Analysis of lung transcriptome of Mice under normoxia or hypoxia conditions and treated with ABT-263 or its vehicle during 2 days
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PROVIDER: PRJNA854817 | ENA |
REPOSITORIES: ENA
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Project description:To explore the role played by senescent cells in mice models of pulmonary hypertension we exposed young C57BL6/j mice to 2 days hypoxia or normoxia and treated with senolytic drug ABT-263 (50mg/kg/day) or its vehicule. We then performed lung gene expression profiling analysis using data obtained from RNA-seq of 4 groups of mice (Normoxia+Vehicule; Normoxia+ABT-263; Hypoxia+Vehicule; Hypoxia+ABT-263)
2022-12-16 | GSE207324 | GEO
Project description:To explore the role played by senescent cells in mice models of pulmonary hypertension we exposed young C57BL6/j mice to 8 days hypoxia or normoxia and treated with senolytic drug ABT-263 (50mg/kg/day) or its vehicule. We then performed lung gene expression profiling analysis using data obtained from RNA-seq of 4 groups of mice (Normoxia+Vehicule; Normoxia+ABT-263; Hypoxia+Vehicule; Hypoxia+ABT-263)
2022-12-16 | GSE207256 | GEO
Project description:Analysis of lung transcriptome of Mice under normoxia or hypoxia conditions and treated with ABT-263 or its vehicle during 8 days
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Project description:Hepatocellular carcinoma (HCC) currently lacks effective therapies, leaving a critical need for new treatment options. A previous study identified the Anaplastic Lymphoma Kinase (ALK) amplification in HCC patients, raising the question of whether ALK inhibitors could be a viable treatment. Here, we showed that both ALK inhibitors and ALK knockout effectively halted HCC growth in cell cultures. Lorlatinib, a potent ALK inhibitor, suppressed HCC tumor growth and metastasis across various mouse models. Additionally, in an advanced immunocompetent humanized mouse model, when combined with an anti-PD-1 antibody, lorlatinib more potently suppressed HCC tumor growth, surpassing individual drug efficacy. Lorlatinib induced apoptosis and senescence in HCC cells, and the senolytic agent ABT-263 enhanced the efficacy of lorlatinib. Additional studies identified that the apoptosis-inducing effect of lorlatinib was mediated via GGN and NRG4. These findings establish ALK inhibitors as promising HCC treatments, either alone or in combination with immunotherapies or senolytic agents.
2024-04-29 | GSE178211 | GEO
Project description:RNA expression analysis was performed to compare patterns to sensitivity to BCL2 inhibitors (ABT-263). Overexpression of the prosurvival Bcl-2 family members (Bcl-2, Bcl-xL and Mcl-1) is commonly associated with tumor maintenance, progression and chemoresistance. We previously reported the discovery of ABT-737, a potent, small molecule Bcl-2 family protein inhibitor. A major limitation of ABT-737 is that it is not orally bioavailable. This may limit its use for chronic single agent treatment and the flexibility to dose in combination with parenteral chemotherapy. Here we report the discovery and biological properties of ABT-263, a potent, orally bioavailable Bad-like BH3 mimetic (Kiâ??s of < 1 nM for Bcl-2, Bcl-xL and Bcl-w). The oral bioavailability of ABT-263 in preclinical animal models is 20% - 50%, depending on formulation. ABT-263 disrupts Bcl-2/Bcl-xL interactions with pro-death proteins (e.g., Bim) in cells leading to the initiation of apoptosis within 2 hr post-treatment. In human tumor cells, ABT-263 rapidly induces Bax translocation, cytochrome c release and subsequent programmed cell death. Oral administration of ABT-263 alone induces complete tumor regressions in xenograft models of small cell lung cancer and acute lymphoblastic leukemia. In xenograft models of aggressive B-cell lymphoma and multiple myeloma where ABT-263 exhibits modest or no single agent activity, it significantly enhances the efficacy of clinically relevant therapeutic regimens. These data provide the rationale for clinical trials evaluating ABT-263 in SCLC and B-cell malignancies. The oral efficacy of ABT-263 should provide dosing flexibility to maximize clinical utility as both a single agent and in combination with standard chemotherapeutic regimens. Experiment Overall Design: Naive cell lines were isolated in duplicate or triplicate (only a single for H69AR) to determine RNA expression pattern.
2008-06-19 | E-GEOD-10841 | biostudies-arrayexpress
Project description:We test the idea that peripheral cellular senescence is a major driver of age-related cognitive impairment, such that treatment with the brain impermeable senolytic, ABT-263, can preserve cognition and markers of brain aging thought to underlie cognitive decline. Male F344 rats were treated from 12-18 months of age with quercetin + dasatinib or ABT-263 or vehicle and were compared to young (6 month). Senolytic treatments had similar effects in decreasing peripheral markers of senescence and the senescence-associated secretory phenotype (SASP), including plasma levels of several cytokines, rescued memory and hippocampal synaptic transmission, and decreased expression of immune response genes in the dentate gyrus (DG). Across senolytic treatment groups, differential DG gene expression was observed for cellular senescence and pathways linked to senescence, including negative regulation of cell death, ribosomes, and microglial activation consistent with differential access of dasatinib and ABT-263 to the brain. Finally, both senolytic treatments preserved the blood-brain barrier suggesting that leakage of clinically significant amounts of ABT-263 into the brain is unlikely. The results indicate that preserved cognition was due to removal of peripheral senescent cells, decreasing systemic inflammation that normally drives neuroinflammation, BBB breakdown, and impaired synaptic function.
2023-06-07 | GSE220971 | GEO
Project description:RNA expression analysis was performed to compare patterns to sensitivity to BCL2 inhibitors (ABT-263). Overexpression of the prosurvival Bcl-2 family members (Bcl-2, Bcl-xL and Mcl-1) is commonly associated with tumor maintenance, progression and chemoresistance. We previously reported the discovery of ABT-737, a potent, small molecule Bcl-2 family protein inhibitor. A major limitation of ABT-737 is that it is not orally bioavailable. This may limit its use for chronic single agent treatment and the flexibility to dose in combination with parenteral chemotherapy. Here we report the discovery and biological properties of ABT-263, a potent, orally bioavailable Bad-like BH3 mimetic (Kiâ??s of < 1 nM for Bcl-2, Bcl-xL and Bcl-w). The oral bioavailability of ABT-263 in preclinical animal models is 20% - 50%, depending on formulation. ABT-263 disrupts Bcl-2/Bcl-xL interactions with pro-death proteins (e.g., Bim) in cells leading to the initiation of apoptosis within 2 hr post-treatment. In human tumor cells, ABT-263 rapidly induces Bax translocation, cytochrome c release and subsequent programmed cell death. Oral administration of ABT-263 alone induces complete tumor regressions in xenograft models of small cell lung cancer and acute lymphoblastic leukemia. In xenograft models of aggressive B-cell lymphoma and multiple myeloma where ABT-263 exhibits modest or no single agent activity, it significantly enhances the efficacy of clinically relevant therapeutic regimens. These data provide the rationale for clinical trials evaluating ABT-263 in SCLC and B-cell malignancies. The oral efficacy of ABT-263 should provide dosing flexibility to maximize clinical utility as both a single agent and in combination with standard chemotherapeutic regimens. Keywords: cell line comparison
2008-05-01 | GSE10841 | GEO
Project description:ALK inhibitors suppress HCC and synergize with anti-PD-1 therapy and ABT-263 in preclinical models
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Project description:Hypoxia, a characteristic of most human solid tumors, is a major obstacle to successful radiotherapy. While moderate acute hypoxia increases cell survival, chronic cycling hypoxia triggers adaptation processes, leading to the clonal selection of hypoxia-tolerant, apoptosis-resistant cancer cells. Our results demonstrate that exposure to acute and adaptation to chronic cycling hypoxia alters the balance of Bcl-2 family proteins in favor of anti-apoptotic family members, thereby elevating the apoptotic threshold and attenuating the success of radiotherapy. Of note, inhibition of Bcl-2 and Bcl-xL by BH3-mimetic ABT-263 enhanced the sensitivity of HCT116 colon cancer and NCI-H460 lung cancer cells to the cytotoxic action of ionizing radiation. Importantly, we observed this effect not only in normoxia, but also in severe hypoxia to a similar or even higher extent. ABT-263 furthermore enhanced the response of xenograft tumors of control and hypoxia-selected NCI-H460 cells to radiotherapy, thereby confirming the beneficial effect of combined treatment in vivo. Targeting the Bcl-2 rheostat with ABT-263, therefore, is a particularly promising approach to overcome radioresistance of cancer cells exposed to acute or chronic hypoxia with intermittent reoxygenation. Moreover, we found intrinsic as well as ABT-263- and irradiation-induced regulation of Bcl-2 family members to determine therapy sensitivity. In this context, we identified Mcl-1 as a resistance factor that interfered with apoptosis induction by ABT-263, ionizing radiation, and combinatorial treatment. Collectively, our findings provide novel insights into the molecular determinants of hypoxia-mediated resistance to apoptosis and radiotherapy and a rationale for future therapies of hypoxic and hypoxia-selected tumor cell fractions.
| S-EPMC8277842 | biostudies-literature
Project description:Estrogen receptor alpha plays a critical role in breast cancer and is a major target in endocrine therapy. HIF-1 alpha have been associated with ER alpha and predict a worse outcome. Recent studies indicate that histone demethylase JMJD2B is a HIF-1 alpha target. However, little is known about the biological functions of JMJD2B, especially in breast cancer. To elucidate the mechanism by which JMJD2B reguates gene expression in normoxia and hypoxia, MCF-7 breast cancer cells were depleted forJMJD2B in normoxia and hypoxia. Our results provide insight into JMJD2B regulation of gene expression in breast cancer cells in normoxia and hypoxia.
2010-09-01 | GSE18384 | GEO