Researcher:
Kazancıoğlu, Selena

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Undergraduate Student

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Selena

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Kazancıoğlu

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Kazancıoğlu, Selena

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2016 - 20174

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Researcher Of Publications: search.filters.isAuthorOfPublication.141ec969-75ca-49a8-8077-eee5b043a6ef

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    Mitoxantrone potentiates TRAIL-induced apoptosis in glioblastoma multiforme
    (Oxford Univ Press, 2016) Ayhan, Ceyda Açılan; N/A; N/A; N/A; Department of Molecular Biology and Genetics; N/A; N/A; Şenbabaoğlu, Filiz; Cingöz, Ahmet; Kaya, Ezgi; Kazancıoğlu, Selena; Lack, Nathan Alan; Önder, Tuğba Bağcı; PhD Student; Researcher; PhD Student; Undergraduate Student; Faculty Member; Faculty Member; Department of Molecular Biology and Genetics; Graduate School of Health Sciences; Graduate School of Health Sciences; Graduate School of Health Sciences; College of Sciences; School of Medicine; School of Medicine; N/A; N/A; N/A; N/A; 120842; 184359
    Glioblastoma multiforme (GBM) is the most aggressive and frequent type of primary brain tumor with dismal survival rates. As GBM cells suppress apoptosis and evade death, re-activating dormant apoptotic programs with pro-apoptotic ligands or small molecules might be a promising approach. As such, the tumor-selective killing capacity of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potential treatment option in GBM. However, many tumor cells are intrinsically resistant and/or acquire resistance to TRAIL. In this study, we conducted an extensive drug-re-profiling screen to identify FDA-approved compounds that can be used clinically as TRAIL-sensitizing agents in GBM. Using selected isogenic GBM cell pairs with differential levels of TRAIL sensitivity, we revealed 26 TRAIL-sensitizing compounds, 13 of which were effective as single agents. One drug, Mitoxantrone, a DNA-damaging agent, did not cause toxicity to non-malignant cells at the doses that synergized with TRAIL on tumor cells. We investigated the downstream changes in apoptosis pathway components upon Mitoxantrone treatment, and observed that Death Receptors (DR4 and DR5) expression was upregulated, and pro-apoptotic and anti-apoptotic gene expression patterns were altered in favor of apoptosis. Together, our results suggest that combination of Mitoxantrone and TRAIL can be a promising therapeutic approach for GBM patients.
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    Identification of mitoxantrone as a trail-sensitizing agent for glioblastoma multiforme
    (Taylor & Francis Inc, 2016) Ayhan, Ceyda Açılan; N/A; N/A; N/A; Department of Molecular Biology and Genetics; N/A; N/A; Şenbabaoğlu, Filiz; Cingöz, Ahmet; Kaya, Ezgi; Kazancıoğlu, Selena; Lack, Nathan Alan; Önder, Tuğba Bağcı; PhD Student; Researcher; PhD Student; Undergraduate Student; Faculty Member; Faculty Member; Department of Molecular Biology and Genetics; Graduate School of Health Sciences; Graduate School of Health Sciences; Graduate School of Health Sciences; College of Sciences; School of Medicine; School of Medicine; Koç University Hospital; N/A; N/A; N/A; N/A; 120842; 184359
    Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) has tremendous promise in treating various forms of cancers. However, many cancer cells exhibit or develop resistance to TRAIL. Interestingly, many studies have identified several secondary agents that can overcome TRAIL resistance. To expand on these studies, we conducted an extensive drug-re-profiling screen to identify FDA-approved compounds that can be used clinically as TRAIL-sensitizing agents in a very malignant type of brain cancer, Glioblastoma Multiforme (GBM). Using selected isogenic GBM cell pairs with differential levels of TRAIL sensitivity, we revealed 26 TRAIL-sensitizing compounds, 13 of which were effective as single agents. Cardiac glycosides constituted a large group of TRAIL-sensitizing compounds, and they were also effective on GBM cells as single agents. We then explored a second class of TRAIL-sensitizing drugs, which were enhancers of TRAIL response without any effect on their own. One such drug, Mitoxantrone, a DNA-damaging agent, did not cause toxicity to non-malignant cells at the doses that synergized with TRAIL on tumor cells. We investigated the downstream changes in apoptosis pathway components upon Mitoxantrone treatment, and observed that Death Receptors (DR4 and DR5) expression was upregulated, and pro-apoptotic and anti-apoptotic gene expression patterns were altered in favor of apoptosis. Together, our results suggest that combination of Mitoxantrone and TRAIL can be a promising therapeutic approach for GBM patients.
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    Mitoxantrone as a TRAIL-sensitizing agent for glioblastoma multiforme
    (Elsevier, 2016) Ayhan, Ceyda Açılan; N/A; N/A; N/A; Department of Molecular Biology and Genetics; N/A; N/A; Şenbabaoğlu, Fatih; Cingöz, Ahmet; Kaya, Ezgi; Kazancıoğlu, Selena; Lack, Nathan Alan; Önder, Tuğba Bağcı; Master Student; Researcher; PhD Student; Undergraduate Student; Faculty Member; Faculty Member; Department of Molecular Biology and Genetics; Graduate School of Sciences and Engineering; Graduate School of Health Sciences; Graduate School of Health Sciences; College of Sciences; School of Medicine; School of Medicine; N/A; N/A; N/A; N/A; 120842; 184359
    Background: Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) has tremendous promise in treating various forms of cancers. However, many cancer cells exhibit or develop resistance to TRAIL. Interestingly, many studies have identified several secondary agents that can overcome TRAIL resistance. To expand on these studies, we conducted an extensive drug-re-profiling screen to identify FDA-approved compounds that can be used clinically as TRAIL-sensitizing agents in a very malignant type of brain cancer, glioblastoma multiforme (GBM). Material and Methods: GBM cell lines U87MG, U373 and non-malignant cell lines BJ fibroblasts and Normal Human Astrocytes were used in in vitro experiments. 1,200 FDA approved drugs containing library was screened as single agents (5 uM) and/or TRAIL (25 ng/ml) in U87MG and U87MGR50. Cell viability was detected by an ATP-based assay after 24−48 hours. Chosen lead, Mitoxantrone was further studied by cell viability assays, proliferation by live cell imaging, apoptotic gene expression levels by qRT-PCR and death receptor and apoptotic protein expression levels by Western Blot. Results: Using selected isogenic GBM cell pairs with differential levels of TRAIL sensitivity, we revealed 26 TRAIL-sensitizing compounds, 13 of which were effective as single agents. Cardiac glycosides constituted a large group of TRAIL-sensitizing compounds, and they were also effective on GBM cells as single agents. We then explored a second class of TRAIL-sensitizing drugs, which were enhancers of TRAIL response without any effect on their own. One such drug, Mitoxantrone, a DNA-damaging agent, did not cause toxicity to non-malignant cells at the doses that synergized with TRAIL on tumor cells. We investigated the downstream changes in apoptosis pathway components upon Mitoxantrone treatment, and observed that Death Receptors (DR4 and DR5) expression was upregulated, and pro-apoptotic and anti-apoptotic gene expression patterns were altered in favor of apoptosis. Conclusions: Together, our results suggest that combination of Mitoxantrone and TRAIL can be a promising therapeutic approach for GBM patients.
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    PublicationOpen Access
    Kdm2b, an h3k36-specific demethylase, regulates apoptotic response of gbm cells to trail
    (Nature Publishing Group (NPG), 2017) Gumus, Zeynep H.; Kurt, İbrahim Çağrı; Sur, İlknur Erdem; Kaya, Ezgi; Cingöz, Ahmet; Kazancıoğlu, Selena; Kahya, Zeynep; Toparlak, Ömer Duhan; Şenbabaoğlu, Filiz; Kaya, Zeynep; Özyerli, Ezgi; Karahüseyinoğlu, Serçin; Lack, Nathan Alan; Önder, Tamer Tevfik; Önder, Tuğba Bağcı; PhD Student; Undergraduate Student; Other; PhD Student; Faculty Member; Faculty Member; Faculty Member; Graduate School of Health Sciences; School of Medicine; N/A; N/A; N/A; N/A; N/A; N/A; N/A; N/A; N/A; N/A; 110772; 120842; 42946; 184359
    Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can selectively kill tumor cells. TRAIL resistance in cancers is associated with aberrant expression of the key components of the apoptotic program. However, how these components are regulated at the epigenetic level is not understood. In this study, we investigated novel epigenetic mechanisms regulating TRAIL response in glioblastoma multiforme (GBM) cells by a short-hairpin RNA loss-of-function screen. We interrogated 48 genes in DNA and histone modification pathways and identified KDM2B, an H3K36-specific demethylase, as a novel regulator of TRAIL response. Accordingly, silencing of KDM2B significantly enhanced TRAIL sensitivity, the activation of caspase-8, -3 and -7 and PARP cleavage. KDM2B knockdown also accelerated the apoptosis, as revealed by live-cell imaging experiments. To decipher the downstream molecular pathways regulated by KDM2B, levels of apoptosis-related genes were examined by RNA-sequencing upon KDM2B loss, which revealed derepression of proapoptotic genes Harakiri (HRK), caspase-7 and death receptor 4 (DR4) and repression of antiapoptotic genes. The apoptosis phenotype was partly dependent on HRK upregulation, as HRK knockdown significantly abrogated the sensitization. KDM2B-silenced tumors exhibited slower growth in vivo. Taken together, our findings suggest a novel mechanism, where the key apoptosis components are under epigenetic control of KDM2B in GBM cells.