PMCID string | Title string | Sentences string |
|---|---|---|
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | KIT proto-oncogene, receptor tyrosine kinase (KIT, CD117) and platelet-derived growth factor-alpha (PDGFRA) are key drivers of gastrointestinal stromal tumors (GIST), but resistance to targeted therapy often arises from tumor protein p53 (p53) alterations and loss of cell cycle control. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | However, the role of p53 status in GIST therapeutic potential has rarely been studied, so this study aimed to employ both wild-type and mutant p53 GIST models to investigate how p53 dysfunction influences the efficacy of p53 pathway-targeted therapies. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | The efficacy of the mouse double minute 2 homolog (MDM2) inhibitor (HDM201) and the Wee1 G2 checkpoint kinase (Wee1) inhibitor (adavosertib) was confirmed in both p53 wild-type (p53 WT) and p53 mutant (p53 MT) GIST cells. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | The anti-proliferative effects were assessed using the Cell Counting Kit-8 (CCK-8) assay. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | Flow cytometry (FACS) and immunoblotting were employed to evaluate apoptosis and the expression of proteins related to drug efficacy. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | These findings were further validated in a xenograft model. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | HDM201 selectively inhibited growth and triggered apoptosis in p53 WT GIST cells, while adavosertib was effective mainly in p53 MT cells. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | Western blot analysis revealed that HDM201 increased p53 and p21 levels in p53 WT cells, and adavosertib affected Wee1 and phospho-cdc2 expression in both p53 WT and p53 MT cells. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | In a xenograft mouse model, HDM201 significantly reduced the tumor volume and weight in p53 WT GIST cells, whereas p53 MT tumors showed only a moderate size reduction with adavosertib, without significant changes. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | Our results highlight the importance of p53 status in guiding GIST treatment. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | p53 WT tumors respond to MDM2 inhibitors, while p53 MT tumors show greater sensitivity to Wee1 inhibitors, supporting p53 pathway targeting as a promising strategy for GIST patients. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | Gastrointestinal stromal tumors (GISTs) belong to a category of mesenchymal tumors that originate in the gastrointestinal tract. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | More than 90% of GISTs overexpress the KIT proto-oncogene, receptor tyrosine kinase (KIT, CD117) protein [1–3]. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | A deeper understanding of GISTs has emerged with the identification of KIT expression and the KIT gene (c-Kit) . |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | An additional 5%–10% of GISTs contain mutations that overexpress platelet-derived growth factor-alpha (PDGFRA) . |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | Small-molecule targeted therapies utilizing tyrosine kinase inhibitors (TKIs) have been developed to treat GIST . |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | While the majority of GISTs are characterized by mutations in the KIT or PDGFRA kinase genes, approximately 5%–10% of GISTs deviate from this pattern and lack mutations in either KIT or PDGFRA. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | These tumors were categorized as KIT/PDGFRA wild-type (WT) GISTs. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | The tumor protein p53 (TP53) gene, which encodes the p53 tumor suppressor protein, is often referred to as the guardian of the genome. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | It is mutated in most human cancers, with mutation frequencies that vary according to the specific cancer type . |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | Wild-type p53 (p53 WT) protein plays a crucial role in the cellular response to DNA damage by initiating cell cycle arrest, DNA repair, and apoptosis . |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | The occurrence and potential prognostic relevance of TP53 mutations (p53 MT) have been explored in a spectrum of cancer types [7–9]. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | However, in gastrointestinal stromal tumors (GISTs), p53 has received less attention, as GIST oncogenesis is primarily driven by the dysregulation of KIT and PDGFRA . |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | Key molecular events, such as cyclin-dependent kinase inhibitor 2A (CDKN2A) loss, mouse double minute 2 homolog (MDM2) overexpression, and p53 inactivation, are critical in GIST progression . |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | Given its role in cell cycle regulation and DNA damage response, p53 is implicated in the progression of high-risk GISTs. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | Although TP53 mutations are uncommon in GIST, they are more prevalent in high-risk cases and are significantly associated with poorer relapse-free survival . |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | Furthermore, p53 expression serves as an independent prognostic factor in advanced GISTs treated with imatinib . |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | Collectively, these findings highlight the critical role of p53 expression and TP53 mutations in GIST progression. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | In p53 WT high-risk GISTs, the p53 signaling pathway is often disrupted due to MDM2 overexpression, which impairs p53’s tumor-suppressive functions, leading to genomic instability, uncontrolled proliferation, and oncogene activation. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | Consequently, targeting MDM2 or other components of the p53 pathway represents a promising therapeutic approach for GISTs . |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | These insights support the development of p53 pathway-targeted therapies as a novel strategy for GIST treatment. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | Previous studies have revealed that inhibiting Wee1 G2 checkpoint kinase (Wee1) promotes autophagic degradation of KIT, suggesting that targeting Wee1 could offer a novel therapeutic strategy for GIST . |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | Wee1 plays a critical role in regulating the G2/M cell cycle checkpoint, allowing cancer cells with DNA damage to continue through the replication cycle . |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | Furthermore, Wee1 inhibition with adavosertib (MK1775) disrupts the G2/M checkpoint by preventing phosphorylation of cyclin-dependent kinase-1 (CDK1, cdc2), thereby inducing apoptosis in p53-mutant ovarian and lung cancer cells . |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | p53 transcriptionally activates MDM2, which in turn promotes negative autoregulation of p53 through ubiquitination . |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | As a result, MDM2 is classified as an oncogene, and its amplification or overexpression has the potential to enhance tumor cell proliferation by suppressing the activity of p53 . |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | As MDM2 expression is associated with poor prognosis in GIST, MDM2 inhibitors (nutlin-3) have been shown to suppress growth and induce apoptosis in p53 WT GIST cells . |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | HDM201 (siremadlin) is a novel, highly potent, and selective inhibitor of the p53-MDM2 interaction. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | The use of MDM2 inhibitors may provide an additional strategy beyond targeted therapy drugs such as imatinib, sunitinib, regorafenib, and ripretinib in future studies . |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | This study aimed to confirm the association among p53 status, HDM201, and adavosertib activity in GIST. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | This study used three human GIST cell lines: GIST430 with wild-type p53 (p53 WT), GIST882, and GIST-T1 with mutant p53 (p53 MT). |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | All cell lines were kindly provided by Dr. Nai Jung Chiang (Taipei Veterans General Hospital, Taipei, Taiwan). |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | GIST430 cells were cultured in Iscove’s Modified Dulbecco’s Medium (IMDM) (Gibco, 12440053, Waltham, MA, USA) supplemented with 20% heat-inactivated fetal bovine serum (FBS) (Gibco, 10437-028). |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | GIST882 cells were cultured in Roswell Park Memorial Institute (RPMI) medium 1640 (Gibco, 11875-085) supplemented with 20% FBS, and GIST-T1 cells were maintained in Dulbecco’s Modified Eagle’s Medium (DMEM) (Gibco, 11965-984) supplemented with 10% FBS. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | All three GIST cell lines were cultured with 100 μg/mL streptomycin and 100 μg/mL penicillin (Gibco, 15140-122) in a humidified atmosphere containing 5% CO2 at 37°C. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | All the cell lines used in this study were verified to be free of mycoplasma contamination and authenticated through short tandem repeat (STR) profiling. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | GIST430, GIST882, and GIST-T1 cells were seeded in 96-well plates (3 × 10/well) and incubated overnight, and then treated with HDM201 (obtained from Novartis under a material transfer agreement (MTA), GST0000026313, Basel, Basel-Stadt, Switzerland) or adavosertib (MedChemExpress, Basel, Basel-Stadt, Switzerland) for 96... |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | Cell viability was assessed using the Cell Counting Kit-8 (CCK8, Dojindo Molecular Technologies, Rockville, MD, USA) method, and the optical density was measured at 450 nm using a microplate reader (Synergy HTX Multi-Mode Reader, BioTek, Winooski, VT, USA). |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | TP53 siRNA (siTP53-1 sense: 5-CCACCAUCCACUACAACUAdTdT-3, antisense: 5-UAGUUGUA GUGGAUGGUGGdTdT-3 and siTP53-2 sense: 5-GAUGUUCCGAGAGCUGAAUdTdT-3, antisense: 5-AUUCAGCUCUCGGAACAUCdTdT-3) or negative control siRNA (siNC) (sense: 5-UUCU CCGAACGUGUCACGUTT-3, antisense: 5-ACGUGACACGUUCGGAGAATT-3) were transfected into GIST4... |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | After successful TP53 knockdown, CCK8, a growth inhibition assay, was performed to evaluate the effect of HDM201 or adavosertib on p53 knockdown GIST430 cells. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | GIST cells, treated with siRNA, HDM201, or adavosertib, were lysed in Pierce RIPA Lysis and Extraction Buffer (Thermo Scientific, Waltham, MA, USA) supplemented with protease inhibitors (Roche, Basel, Switzerland). |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | The lysates were centrifuged at 12,000× g for 20 min at 4°C, and the protein concentration of the supernatants was measured using the Pierce BCA Protein Assay Kit (Thermo Scientific, 23225). |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | Total cell lysates were separated on 10% SDS-PAGE gels and transferred to nitrocellulose membranes (Amersham, Cytiva, Marlborough, MA, USA). |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | Membranes were blocked with 5% skim milk in Tris-buffered saline containing 0.1% Tween 20 (TBST) at room temperature. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | After blocking, the membranes were incubated overnight at 4°C with primary antibodies, followed by TBST washes and incubation with secondary antibodies, in 5% skim milk for 1–2 h at room temperature. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | Protein detection was performed using chemiluminescence with horseradish peroxidase-conjugated goat anti-mouse or anti-rabbit secondary antibodies (1:5000, Jackson ImmunoResearch Laboratories, mouse: #115-035-0031, rabbit: #11-035-003, West Grove, PA, USA), and protein bands were visualized using the UVP ChemStudio PLU... |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | The primary antibodies used were as follows: p53 (1:1000, GeneTex, GTX34938, Irvine, CA, USA), KIT (1:1000, ABclonal Technology, A0357, Woburn, MA, USA), phospho-KIT (1:1000, ABclonal Technology, AP0385), Wee1 (1:1000, GeneTex, GTX111392), phospho-Wee1 (1:1000, Cell Signaling Technology, #4910, Danvers, MA, USA), cdc2 ... |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | GIST cells in 6-well plates (4 × 10/well) were treated with 1 μM HDM201 or adavosertib for 48 h. For the cell cycle distribution assay, both floating and adherent cells were collected, fixed with cold 70% ethanol, and incubated with Propidium Iodide (PI)/RNase Staining Solution (Cell Signaling Technology, #4087) for 20... |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | The samples were then analyzed for DNA content using a FACSCalibur flow cytometer (Becton Dickinson, Franklin Lakes, NJ, USA) and CellQuest Pro software (Becton Dickinson), with results processed in FlowJo vX software (Becton Dickinson). |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | The FITC Annexin V Apoptosis Detection Kit I (Becton Dickinson, 556547) was used for the apoptosis assays. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | The cells were washed twice with cold 1 × PBS (pH 7.4), resuspended in binding buffer, and stained with fluorescein isothiocyanate (FITC), Annexin V, and PI according to manufacturer’s protocol. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | After 15 min of incubation at room temperature in the dark, the cells were analyzed using a FACSCalibur flow cytometer (Becton Dickinson). |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | The proportion of early and late apoptotic cells was calculated using FlowJo vX software (Becton Dickinson). |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | GIST430, GIST882, and GIST-T1 cells were seeded in white 96-well white plates (1 × 10/well) and treated with 1 μ M HDM201 or adavosertib for 24 h. Caspase-3/7 enzymatic activities were measured using a luminometer (Synergy HTX Multi-Mode Reader, BioTek), after adding a 1:1 ratio of Caspase Glo-3/7 reagent (Promega, G80... |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | The animal studies were approved by the Institutional Animal Care and Use Committee (IACUC, No. 2019032003) of Chang Gung Memorial Hospital at Linkou. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | All animal experiments were conducted in accordance with the Guide for the Care and Use of Laboratory Animals . |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | The animals were housed in an Association for Assessment and Accreditation of Laboratory Animal Care International (AAALAC)-approved facility in our hospital, under controlled temperature (24°C) and a 12-h light/dark cycle. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | A total of 20 specific pathogen-free, immunodeficient NonObese Diabetic/Severe Combined Immunodeficiency (NOD/SCID) male mice, aged four weeks and weighing about 20 g, were obtained from BioLASCO Co., Ltd., Taiwan. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | Based on previous studies [26–28], 1 × 10 GIST430 or GIST882 cells were suspended in 50 μL of PBS (pH 7.2) mixed with an equal volume of Matrigel (1:1, Corning, 354262, Corning, NY, USA) and then subcutaneously injected into NOD/SCID mice. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | When the average tumor size reached 100 mm, the mice were randomized into two groups (five per group) and treated via oral gavage. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | The GIST430 group received either vehicle (0.5% methylcellulose) or HDM201 (100 mg/kg/day, 2 days/week) according to a previous study . |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | Similarly, the GIST882 group received either vehicle or adavosertib (50 mg/kg/day, 5 days/week) based on a prior study . |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | During the treatment period, tumor size, , and pain/distress classifications were monitored twice a week until the largest tumor approached but did not exceed 2 cm in diameter, which was designated as the endpoint. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | On day 11 in our two animal studies, mice were sacrificed for tumor collection. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | The results shown in Figs. 1–3 represent data from three independent experiments and were analyzed statistically. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | Values are expressed as the mean ± standard error of the mean (SEM). |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | All statistical tests were performed using the GraphPad Prism 8 software (GraphPad Software, San Diego, CA, USA). |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | p-values represent the results of unpaired t-tests or two-way analysis of variance (ANOVA), and differences with p-values less than 0.05 were considered statistically significant. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | GIST430, GIST882, and GIST-T1 cells were treated with HDM201 (Fig. 1A) and adavosertib (Fig. 1B) for 96 h. Growth inhibition by HDM201 was observed in GIST430 cells, a wild-type p53 cell line, but not in p53 mutated cells, including GIST882 and GIST-T1 cells (Fig. 1A). |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | In contrast, adavosertib inhibited the growth of GIST882 and GIST-T1 cells but not of GIST430 cells (Fig. 1B). |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | Two siRNAs targeting TP53 (siTP53-1 and 2) successfully suppressed the expression of p53 in GIST430 cells (Fig. 1C, the uncropped Western blot images are provided in Fig. S1). |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | When GIST430 cells were treated with 1 µM HDM201, the growth inhibitory activity decreased after suppression of wild-type p53 expression indicating that the activity of HDM201 is p53-dependent. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | However, no significant difference was observed in cell survival among the cells treated with adavosertib after p53 knockdown (Fig. 1D). |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | The cell proliferation assay showed that HDM201 effectively inhibited the growth of p53 WT cells, whereas adavosertib effectively inhibited the growth of p53 MT cells. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | GIST cells were treated with HDM201 (1 µM) or adavosertib (1 µM) for 48 h. In GIST430 cells, HDM201 decreased the number of S-phase cells, whereas no significant effect was observed in GIST882 and GIST-T1 cells. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | Adavosertib treatment led to increased S and G2/M phase arrest in GIST-T1 cells and induced S phase arrest in GIST882 cells (Fig. 2A,B). |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | HDM201 significantly increased the sub-G1 population of GIST430 cells but did not affect GIST882 or GIST-T1 cells. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | Conversely, adavosertib significantly increased the number of sub-G1 GIST882 and GIST-T1 cells, but not the number of GIST430 cells (Fig. 2A,C). |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | Flow cytometry staining with annexin V showed that HDM201 treatment enhanced apoptosis in GIST430 cells, and adavosertib promoted early and late apoptotic cell production in GIST882 and GIST-T1 cells (Fig. 3A,B). |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | Furthermore, caspase 3/7 activity was increased two-fold in GIST430 cells treated with HDM201 (1 µM) compared to the control group, as observed in GIST882 and GIST-T1 cells (Fig. 3C). |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | When GIST cells were treated with adavosertib, caspase 3/7 activity tripled in GIST882 and GIST-T1 cells compared to that in both control and GIST430 cells (Fig. 3D). |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | Cell cycle distribution, annexin V, and caspase 3/7 results showed that HDM201 decreased the S phase population and increased the sub-G1 phase population and apoptosis in p53 WT cells, whereas adavosertib increased apoptosis in p53 MT cells, along with an increase in the sub-G1 phase and induction of S phase and/or G2/... |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | To explore the on-target effects of HDM201 and adavosertib, western blot analysis of the three cell lines treated with these drugs was conducted. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | We analyzed the proteins associated with p53 activity (p53 and p21), which are regulated by MDM2, and cell cycle-related proteins (cdc2, p-cdc2, Wee1, and p-Wee1), which are influenced by adavosertib in these cells (Fig. 4). |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | As depicted by western blotting, compared with DMSO-treated GIST cells, all GIST cells treated with adavosertib increased the expression of phosphorylation of Wee1 and decreased the expression of phospho-cdc2. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | In addition, no changes were observed in the expression of Wee1 and cdc2. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | GIST430 treated with HDM201 showed over-expression of p53 and p21; however, no difference was observed in expression between GIST882 and GIST-T1 treated with HDM201 and DMSO. |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | Additionally, consistent with previous studies, the use of adavosertib alone did not affect KIT phosphorylation . |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | Wee1 inhibition did not significantly decrease the phosphorylation of KIT (Y721) in Fig. 4 (The uncropped Western blot images are provided in Figs. S2 and S3). |
PMC12573211 | Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status | HDM201 reactivated p53 WT but did not influence KIT expression. |
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