Researcher:
Şahin, İrem Durmaz

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İrem Durmaz

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Şahin

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Şahin, İrem Durmaz

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2019 - 201912020 - 20223

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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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    Design, synthesis and biological evaluation of novel triazolothiadiazoles derived from NSAIDs as anticancer agents
    (Bentham Science Publication Ltd, 2022) Aytaç, Peri; Atalay, Rengül Çetin; Tozkoparan, Birsen; Şahin, İrem Durmaz; Faculty Member; School of Medicine; Koç University Hospital; 303825
    Background: Although transplantation, surgical resection, and tumor ablation are treatment options available following early diagnosis of HCC, poor prognosis and high recurrence rates restrict the efficacy of these approaches. Hence, small molecules with high selectivity and bioactivity are urgently required. Objective: This study presents the synthesis of a series of new triazolothiadiazole derivatives (1a-3j) with NSAID moieties and their cytotoxic bioactivities. Methods: The new synthetic derivatives (1-3; 1a-3j) and NSAIDs ibuprofen, naproxen, and flurbiprofen that commonly used in clinics were screened against human liver (Huh7), breast (MCF7), and colon (HCT116) carcinoma cell lines under in vitro conditions via NCI-sulforhodamine B assay. Results: The 4-methoxyphenyl substituted condensed derivatives 1h, 2h, and 3h were the most active compounds. Based on its high potency, compound 3h was selected for the further biological evaluation of hepatocellular carcinoma cell lines, and the mechanisms underlying cell death induced by 3h were determined. The results revealed that compound 3h induced apoptosis and cell cycle arrest in the sub G1 phase in human liver cancer cells. Conclusion: These new small molecules may be used for the development of new lead compounds.
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    PublicationOpen Access
    A small library of chalcones induce liver cancer cell death through Akt phosphorylation inhibition
    (Nature Publishing Group (NPG), 2020) Christodoulou, Michael S.; Güzelcan, Ece Akhan; Koyaş, Altay; Karaca, Çiğdem; Passarella, Daniele; Çetin-Atalay, Rengül; Şahin, İrem Durmaz; Faculty Member; School of Medicine; 303825
    Hepatocellular carcinoma (HCC) ranks as the fifth most common and the second deadliest cancer worldwide. HCC is extremely resistant to the conventional chemotherapeutics. Hence, it is vital to develop new treatment options. Chalcones were previously shown to have anticancer activities in other cancer types. In this study, 11 chalcones along with quercetin, papaverin, catechin, Sorafenib and 5FU were analyzed for their bioactivities on 6 HCC cell lines and on dental pulp stem cells (DPSC) which differentiates into hepatocytes, and is used as a model for untransformed control cells. 3 of the chalcones (1, 9 and 11) were selected for further investigation due to their high cytotoxicity against liver cancer cells and compared to the other clinically established compounds. Chalcones did not show significant bioactivity (IC 50> 20 μ M) on dental pulp stem cells. Cell cycle analysis revealed that these 3 chalcone-molecules induced SubG1/G1 arrest. Akt protein phosphorylation was inhibited by these molecules in PTEN deficient, drug resistant, mesenchymal like Mahlavu cells leading to the activation of p21 and the inhibition of NFκB-p65 transcription factor. Hence the chalcones induced apoptotic cell death pathway through NFκB-p65 inhibition. On the other hand, these molecules triggered p21 dependent activation of Rb protein and thereby inhibition of cell cycle and cell growth in liver cancer cells. Involvement of PI3K/Akt pathway hyperactivation was previously described in survival of liver cancer cells as carcinogenic event. Therefore, our results indicated that these chalcones can be considered as candidates for liver cancer therapeutics particularly when PI3K/Akt pathway involved in tumor development.
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    PublicationOpen Access
    Homologous recombination repair mechanisms in serous endometrial cancer
    (Multidisciplinary Digital Publishing Institute (MDPI), 2021) Jonsson, Jenny-Maria; Baath, Maria; Bjornheden, Ida; Masback, Anna; Hedenfalk, Ingrid; Şahin, İrem Durmaz; Faculty Member; School of Medicine; 303825
    Serous endometrial cancer (SEC) resembles high-grade serous ovarian cancer (HGSOC) genetically and clinically, with recurrent copy number alterations, TP53 mutations and a poor prognosis. Thus, SEC patients may benefit from targeted treatments used in HGSOC, e.g., PARP inhibitors. However, the preclinical and clinical knowledge about SEC is scarce, and the exact role of defective DNA repair in this tumor subgroup is largely unknown. We aimed to outline the prevalence of homologous recombination repair deficiency (HRD), copy-number alterations, and somatic mutations in SEC. OncoScan SNP arrays were applied to 19 tumors in a consecutive SEC series to calculate HRD scores and explore global copy-number profiles and genomic aberrations. Copy-number signatures were established and targeted sequencing of 27 HRD-associated genes was performed. All factors were examined in relation to HRD scores to investigate potential drivers of the HRD phenotype. Ten of the 19 SEC tumors (53%) had an HRD score > 42, considered to reflect an HRD phenotype. Higher HRD score was associated with loss of heterozygosity in key HRD genes, and copy-number signatures associated with non-BRCA1/2 dependent HRD in HGSOC. A high number of SECs display an HRD phenotype. It remains to be elucidated whether this also confers PARP inhibitor sensitivity.