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Subject: search.filters.subject.Apoptosis

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    Crizotinib and PARP inhibitors act synergistically by triggering apoptosis in high-grade serous ovarian cancer
    (2019) Jönsson, Jenny-Maria; Hedenfalk, Ingrid; N/A; Şahin, İrem Durmaz; Faculty Member; School of Medicine; 303825
    High-grade serous ovarian cancer (HGSOC) is the predominant and most lethal histological type of epithelial ovarian cancer. During the last few years, several new treatment options with PARP inhibitors have emerged. The FDA has approved the PARP inhibitor olaparib (Lynparza™) as maintenance treatment after first-line platinum-containing chemotherapy and olaparib, niraparib (Zejula™) and rucaparib (Rubraca™) are approved as maintenance therapies in the recurrent, platinum-sensitive setting; nevertheless, development of resistance limits their efficacy. In this study, new combinatorial treatment strategies targeting key signaling pathways were explored to enhance the activity of PARP inhibitors in HGSOC. Carboplatin, olaparib, niraparib, the PI3K inhibitor LY294002 and the c-Met inhibitor crizotinib were used for this investigation. PARP inhibitors and carboplatin alone and in combination caused accumulation of DNA double-strand breaks and G2/M cell cycle arrest. In contrast, crizotinib alone or in combination with PARP inhibitors induced accumulation of cells in sub-G1. Crizotinib together with either of the PARP inhibitors was more strongly synergistic than combinations with a PARP inhibitor and carboplatin or the PI3K inhibitor. Sequential combination of crizotinib and a PARP inhibitor resulted in activation of ATM/CHK2 and inhibition of c-Met pathways, contributing to a decrease in RAD51 levels and induction of caspase-3 dependent apoptotic cell death and suggesting that the combination of crizotinib with a PARP inhibitor may be considered and further explored as a new therapeutic strategy in HGSOC.
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    Epigenetic regulation of the "peroxisome proliferator activated receptor-gamma" gene in acute myeloid leukemia patients
    (Türkiye Klinikleri, 2019) Gören Şahin, Deniz; Gündüz, Eren; Yurteri, Buket; Yeşilyurt, Ahmet; Andiç, Neslihan; Üsküdar Teke, Hava; Akay, Olga Meltem; Faculty Member; School of Medicine; 170966
    Objective: Peroxisome proliferator activated receptor gamma (PPAR) is a member of the nuclear hormone receptor family that regulates cellular growth, differentiation and apoptosis. PPAR gamma expression is present in normal bone marrow and peripheral CD34+ cells. There are studies showing that this regulation is decreased in acute myeloblastic leukemia (AML). However, there is no study of whether this reduction is transcriptional or epigenetic. For this purpose we investigated the expression and methylation levels of the PPAR gamma gene in AML and healthy control group. Material and Methods: Thirty-one newly diagnosed cases of AML and 25 healthy individuals were included in the study. Differences in the PPAR gamma gene expression between the study group and the control group were analyzed by real time polymerase chain reaction (RT-PCR) technique. Methylation-specific PCR was performed using the Epitect bisulfite protocol. After primers were designed, bisulfite DNA transformation was performed. The methylation level of the PPAR gamma gene was measured by the Epitect HRM PCR protocol. Results: As a result of RT-PCR, the expression of PPAR gamma gene in AML cases was found to be reduced by about 1.5 times compared to healthy individuals. When the methylation status of the PPAR gamma promoter region was examined by methylation-specific PCR in the cases where the PPAR gamma expression was decreased, methylation in the candidate gene region in AML cases was significantly increased (29% in AML cases and 8% in control group, p<0.001). Conclusion: In our study, the expression of the PPAR gamma gene was significantly reduced in patients with AML. It has also been shown that over-methylation of the promoter region may be responsible for suppression of this gene expression. / Öz: Amaç: Peroksizom proliferatör aktive edici reseptör (PPAR) gama; hücresel büyüme, farklılaşma ve apopitozisi düzenleyen nükleer hormon reseptör ailesinin bir üyesidir. Normal kemik iliğinde ve periferik CD34+ hücrelerde PPAR gama ifadesi mevcuttur. Akut miyeloid lösemi (AML)'de bu ifadenin azaldığını gösteren çalışmalar vardır. Ancak, bu azalmanın transkripsiyonel mi yoksa epigenetik mi olduğuna dair çalışma yoktur. Hipotezimiz, AML hastalarında PPAR gama ifadesinin azalmasının, bu gen bölgesinin aşırı metilasyonu sonucu olduğudur. Bu amaca yönelik olarak çalışmamızda, AML ve sağlıklı kontrol grubunda PPAR gama geninin ifadesi ve metilasyon düzeylerini araştırdık. Gereç veYöntemler: Çalışmaya yeni tanı konulmuş 31 AML hastası, 25 sağlıklı birey dâhil edildi. PPAR gama gen ifadesinin farklılığına gerçek zamanlı polimeraz zincir reaksiyonu (RT-PCR) tekniği ile bakıldı. Aynı hastalarda Epitect bisülfit protokolü uygulanarak metilasyon spesifik PCR yapıldı. PPAR gama gen bölgesinde aşırı metilasyon olabilecek promoter bölgesine uygun primerler dizayn edildi. Ardından termal cycler ile bisülfit DNA dönüşümü yapıldı. Epitect HRM PCR protokülü ile PPAR gama genindeki metilasyon düzeyi ölçüldü. Bulgular: RT-PCR sonucunda AML hastalarında PPAR gama gen ifadesinin sağlıklı bireylere göre yaklaşık 1,5 kat kadar azaldığı tespit edildi. PPAR gama ifadesinin azaldığı gösterilen hastalarda metilasyon spesifik PCR ile PPAR gama geni promoter bölgesinin metilasyon durumu incelendiğinde, AML hastalarında aday gen bölgesinde metilasyonun anlamlı olarak arttığı (AML hastalarında %29 ve kontrol grubunda %8, p<0,001) tespit edildi. Sonuç: Çalışmamızda, kemik iliğindeki hematopoetik süreci düzenleyen genlerden biri olan PPAR gama geninin ifadesinin AML hastalarında anlamlı olarak azaldığı izlenmiştir. Bunun yanı sıra, bu gen ifadesinin baskılanmasından, genin promoter bölgesinin aşırı metilasyonunun sorumlu olabileceği gösterilmiştir.
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    Organic polymers for triggering cell death in cancer cells
    (Koç University, 2022) Öz, Fatma; Yalçın, Özlem; 0000-0001-5547-6653; Koç University Graduate School of Sciences and Engineering; Bio-Medical Sciences and Engineering; 218440