Homo sapiens
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PROVIDER: PRJNA254983 | ENA |
REPOSITORIES: ENA
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Project description:METRONOMIC TOPOTECAN CAUSES THERAPY-INDUCED TUMOR CELL SENESCENCE AND LOSS OF AGGRESSIVE PROPERTIES IN MYCN-AMPLIFIED CHILDHOOD CANCER [IN VIVO]
| PRJNA254982 | ENA
Project description:METRONOMIC TOPOTECAN CAUSES THERAPY-INDUCED TUMOR CELL SENESCENCE AND LOSS OF AGGRESSIVE PROPERTIES IN MYCN-AMPLIFIED CHILDHOOD CANCER [Affymetrix Cytoscan HD]
| PRJNA255506 | ENA
Project description:Evidence is accumulating that senescence drives cure in various murine and human malignancies. We demonstrate that metronomic, repetitive low-dose topotecan treatment leads to tumor cell senescence in vitro and in vivo and long-term cure in a model for the aggressive childhood cancer neuroblastoma. By using the senescence-associated secretory phenotype (SASP) as a discriminator for beneficial versus adverse effects of senescence, we identified topotecan as inducer of a favorable SASP. Senescent tumor cells are growth arrested and act growth inhibitory on co-cultured non-senescent tumor cells. MYCN oncogene amplification and expression, hallmarks of aggressive neuroblastoma, are significantly reduced, supporting an initial transition to a more favorable phenotype. These new aspects of metronomic drug treatment are clinically relevant and might apply to other tumor entities. Keywords: stress response, therapy induced senescence, cellular response, cancer treatment, neuroblastoma
2014-12-31 | GSE59297 | GEO
Project description:Evidence is accumulating that senescence drives cure in various murine and human malignancies. We demonstrate that metronomic, repetitive low-dose topotecan treatment leads to tumor cell senescence in vitro and in vivo and long-term cure in a model for the aggressive childhood cancer neuroblastoma. By using the senescence-associated secretory phenotype (SASP) as a discriminator for beneficial versus adverse effects of senescence, we identified topotecan as inducer of a favorable SASP. Senescent tumor cells are growth arrested and act growth inhibitory on co-cultured non-senescent tumor cells. MYCN oncogene amplification and expression, hallmarks of aggressive neuroblastoma, are significantly reduced, supporting an initial transition to a more favorable phenotype. These new aspects of metronomic drug treatment are clinically relevant and might apply to other tumor entities. Keywords: stress response, therapy induced senescence, cellular response, cancer treatment, neuroblastoma
2014-12-31 | GSE59296 | GEO
Project description:Evidence is accumulating that senescence drives cure in various murine and human malignancies. We demonstrate that metronomic, repetitive low-dose topotecan treatment leads to tumor cell senescence in vitro and in vivo and long-term cure in a model for the aggressive childhood cancer neuroblastoma. By using the senescence-associated secretory phenotype (SASP) as a discriminator for beneficial versus adverse effects of senescence, we identified topotecan as inducer of a favorable SASP. Senescent tumor cells are growth arrested and act growth inhibitory on co-cultured non-senescent tumor cells. MYCN oncogene amplification and expression, hallmarks of aggressive neuroblastoma, are significantly reduced, supporting an initial transition to a more favorable phenotype. These new aspects of metronomic drug treatment are clinically relevant and might apply to other tumor entities.
2014-12-31 | GSE59529 | GEO
Project description:Neuroblastoma is the third most common pediatric cancer and is responsible for approximately 15% of all childhood cancer deaths (Maris & Matthay, 1999). In our analysis, we found that poor patient survival with increasing mRNA expression level of AURKA and AURKB in Mycn-amplified neuroblastoma. In the light of this evidence, we were able to find possibilities of existing inhibitors for therapy. According to the following experiments, we found that tozasertib, a pan-Aurora kinase inhibitor, has high therapeutic potential in neuroblastoma treatment. First, we performed in vitro experiments to reveal that tozasertib suppressed cell proliferation in multiple Mycn-amplified neuroblastoma cell lines. Next, we evaluated ex vivo not only in Mycn-amplified neuroblastoma xenograft mouse model but also TH-Mycn transgenic mouse model. The results showed that tozasertib significantly inhibited the tumor growth and prolonged the survival probability in both animal models. Finally, we explored the mechanism of tozasertib-treated tissues in two animal models by iTRAQ proteomic.
2019-09-30 | PXD007640 | Pride
Project description:An alternative or follow-up adjunct to conventional maximum tolerated dose (MTD) chemotherapy now in advanced phase III clinical trial assessment is metronomic chemotherapy?the close regular administration of low doses of drug with no prolonged breaks. A number of preclinical studies have shown metronomic chemotherapy can cause long term survival of mice with advanced cancer, including metastatic disease, in the absence of overt toxicity, especially when combined with targeted antiangiogenic drugs. However, similar to MTD chemotherapy acquired resistance eventually develops, the basis of which is unknown. Using a preclinical model of advanced human ovarian (SKOV-3-13) cancer in SCID mice, we show that acquired resistance can develop after terminating prolonged (over 3 months) successful therapy utilizing daily oral metronomic topotecan plus pazopanib, an oral antiangiogenic tyrosine kinase inhibitor (TKI). Two resistant sublines were isolated from a single mouse, one from a solid tumor (called KH092-7SD, referred to as 7SD) and another from ascites tumor cells (called KH092-7AS, referred to as 7AS). Using these sublines we show acquired resistance to the combination treatment is due to tumor cell alterations that confer relative refractoriness to topotecan. The resistant phenotype is heritable, associated with reduced cellular uptake of topotecan and could not be reversed by switching to MTD topotecan or to another topoisomerase-1 inhibitor, CPT-11, given either in a metronomic or MTD manner nor switching to another antiangiogenic drug, e.g. the anti-VEGFR-2 antibody, DC101, or another TKI, sunitinib. Thus, in this case cross resistance seems to exist between MTD and metronomic topotecan, the basis of which is unknown. However, gene expression profiling revealed several potential genes that are stably upregulated in the resistant lines, that previously have been implicated in resistance to various chemotherapy drugs, and which, therefore, may contribute to the drug resistant phenotype. Two-condition experiment, ovarian cell line (SKOV-3-13) sensitive to daily oral metronomic topotecan plus pazopaniband treatemnt compared to two in- vivo selected resistant sublines from a solid tumor (called KH092-7SD) and another from ascites tumor cells (called KH092-7AS). Biological replicates: 4 independently grown and harvested cell line passages. Two technical replicate per condition (including dye swap).
2014-02-04 | E-GEOD-54621 | biostudies-arrayexpress
Project description:An alternative or follow-up adjunct to conventional maximum tolerated dose (MTD) chemotherapy now in advanced phase III clinical trial assessment is metronomic chemotherapy?the close regular administration of low doses of drug with no prolonged breaks. A number of preclinical studies have shown metronomic chemotherapy can cause long term survival of mice with advanced cancer, including metastatic disease, in the absence of overt toxicity, especially when combined with targeted antiangiogenic drugs. However, similar to MTD chemotherapy acquired resistance eventually develops, the basis of which is unknown. Using a preclinical model of advanced human ovarian (SKOV-3-13) cancer in SCID mice, we show that acquired resistance can develop after terminating prolonged (over 3 months) successful therapy utilizing daily oral metronomic topotecan plus pazopanib, an oral antiangiogenic tyrosine kinase inhibitor (TKI). Two resistant sublines were isolated from a single mouse, one from a solid tumor (called KH092-7SD, referred to as 7SD) and another from ascites tumor cells (called KH092-7AS, referred to as 7AS). Using these sublines we show acquired resistance to the combination treatment is due to tumor cell alterations that confer relative refractoriness to topotecan. The resistant phenotype is heritable, associated with reduced cellular uptake of topotecan and could not be reversed by switching to MTD topotecan or to another topoisomerase-1 inhibitor, CPT-11, given either in a metronomic or MTD manner nor switching to another antiangiogenic drug, e.g. the anti-VEGFR-2 antibody, DC101, or another TKI, sunitinib. Thus, in this case cross resistance seems to exist between MTD and metronomic topotecan, the basis of which is unknown. However, gene expression profiling revealed several potential genes that are stably upregulated in the resistant lines, that previously have been implicated in resistance to various chemotherapy drugs, and which, therefore, may contribute to the drug resistant phenotype.
2014-02-04 | GSE54621 | GEO
Project description:Overexpression of MYC family members is linked to poor clinical outcome in many human cancers. These oncoproteins drive proliferation, alter metabolism, and mediate an antioxidant response to maintain tumor cell redox balance. However, to date, there are no effective inhibitors that specifically target MYC-amplified tumors. We demonstrate that MYCN-amplified, aggressive childhood neuroblastoma cells undergo ferroptotic cell death in vivo in the absence of intracellular cysteine, thus implicating MYCN as a predictive biomarker for ferroptosis sensitivity in neuroblastoma. Although cysteine is provided by both uptake from the microenvironment and MYCN-induced transsulfuration of methionine, glutathione levels remain low in these highly proliferative cancer cells due to concomitant cysteine utilization for protein and nucleotide synthesis. Consequently, MYCN-amplified neuroblastoma cells are highly susceptible to lipid peroxidation and ferroptosis, which must be counteracted by GPX4 activity. Pharmacological inhibition of both cystine uptake and transsulfuration combined with GPX4 inactivation resulted in tumor remission in an orthotopic MYCN-amplified neuroblastoma model. Our data show that MYCN-amplified neuroblastoma is sensitized to ferroptosis, which can be exploited therapeutically, by depleting the intracellular cysteine pool with concomitant GPX4 inactivation. These findings may help to develop novel clinical strategies to target MYCN-amplified tumors by inducing ferroptotic cell death.
2022-01-18 | GSE189174 | GEO