Kevetrin induces apoptosis in TP53 wild-type and mutant acute myeloid leukemia cells
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PROVIDER: PRJNA565968 | ENA |
REPOSITORIES: ENA
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Project description:Tumor protein p53 is a key regulator of several cellular pathways, including DNA repair, cell cycle and angiogenesis. Kevetrin exhibits p53-dependent as well as independent activity in solid tumors, while its effects on leukemic cells remain unknown. We analyzed the response of acute myeloid leukemia (AML) cell lines (TP53 wild-type: OCI-AML3 and MOLM-13; and TP53-mutant: KASUMI-1 and NOMO-1) to kevetrin at a concentration range of 85-340 μM. Kevetrin induced cell growth arrest and apoptosis in all cell lines and in primary cells, with TP53-mutant models displaying a higher sensitivity and p53 induction. Gene expression profiling revealed a common core transcriptional program altered by drug exposure and the downregulation of glycolysis, DNA repair and unfolded protein response signatures. These findings suggest that kevetrin may be a promising therapeutic option for patients with both wild-type and TP53-mutant AML.
2020-09-03 | GSE137574 | GEO
Project description:Tumor protein p53 is a key regulator of several cellular pathways, including DNA repair, cell cycle and angiogenesis. Kevetrin exhibits p53‑dependent as well as‑independent activity in solid tumors, while its effects on leukemic cells remain unknown. The aim of the present study was to analyze the response of acute myeloid leukemia (AML) cell lines (TP53 wild‑type: OCI‑AML3 and MOLM‑13; and TP53‑mutant: KASUMI‑1 and NOMO‑1) to kevetrin at a concentration range of 85‑340 µM. The cellular and molecular effects of the treatment were analyzed in terms of cell growth, viability [Annexin V‑propidium iodide (PI) staining] and cell cycle alterations (PI staining). Gene expression profiling, western blotting and immunofluorescence were performed to elucidate the pathways underlying kevetrin activity. Pulsed exposure exerted no effect on the wild‑type cells, but was effective on mutant cells. After continuous treatment, significant cell growth arrest and apoptosis were observed in all cell lines, with TP53‑mutant models displaying a higher sensitivity and p53 induction. Kevetrin also displayed efficacy against TP53 wild‑type and mutant primary AML, with a preferential cytotoxic activity against blast cells. Gene expression profiling revealed a common core transcriptional program altered by drug exposure and the downregulation of glycolysis, DNA repair and unfolded protein response signatures. These findings suggest that kevetrin may be a promising therapeutic option for patients with both wild‑type and TP53‑mutant AML.
| S-EPMC7448420 | biostudies-literature
Project description:In the present study we show that in the subset of acute myeloid leukemias (AML) with mutations in TP53, associated with poor prognosis, DNMTis, important drugs for treatment of AML, enable expression of ERVs and IFN and inflammasome signaling in a STING1 dependent manner. We previously reported in solid tumors that PARPis combined with DNMTis induce an IFN/inflammasome response that is dependent on STING1 and is mechanistically linked to generation of a homologous recombination defect (HRD). We now show that STING1 activity is actually increased in TP53 mutant compared with WT TP53 AML. Moreover, in TP53 mutant AML, STING1-dependent IFN/inflammatory signaling is increased by DNMTi treatment, whereas in AMLs with wild-type (WT) TP53, DNMTis alone have no effect. However, while combining DNMTis with PARPIs now increases IFN/inflammatory gene expression in WT TP53 AML cells, signaling induced in TP53 mutant AML is still several-fold higher. Notably, induction of HRD in both TP53 mutant and WT AMLs follows the pattern of STING1-dependent IFN and inflammatory signaling we have observed with drug treatments. These findings increase our understanding of the mechanisms that underlie DNMTi+PARPi treatment, and also DNMTi combinations with immune therapies, and a personalized approach, stratifying by p53 status, for use of such therapies, including potential immune activation of STING1 in AML and other cancers.
2022-03-07 | GSE197405 | GEO
Project description:Recent preclinical studies suggest that combining MEK and MDM2 inhibition synergize to induce apoptosis in RAS/BRAF-mutant and TP53 wild-type CRC models. In vitro, in RKO cell lines (poorly differentiated colon carcinoma cell line resistant to single agent targeting MDM2 and MEK and BRAF inhibition), the MDM2 plus MEK inhibitor combination generated a synergistic increase in apoptotic index. In vivo, in mice harboring human RKO colon tumor xenografts the combination of MDM2 plus MEK inhibition elicited 93% decreases in tumor volume.
This trial is to conduct a single-center, Phase 1 dose escalation study of trametinib combined with HDM201 (a HDM2 inhibitor) in patients with advanced/metastatic RAS/RAF mutant and TP53 wt CRC.
| 2287507 | ecrin-mdr-crc
Project description:TP53-mutant blood cancers remain a major clinical challenge. BH3-mimetic drugs inhibit BCL-2 pro-survival proteins to promote cancer cell apoptosis. Despite acting downstream of TP53, functional TP53 is required for maximal cancer cell killing by BH3-mimetics through an unknown mechanism. Here, we report TP53 can be activated following BH3-mimetic induced mitochondrial outer membrane permeabilization, which leads to induction of BH3-only proteins, thereby potentiating the pro-apoptotic signal. TP53-deficient lymphomas lack this feed-forward loop, providing opportunities for survival and disease relapse after BH3-mimetic treatment. The therapeutic barrier imposed by defects in TP53 could be overcome by direct activation of the cGAS/STING pathway, which promotes apoptosis of blood cancer cells through TP53-independent BH3-only protein upregulation. Combining clinically relevant STING agonists with BH3-mimetics efficiently killed TP53-mutant mouse B lymphoma, human NK/T lymphoma and acute myeloid leukemia cells. This represents a promising therapy regime that can be fast-tracked to tackle TP53-mutant blood cancers in the clinic.
2024-04-25 | GSE261373 | GEO
Project description:Luteoloside inhibits proliferation, induces apoptosis and differentiation via β-catenin/c-Myc axis in acute myeloid leukemia
| PRJNA1129862 | ENA
Project description:Activating STING1-dependent immune signaling in TP53 mutant and wild-type acute myeloid leukemia
| PRJNA810170 | ENA
Project description:BackgroundTP53 mutation (TP53mut ) confers an adverse prognosis in acute myeloid leukemia (AML). Venetoclax with hypomethylating agents is a current standard for older patients; however, recent reports suggest that TP53mut confers resistance to venetoclax. The authors investigated the outcomes of patients with TP53mut AML who were treated with a 10-day decitabine and venetoclax (DEC10-VEN) (ClinicalTrials.gov identifier NCT03404193).MethodsPatients with newly diagnosed AML received decitabine 20 mg/m2 for 10 days every 4 to 6 weeks for induction, followed by decitabine for 5 days after response. The venetoclax dose was 400 mg daily. TP53mut was identified in bone marrow samples using next-generation sequencing, with sensitivity of 5%. Outcomes were analyzed according to European LeukemiaNet 2017 guidelines.ResultsAmong 118 patients (median age, 72 years; age range, 49-89 years), 63 (53%) had secondary AML, 39 (33%) had AML with complex karyotype, and 35 (30%) had TP53mut AML. The median TP53 variant allele frequency was 32% (interquartile range, 16%-65%), 8 patients (23%) had only a single TP53 mutation, 15 (43%) had multiple mutations, and 12 (34%) had mutation and deletion. Outcomes were significantly worse in patients who had TP53mut AML compared with those who had wild-type TP53 AML, with an overall response rate of 66% vs 89% (P = .002), a complete response/complete response with incomplete hematologic recovery rate of 57% vs 77% (P = .029), and a 60-day mortality of 26% vs 4% (P < .001), respectively. Patients with TP53mut versus wild-type TP53 had shorter overall survival at 5.2 versus 19.4 months, respectively (hazard ratio, 4.67; 95% CI, 2.44-8.93; P < .0001), and shorter relapse-free survival at 3.4 versus 18.9 months (hazard ratio, 4.80; 95% CI, 1.97-11.69; P < .0001), respectively. Outcomes with DEC10-VEN in patients with TP53mut AML were comparable to historical results with 10-day decitabine alone.ConclusionsPatients with TP53mut AML have lower response rates and shorter survival with DEC10-VEN.
| S-EPMC10462434 | biostudies-literature
Project description:Background: Acute myeloid leukemia (AML) is the most common leukemia in adults, that has a poor prognosis due in part to low response to treatment and high recurrence. And drugs commonly used in conventional treatment strategies often cause serious side-effects. Purpose: To investigate the high efficacy and low toxicity of luteoloside on AML and explore its mechanism of action. Methods:The proliferation of AML cells treated with different concentrations of luteoloside was assessed by the CCK-8 assay and colony formation assay, and apoptosis and differentiation were detected by flow cytometry. RNA-Seq analysis and western blotting were performed to explore the mechanism by which luteoloside exerted anti-AML effects. The patient-derived xenografts (PDX) model was established to assess anti-AML effect of luteoloside in vivo, and construction of an orthotopic AML mouse model explored the combination therapy of luteoloside and cytarabine. Results: Herein, we found that luteoloside could dramatically impair the proliferation and clonogenic capacity of AML cells and induce S phase arrest associated with decrease of Cyclin D1 and increase of Cyclin A2. Furthermore, luteoloside induced apoptosis and promoted differentiation of AML cells. Activation of Wnt/β-catenin signaling by GSK3β inhibitor LiCl reversed the inhibitory effect of luteoloside on AML cell proliferation, apoptosis, and differentiation, due to β-catenin entering into nucleus and reducing the expression of c-Myc. Luteoloside significantly reduced the transplantation rate of primary AML cells in PDX model, and the combination of luteoloside and cytarabine showed a synergistic anti-AML effect in orthotopic AML model. Conclusion: Our findings demonstrate that luteoloside inhibits proliferation, induces apoptosis and differentiation of AML cells via suppression of β-catenin/c-Myc axis, suggesting that luteoloside can be developed as a potential anti-AML drug.
2024-07-04 | GSE271106 | GEO
Project description: Not available
| S-EPMC10428793 | biostudies-literature