Drug repurposing towards targeting cancer stem cells in pediatric brain tumors

Bahmad, Hisham F.; Elajami, Mohamad K.; Bou-Gharios, Jolie; Abou-Antoun, Tamara; Abou-Kheir, Wassim

doi:10.1007/s10555-019-09840-2

Cited by 34 publications

(36 citation statements)

References 169 publications

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“…Results showed downregulation of ALDH1A1 and ALDH3A1 in H1792 cells and Aldh1a1 in MDA-F471 cells, which are known to be overexpressed in KRAS-mutant LUAD CSCs, the downregulation of CCL20 in H1792 and MDA-F471, which plays a major role in the growth and metastasis of lung cancer cells, and the downregulation of Alcam and Tnf in MDA-F471, epithelial cell marker and proinflammatory cytokine, respectively [48]. These findings are consistent with other studies that stated the effects of anti-tumor agents on the CSC population using sphere-forming assay [46][47][48][49][50]57,58]. Furthermore, they motivate further investigations to determine the ability of AlgSulf n to target and affect CSCs growth and the pathway that is affected by the AlgSulf n .…”

Section: Discussionsupporting

confidence: 85%

“…Moreover, Riedl et al showed that 3D sphere-forming assays are more representative of the in vivo response to anti-cancer drugs and may in cases be contradictory to results of 2D models [45]. Targeting CSCs is one of the aims of targeted cancer therapy given the evidence that supports the role of CSCs in tumorigenesis and tumor re-occurrence [46,47]. Based on a previous study from our team that showed the significant expression of CSC-properties in H1792 and MDA-F471 spheres at G2 and G5 [48], we analyzed the sphere-forming potentials of AlgSulf n -treated LUAD cells at G2.…”

Section: Discussionmentioning

confidence: 99%

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Anti-Tumor Effects of Biomimetic Sulfated Glycosaminoglycans on Lung Adenocarcinoma Cells in 2D and 3D In Vitro Models

et al. 2020

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Lung cancer development relies on cell proliferation and migration, which in turn requires interaction with extracellular matrix (ECM) components such as glycosaminoglycans (GAGs). The mechanisms through which GAGs regulate cancer cell functions are not fully understood but they are, in part, mediated by controlled interactions with cytokines and growth factors (GFs). In order to mechanistically understand the effect of the degree of sulfation (DS) of GAGs on lung adenocarcinoma (LUAD) cells, we synthesized sulfated alginate (AlgSulf) as sulfated GAG mimics with DS = 0.0, 0.8, 2.0, and 2.7. Human (H1792) and mouse (MDA-F471) LUAD cell lines were treated with AlgSulf of various DSs at two concentrations 10 and 100 µg/mL and their anti-tumor properties were assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), trypan blue exclusion, and wound healing assays for 2D models and sphere formation assay for the 3D model. The proliferation and number of live MDA-F471 cells at the concentration of 100 µg/mL decreased significantly with the increase in the DS of biomimetic GAGs. In addition, the increase in the DS of biomimetic GAGs decreased cell migration (p < 0.001 for DS = 2.0 and 2.7 compared to control) and decreased the diameter and number of spheres formed (p < 0.001). The increased DS of biomimetic GAGs attenuated the expression of cancer stem cell (CSC)/progenitor markers in the 3D cultures. In conclusion, GAG-mimetic AlgSulf with increased DS exhibit enhanced anti-proliferative and migratory properties while also reducing growth of KRAS-mutant LUAD spheres in vitro. We suggest that these anti-tumor effects by GAG-mimetic AlgSulf are possibly due to differential binding to GFs and consequential decreased cell stemness. AlgSulf may be suitable for applications in cancer therapy after further in vivo validation.

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Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Anti-Tumor Effects of Biomimetic Sulfated Glycosaminoglycans on Lung Adenocarcinoma Cells in 2D and 3D In Vitro Models

et al. 2020

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“…At a phenotypic and molecular level, the pediatric brain tumors differ from adult brain tumors such as GBM [38]. However, it is noteworthy that the CSC in both, adult, and the pediatric brain tumors, retain the functionality of pluripotency-biomarkers such as NANOG, SOX2, and OCT4 [39,40]. In our research to analyze the differential sequences of ES genes associated with cancer exosomes, we found many-fold more SNPs and also a cancer-specific SNP associated with GBM-derived exosomes.…”

Section: Sox2mentioning

confidence: 99%

DNA Associated with Circulating Exosomes as a Biomarker for Glioma

Vaidya

Sugaya

2020

Genes

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Cancerous and non-cancerous cells secrete exosomes, a type of nanovesicle known to carry the molecular signature of the parent for intercellular communications. Exosomes secreted by tumor cells carry abnormal DNA, RNA, and protein molecules that reflect the cancerous status. DNA is the master molecule that ultimately affects the function of RNA and proteins. Aberrations in DNA can potentially lead a cell to malignancy. Deviant quantities and the differential sequences of exosomal DNA are useful characteristics as cancer biomarkers. Since these alterations are either associated with specific stages of cancer or caused due to a clinical treatment, exosomal DNA is valuable as a diagnostic, prognostic, predictive, and therapeutic-intervention response biomarker. Notably, the exosomes can cross an intact blood–brain barrier and anatomical compartments by transcytosis. As such, the cancer-specific trademark molecules can be detected in systemic blood circulation and other body fluids, including cerebrospinal fluid, with non-invasive or minimally invasive procedures. This comprehensive review highlights the cancer-specific modulations of DNA associated with circulating exosomes that are beneficial as glioma biomarkers.

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“…Therefore, eradication of CSCs is a potential therapeutic avenue to increase the survival rate of EOC patients. Recently, studies have shown that targeting key molecular players and genetic aberrations in CSCs using small molecule inhibitors, including rapamacyin and triciribine can eradicate CSCs in brain tumors and improve overall survival in glioblastoma and neuroblastoma patients [ 4 , 8 , 9 , 10 , 11 , 12 ]. Identifying the molecular signature of ovarian CSCs will provide a novel therapeutic strategy to selectively target this subpopulation of cells and improve overall survival.…”

Section: Introductionmentioning

confidence: 99%

“…Due to the heterogeneous nature of the tumor [ 6 , 14 ], it is critical to differentiate CSCs from cancer cells (CCs). Although, various cell surface and non-surface markers are currently in use for the identification and isolation of ovarian CSCs [ 6 , 15 , 16 ], the phenotypic and functional heterogeneity in CCs within the tumor require further dissection to understand intra-tumor cell population complexity to eradicate CSCs more effectively [ 11 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

Bioinformatics analysis and verification of molecular targets in ovarian cancer stem-like cells

Behera

Ashraf

Srivastava

et al. 2020

Heliyon

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Background Epithelial ovarian cancer (EOC) is a lethal and aggressive gynecological malignancy. Despite recent advances, existing therapies are challenged by a high relapse rate, eventually resulting in disease recurrence and chemoresistance. Emerging evidence indicates that a subpopulation of cells known as cancer stem-like cells (CSLCs) exists with non-tumorigenic cancer cells (non-CSCs) within a bulk tumor and is thought to be responsible for tumor recurrence and drug-resistance. Therefore, identifying the molecular drivers for cancer stem cells (CSCs) is critical for the development of novel therapeutic strategies for the treatment of EOC. Methods Two gene datasets were downloaded from the Gene Expression Omnibus (GEO) database based on our search criteria. Differentially expressed genes (DEGs) in both datasets were obtained by the GEO2R web tool. Based on log 2 (fold change) >2, the top thirteen up-regulated genes and log 2 (fold change) < -1.5 top thirteen down-regulated genes were selected, and the association between their expressions and overall survival was analyzed by OncoLnc web tool. Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) and Reactome pathways analysis, and protein-protein interaction (PPI) networks were performed for all the common DEGs found in both datasets. SK-OV-3 cells were cultured in an adherent culture medium and spheroids were generated in suspension culture with CSCs specific medium. RNA from both cell population was extracted to validate the selected DEGs expression by q-PCR. Growth inhibition assay was performed in SK-OV-3 cells after carboplatin treatment. Results A total of 200 DEGs, 117 up-regulated and 83 down-regulated genes were commonly identified in both datasets. Analysis of pathways and enrichment tests indicated that the extracellular matrix part, cell proliferation, tissue development, and molecular function regulation were enriched in CSCs. Biological pathways such as interferon-alpha/beta signaling, molecules associated with elastic fibers, and synthesis of bile acids and bile salts were significantly enriched in CSCs. Among the top 13 up-regulated and down-regulated genes, MMP1 and PPFIBP1 expression were associated with overall survival. Higher expression of ADM, CXCR4, LGR5, and PTGS2 in carboplatin treated SK-OV-3 cells indicate a potential role in drug resistance. Conclusions The molecular signature and signaling pathways enriched in ovarian CSCs were identified by bioinformatics analysis. This analysis could provide further research ideas to find the new mechanism and novel potential therapeutic targets for ovarian CSCs.

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Drug repurposing towards targeting cancer stem cells in pediatric brain tumors

Cited by 34 publications

References 169 publications

Anti-Tumor Effects of Biomimetic Sulfated Glycosaminoglycans on Lung Adenocarcinoma Cells in 2D and 3D In Vitro Models

Anti-Tumor Effects of Biomimetic Sulfated Glycosaminoglycans on Lung Adenocarcinoma Cells in 2D and 3D In Vitro Models

DNA Associated with Circulating Exosomes as a Biomarker for Glioma

Bioinformatics analysis and verification of molecular targets in ovarian cancer stem-like cells

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