting tumor growth and metastasis. p53 missense mutant proteins are losing their wild-type tumor suppressor activity and acquire oncogenic potential, possessing diverse transforming abilities in cell and mouse models. Whether various mutant p53s differ in their oncogenic potential has been a matter of debate. Recent discoveries are starting to uncover the existence of mutant p53 downstream programs that are common to different mutant p53 variants. In this review, we discuss a number of studies on mutant p53, underlining the advantages and disadvantages of alternative experimental approaches that have been used to describe the numerous mutant p53 gain-of-function activities. Therapeutic possibilities are also discussed, taking into account targeting either individual or multiple mutant p53 proteins in human cancer.

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Section: Targeting Mutant P53 In Cancermentioning

confidence: 89%

Mutant p53: One, No One, and One Hundred Thousand

2015

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“…The PRIMA-1 concentration (25 µM) required for statistically significant stimulation of erythrocyte cell membrane scrambling was higher than those triggering apoptosis in tumor cells [12,16]. PRIMA-1 tended to increase phosphatidylserine exposure at lower concentrations (10 µM), an effect, however, not reaching statistical significance.…”

Section: Discussionmentioning

confidence: 99%

“…The substance is at least partially effective by reactivating the proapoptotic transcription factor p53 [1,3,4,5,7,8,11,12,13,14,16,18,19,20,21,23,25,26,27,30]. Moreover, PRIMA-1 up-regulates the related transcription factors p63 and p73 [2,26].…”

Section: Introductionmentioning

confidence: 99%

“…PRIMA-1 (p53 reactivation and induction of massive apoptosis 1 or APR-246), a widely used investigational drug for cancer therapy successfully tested in phase I/II clinical trials [1,2,3], triggers apoptosis of tumor cells and augments the tumor cell apoptosis following cytostatic treatment, radiation or hypoxia [1,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29]. The substance is at least partially effective by reactivating the proapoptotic transcription factor p53 [1,3,4,5,7,8,11,12,13,14,16,18,19,20,21,23,25,26,27,30].…”

Section: Introductionmentioning

confidence: 99%

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Stimulation of Suicidal Erythrocyte Death by PRIMA-1

Faggio

Alzoubi

Calabrò

et al. 2015

Cell Physiol Biochem

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Background: The anticarcinogenic drug PRIMA-1 (p53 reactivation and induction of massive apoptosis 1) induces suicidal death of tumor cells, an effect in large part attributed to the up-regulation of the proapoptotic transcription factor p53. Erythrocytes are lacking gene transcription but are nevertheless able to enter eryptosis, a suicidal erythrocyte death characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Stimulators of eryptosis include increase of cytosolic Ca²⁺-activity ([Ca²⁺]_i) and ceramide formation. The present study tested whether PRIMA-1 stimulates eryptosis. Methods: Phosphatidylserine exposure at the cell surface was estimated from annexin V binding, cell volume from forward scatter, [Ca²⁺]_i from Fluo3-fluorescence, ceramide abundance from binding of specific antibodies, and ROS formation from DCFDA fluorescence. Results: A 48 h exposure of human erythrocytes to PRIMA-1 (25 µM) significantly increased the percentage of annexin-V-binding cells without significantly influencing [Ca²⁺]_i or forward scatter. PRIMA-1 (100 µM) induced annexin-V-binding was not significantly blunted by removal of extracellular Ca²⁺ or by the caspase-3 inhibitor zVAD. PRIMA-1 (100 µM) further increased the ceramide abundance at the cell surface and ROS formation. Conclusions: PRIMA-1 stimulates phosphatidylserine translocation at the erythrocyte cell membrane, an effect at least partially due to up-regulation of ceramide abundance and ROS formation.

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“…In vitro experiments have shown that a combination APR-246 with other drugs improves cytotoxicity and can have synergistic effects in cancer cells. For instance, good combination effects have been shown in combination with cisplatin in ovarian cancer cells (Kobayashi, Abedini et al 2013). Similarly, combination with wortmannin (PI3K inhibitor) or rapamycin (mTOR inhibitor) shows an increased cytotoxicity in primary AML cells (Ali, Mohammad et al 2016).…”

Section: New Therapiesmentioning

confidence: 99%

AML displays increased CTCF occupancy associated with aberrant gene expression and transcription factor binding

Mujahed

Miliara

Neddermeyer

et al. 2020

Blood

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CCTC-binding factor (CTCF) is a key regulator of gene expression through organization of the chromatin structure. Still, it is unclear how CTCF binding is perturbed in leukemia or in cancer in general. We studied CTCF binding by chromatin immunoprecipitation sequencing in cells from patients with acute myeloid leukemia (AML) and in normal bone marrow (NBM) in the context of gene expression, DNA methylation, and azacitidine exposure. CTCF binding was increased in AML compared with NBM. Aberrant CTCF binding was enriched for motifs for key myeloid transcription factors such as CEBPA, PU.1, and RUNX1. AML with TET2 mutations was characterized by a particularly strong gain of CTCF binding, highly enriched for gain in promoter regions, while AML in general was enriched for changes at enhancers. There was a strong anticorrelation between CTCF binding and DNA methylation. Gain of CTCF occupancy was associated with increased gene expression; however, the genomic location (promoter vs distal regions) and enrichment of motifs (for repressing vs activating cofactors) were decisive for the gene expression pattern. Knockdown of CTCF in K562 cells caused loss of CTCF binding and transcriptional repression of genes with changed CTCF binding in AML, as well as loss of RUNX1 binding at RUNX1/CTCF-binding sites. In addition, CTCF knockdown caused increased differentiation. Azacitidine exposure caused major changes in CTCF occupancy in AML patient cells, partly by restoring a CTCF-binding pattern similar to NBM. We conclude that AML displays an aberrant increase in CTCF occupancy that targets key genes for AML development and impacts gene expression.

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PRIMA-1 increases cisplatin sensitivity in chemoresistant ovarian cancer cells with p53 mutation: a requirement for Akt down-regulation

Cited by 19 publications

References 37 publications

Mutant p53: One, No One, and One Hundred Thousand

Mutant p53: One, No One, and One Hundred Thousand

Stimulation of Suicidal Erythrocyte Death by PRIMA-1

AML displays increased CTCF occupancy associated with aberrant gene expression and transcription factor binding

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