Papers by Çığır Biray Avci
Medical Oncology, Jan 20, 2022
LncRNAs are associated with malignancies with their tumor suppressor/oncogenic properties. Althou... more LncRNAs are associated with malignancies with their tumor suppressor/oncogenic properties. Although many studies are conducted related to the mechanism of action for dasatinib and ponatinib in chronic myeloid leukemia (CML), their comparative effects on lncRNA expressions are largely unknown. Hence, we aimed to define the lncRNAs involved in the treatment of CML with dasatinib and ponatinib. We measured the cytotoxicities of dasatinib/ponatinib with CCK-8 assay and identified differentially expressed lncRNAs (DEL) by qRT-PCR. We determined the principal functions of DELs by Ingenuity Pathway Analysis (IPA) and performed gene ontology (GO) analysis for apoptosis and anti-proliferation-related lncRNAs. Apoptotic and anti-proliferative activities of dasatinib/ponatinib were confirmed by flow-cytometry. In K562 cells, dasatinib/ponatinib re-regulated lncRNAs which were dysregulated in leukemia. DELs after treatment (forty with dasatinib, thirty-seven with ponatinib) were related to increased cell death; decreased cell viability, proliferation, tumor growth, invasion, migration. Dasatinib-mediated network was related to cancer, hematological disease while ponatinib-mediated network was associated with cancer, cell death/survival, cell-to-cell signaling/interaction. Both treatments predicted activation of IFNγ, IL1β, TNF as upstream regulators, specially this effect was higher in dasatinib. Comparison analysis showed that ponatinib was predicted more effective in cell death of tumor cell line than dasatinib. We confirmed that ponatinib was more potent than dasatinib to induce apoptosis and inhibit proliferation of CML cells, in consensus with IPA and GO analysis results. LncRNAs are specifically involved in anti-leukemic activities of dasatinib and ponatinib. Our findings will contribute to understanding signalization occurring in CML cells after standard treatments.
Leukemia Research, Oct 1, 2014
Cyprus journal of medical sciences, Jun 29, 2020
BACKGROUND/AIMS The purpose of this study was to research the effects of genistein on telomerase ... more BACKGROUND/AIMS The purpose of this study was to research the effects of genistein on telomerase activity and apoptosis in an acute promyelocytic leukemia cell line (HL-60). MATERIAL and METHODS In HL-60 cells, the cytotoxic effect of commercially available genistein was evaluated by the XTT method. The XTT method is a Cell Proliferation Assay. The Annexin V-EGFP method was used to determine apoptosis. The human telomerase reverse transcriptase (hTERT) is a marker of telomerase activity. hTERT gene expression analysis was performed by LightCycler real-time RT-PCR. RESULTS In HL-60 cells, the IC50 of genistein was found to be 50 µM at 72 hours. It was observed that the induction of apoptosis was 4.25-fold higher compared to the genistein untreated cells used as the control group. Compared to the control group, hTERT activity was found to decrease by 5.16, 3.81 and 5.04-fold at 24, 48 and 72 hours, respectively. CONCLUSION Induced apoptosis of HL-60 cells by the reduction of human telomerase reverse transcriptase activity may be a beneficial parameter in leukemia patients.
Gene, Dec 1, 2017
BCR-ABL tyrosine kinase inhibitors (TKIs) are selective therapies for the patients with Chronic M... more BCR-ABL tyrosine kinase inhibitors (TKIs) are selective therapies for the patients with Chronic Myeloid Leukemia (CML). Imatinib and ponatinib have remarkable long-term efficacy on a major molecular response. Although TKI related induction of cytotoxicity and apoptosis have been clearly investigated in molecular levels, their comparative effect on autophagy and miRNome are largely unknown. This study aimed to investigate the involvement of alterations of miRNA expressions in CML progression, and how imatinib and ponatinib affect this process, by comparing CML, imatinib-resistant CML and leukemia stem cells (LSC). Cytotoxicity analysis was conducted by WST-1, apoptosis was evaluated by AnnexinV, autophagy was analyzed by Tb/GFP TR-FRET LC3B assay and changes in miRNomes were evaluated with microarray method. Ponatinib showed higher cytotoxicity and apoptosis at far fewer concentrations than imatinib. Both imatinib and ponatinib was able to trigger autophagy in imatinib-resistant K562ima3 cell line but not in LSC. We pointed that imatinib and ponatinib caused significant miRNA profile alterations, especially in the expressions of miR-214-pre, miR-218, miR-19a-5p, miR-19b-1-5p, miR-27b-pre, miR-23bpre, miR-320e, miR-200a-pre, miR-508-3p, miR-33-pre and miR-766. This study is the first comparative miRNome analysis of CML, resistant CML and LSCs following the imatinib or ponatinib treatment and may guide to identify new markers for diagnosis, follow-up of the disease and to develop novel therapeutic strategies if supported by preclinical studies.
Blood, Nov 16, 2012
Abstract 4679 The aims of this study are transfection of tumor suppressor miR-150 that is down-re... more Abstract 4679 The aims of this study are transfection of tumor suppressor miR-150 that is down-regulated in leukemogenesis into leukemia cells mediated by Polyethylene Glycol - Polyethylenimine (PEG-PEI) nanoparticle and determine the changes in gene expression pattern in chronic myeloid leukemia model cell lines; K-562 and KU812 and non-leukemia cell lines NCI-BL2347 and NCI-BL2171. Characterization studies and stability studies of PEG-PEI copolymers were performed and by using these copolymers 9 nanoparticle formulations were prepared. Three copolymers (named T1, T3 and T9) were eligible for further analysis and nanoparticle complex (named F1, F2 and F3) formulations, particles that their size less than 300 nM have been evaluated. Nanoparticle-mediated substitution of miR-150 reduced the expressions of cell cycle control genes CDK2 and CCNG2, CDK6 7-fold and 2-fold, respectively in K562 leukemia cell model. Nanoparticle-mediated substitution of miR-150 has been evaluated KU812 leukemia cell model and reduced the expression of cell cycle control genes CHEK2, CDK5RAP1 and CCNG2 and CDKN1A 6- fold 5 –fold and 2-fold, respectively. Substitution of deregulated tumor suppressor miR-150 to leukemia cells with non-viral transfection yielded promising results for the treatment of leukemia. Taking into account these results, it should be supported by preclinical studies in animal models, which would add benefit to current treatment protocols in clinical application. Disclosures: No relevant conflicts of interest to declare.
Clinical Lymphoma, Myeloma & Leukemia, Jun 1, 2015
prototype improves research workflow with its streamlined reagent formulation and multiplex assay... more prototype improves research workflow with its streamlined reagent formulation and multiplex assay format, facilitates assessment on the IS without conversion (through integrated ARQ materials traceable to the WHO Primary), and generates results sufficient for studies in deep molecular responses.
Clinical Lymphoma, Myeloma & Leukemia, Jun 1, 2015
Chronic myelogenous leukemia (CML) is a hematological disease resulting from generation of BCR/AB... more Chronic myelogenous leukemia (CML) is a hematological disease resulting from generation of BCR/ABL oncogene. Resveratrol is an important phytoalexin which is contained in many plants and it has cytotoxic effects in various cancer types. Gene promoter methylation causes loss of tumor suppressor gene function in human cancer. CHD4 (Chromodomain/Helicase/DNA- binding domain) gene which contains a CpG island is a member of the cadherin family. In this study we aimed to evaluate the role of epigenetic modification of resveratrol in cadherin family genes in K562 human CML cell line. K562 cells were treated with 100 mM (IC50 dose) resveratrol depend on time and dosage during 72 hours and cytotoxicity was evaluated by using WST-1 assay. The RT-qPCR is used for gene expression analysis. Gene expression levels were evaluated by using RT 2 Profiler PCR Array. RT-qPCR results showed that, CHD4 gene expression increased 3.45 fold, according to the control cells that untreated with resveratrol. Significant upregulation was found in CHD4 gene expression among the cadherin family genes in resveratrol treated K562 cells. CHD4 is affected by methylation and frequently is silenced in CML. Downregulation of CHD4 gene expression could trigger activation of the Wnt-pathway and cause aberant cell-to-cell interactions. After treatment with the resveratrol in K562 cells, CHD4 gene expression was upregulated. Resveratrol could increase the cadherin family gene expressions and activation of the Wntpathway is blocked in CML. Also, resveratrol could demethylate CpG island in CHD4 promoter region and increase CHD4 gene expression. Our results indicate that resveratrol may act as a demethylation agent on the promoter of tumor supresor genes such as CHD4 and increase the expression of these genes. Therefore, resveratrol could be used as a pioneering anti-tumorigenesis drug in CML.
Ege Tıp Dergisi
Amaç: Meme kanseri, dünya genelinde kadınlarda en yaygın gözlenen malignansidir. Bu nedenle mevcu... more Amaç: Meme kanseri, dünya genelinde kadınlarda en yaygın gözlenen malignansidir. Bu nedenle mevcut tedavilerin eksiklerini giderebilecek yeni stratejilerin tanımlanmasına ihtiyaç vardır. Çalışmamızda meme kanseri hücrelerinin hedeflenmesinde kullanılabilecek yeni bitkisel kombinasyon terapileri tanımlamayı hedefledik. Bu amaçla, Centaurea calolepis (CCİ), Origanum sipyleum (OSM) ve Phlomis lycia (PLİ) bitki ekstrelerinin ponatinib ile kombinasyonlarının MCF-7 hücreleri üzerindeki sitotoksik, apoptotik, anti-proliferatif ve hücre döngüsü üzerindeki etkileri araştırılmıştır. Gereç ve Yöntem: MCF-7 hücrelerinde OSM, CCİ, PLİ ve ponatinibin sitotoksik etkileri xCELLigence ile gerçek-zamanlı olarak ölçüldü. Ponatinib ile CCİ (p-CCİ), OSM (p-OSM), PLİ (p-PLİ) kombinasyonlarının analizleri için medyan-etki denklemini kullanıldı. Apoptoz, proliferasyon, hücre döngüsü düzenlenmesi akım sitometride değerlendirildi. Bulgular: MCF-7 hücrelerinde CCİ, OSM ve PLİ ekstrelerinin IC50 dozları sırası...
Amaç: t(4;11), MLL-AF4 translokasyonu sonucu oluşan, 4q21 kromozomal bandına yerleşim gösteren AF... more Amaç: t(4;11), MLL-AF4 translokasyonu sonucu oluşan, 4q21 kromozomal bandına yerleşim gösteren AF4 geninin 11q23 kromozomal bandına yerleşim gösteren MLL genine füzyonu sonucu gelişen kromozomal bir anomalidir. Bu çalışmada, retrospektif olarak 2009-2013 yılları arasındaki akut lenfoblastik lösemi (ALL) hastalarındaki t(4;11) MLL- AF4 translokasyonunun analiz sonuçlarının incelenmesi amaçlandı. Gereç ve Yöntem: Ege Üniversitesi Tıp Fakültesi Tıbbi Biyoloji Anabilim Dalı’na 2009-2013 yılları arasında akut lösemi ön tanısıyla 176 çocuk (70 kız, 106 erkek) ve 144 yetişkin (60 kadın, 84 erkek) olgunun kan veya kemik iliği örnekleri incelendi. Bu olgulara ait 71 kan ve 473 kemik iliği örneğinin t(4;11) translokasyon RNA sonuçları, gerçek zamanlı RT-PCR yöntemi ile kantitatif olarak değerlendirildi. İlk aşamada, kan ve kemik iliği örneklerinden izole edilen total RNA veya mRNA’dan konvansiyonel bir PCR cihazı ile komplementer DNA sentezlendi. İkinci aşamada, gerçek zamanlı PCR cihazı ile t(4;11) kantitasyonu gerçekleştirildi. Olguların kantitatif olarak değerlendirilmesi, pozitif kontrol ve negatif kontrolün karşılaştırılması ile örneklerin negatif yada pozitif (pozitif olgu kopya sayısının referans kopya sayısına oranı) olması şeklinde yapıldı. Bulgular: Çalışmamızda 98’i takip hastası olmak üzere toplam 320 hasta t(4;11) MLL-AF4 translokasyonu için değerlendirildi. Çalışmaların sonucunda toplam 34 olgu (24 çocuk, 10 yetişkin) pozitif ve diğer örnekler negatif olarak bulundu. Sonuç: Bu değerlendirmenin sonuçları, RT-PCR yöntemi ile ALL hastalarında yeni tanı döneminde ve tedavi sürecinde t(4;11) MLL-AF4 translokasyonunun kantitatif tayini, hem tanının kesinleştirilmesinde hem de moleküler remisyon sağlanmasına yönelik tedaviyi yönlendirmesinde değerli bir yöntem olduğunu desteklemektedir.Aim: t(4,11) is a chromosomal abnormality formed by the translocation MLL-AF4, which is the result of the fusion of the AF4 gene, localized on 4q21 chromosomal band, to the MLL gene, localized on 11q23 chromosomal band. The aim of this study is to examine the results of the analysis of t (4;11) MLL-AF4 translocation in acute lymphoblastic leukemia (ALL) patients retrospectively. Materials and Methods: Peripheral blood or bone marrow samples of 176 children (70 girls, 106 boys) and 144 adults (60 women, 84 men) with a preliminary diagnosis of acute leukemia between 2009-2013 were analyzed in the Medical Biology Department of Ege University Faculty of Medicine. The translocation RNA results of 71 peripheral blood and 473 bone marrow samples of these patients were evaluated quantitatively for t(4;11) with real-time RT- PCR. t(4;11) quantitation was performed by real-time qRT-PCR instrument after the synthesis of complementary DNA with conventional PCR from total RNA or mRNA isolated from blood and bone marrow. Quantitative analysis of the patients was performed by comparing positive and negative controls and samples classified as positive or negative (the ratio of the number of positive copies to the number of reference copies). Results: A total of 320 patients, with 98 having also follow-ups, were evaluated for t(4;11) translocation. Totally 34 patients (24 children and 10 adults) were found positive and the other samples were negative. Conclusion: The assessment of these results supports that, quantitative determination of t(4;11) with RT-PCR method among newly diagnosed ALL patients and ALL patients undergoing treatment, is a valuable method for both confirming the diagnosis and guiding the treatment intended to achieve molecular remission
Avci, Cigir Biray/0000-0001-8251-4520WOS: 000486972405062[No abstract available
Amac: Kemik iligindeki hematopoietik hucrelerin anormal birikimiyle karakterize olan kronik myelo... more Amac: Kemik iligindeki hematopoietik hucrelerin anormal birikimiyle karakterize olan kronik myeloid losemi (KML) icin t(9;22) kromozomal translokasyonu tanisal bir belirtectir. Philadelphia kromozomu olusumuyla sonuclanan translokasyon, KML olgularinda gelismekte ve hastalarinin %95’inde gorulmektedir ve akut lenfoblastik losemi (ALL) ve akut myeloid losemi (AML)’de daha kotu bir prognozun gostergesidir. Bu calismada, Tibbi Biyoloji Anabilim dalinda 2004-2013 yillari arasinda gelen KML on tanili hastalarin t(9;22) analizi yapilarak, sonuclarinin degerlendirilmesi amaclanmistir. Yontem ve gerecler: 2004-2013 yillari arasinda gelen KML on tanili olgularin, BCR-ABL fuzyon gen ekspresyonun belirlenmesi, 361 cocuk ve 2433 eriskin olguda gerceklestirilmistir. Cocuk olgularinin 125’i ve eriskin olgularinin 626’si takip hastasi olup 3612 kan (%59) ve 2516 kemik iligi (%41) orneginden total RNA veya mRNA izolasyonu gerceklestirilmistir. Bulgular: Ege Universitesi Tip Fakultesi Tibbi Biyoloji...
European Journal of Pharmacology, 2021
Ponatinib is used for advanced treatment of chronic myeloid leukemia (CML), although low doses to... more Ponatinib is used for advanced treatment of chronic myeloid leukemia (CML), although low doses to prevent side effects do not suppress survival pathways and eradicate leukemia stem cells (LSCs). We evaluated the potential of ponatinib and PI3K/mTOR dual-inhibitor VS-5584 combination (PoVS) therapy to increase the anti-leukemic effects of ponatinib and investigated the underlying mechanisms at the molecular level. We measured the cytotoxicities of ponatinib, VS-5584, and PoVS (CCK-8 assay), and used the median-effect equation for combination analyses. We investigated the effects of inhibitory concentrations on apoptosis, cell viability and cell-cycle regulation (flow cytometry), protein levels (ELISA, western blot), transcriptional activities (dual-luciferase reporter assay), gene expressions (qRT-PCR). VS-5584 exerted selective cytotoxic effects against CML and LSC cell lines. VS-5584 inhibited the PI3K/Akt/mTOR pathway, resulting in reduced cell viability, slightly induced caspase-independent apoptosis, prominent G0/G1 cell-cycle blockade that is not a consequence of quiescence. Normal hematopoietic stem cell line was the least affected. Moreover, ponatinib and VS-5584 mediated synergistic anti-leukemic effects on leukemic cells. VS-5584 reduced the ponatinib dose required to target leukemic cells. PoVS treatment inhibited PI3K/Akt/mTOR pathway more consistently than either of the two agents alone through reducing p-Akt, p-mTOR, p-S6K, p-PRAS40, p-S6. The subsequent downstream effects were an increase in C/EBP transcriptional activity and decreases in activities of E2F/DP1, Myc/Max, CREB, STAT3, NFκB, AP-1, Elk-1/SRF. Transcriptional regulation resulted in alterations in the expression levels of target mRNAs. Our results highlight PoVS can be a promising treatment strategy for eliminating CML cells and LSCs selectively, with the reduced ponatinib doses.
LLM Dergi, 2017
Akut lenfoblastik lösemi (ALL), kemik iliği veya diğer lenfoid dokulardaki lenfoid progenitör hüc... more Akut lenfoblastik lösemi (ALL), kemik iliği veya diğer lenfoid dokulardaki lenfoid progenitör hücrelerin farklılaşma ve çoğalma anomalilerinden kaynaklanan hematolojik malignitedir. Telomeraz inhibitörleri çoğalmayı ve büyümeyi önleyen bir diğer önemli antikanser ajanlardır. BIBR1532, keşfedildiği günden beri, oldukça etkili bir hTERT inhibitörü olarak kullanılmaktadır. Bu çalışmada, BIBR1532'nin yetişkin akut lenfoblastik lösemi hücre hattı olan CCRF-CEM üzerindeki sitotoksik etkisinin kontrol grubuyla kıyaslanarak belirlenmesi amaçlanmıştır. Hastalar ve Yöntem: BIBR1532'nin CCRF-CEM hücre hattı üzerindeki etkisi WST-1 analizi ile belirlenmiştir. Apoptozun belirlenmesinde Annexin V yöntemi kullanılmıştır. Gen ekspresyon değişiklikleri gerçek zamanlı polimeraz zincir reaksiyonu (PCR) ile belirlenmiştir. Bulgular: BIBR1532'nin CCRF-CEM hücre hattı üzerindeki IC 50 dozu 48 saat sonunda 89 μM olarak belirlenmiştir. Aynı zamanda apoptozu kontrole göre %7 artırdığı ve CDH13, DAPK1 ve NR4A3 genlerinin ekspresyon seviyelerinde belirgin bir artışa sebep olduğu belirlenmiştir. Sonuç: Sonuç olarak elde ettiğimiz bulgulara göre ALL tedavisinde telomeraz inhibitörü BIBR1532 kullanımı, telomeraz aktivitesini düşürebileceği gibi apoptotik hücre ölümünü de uyarabilir. Ayrıca bu yolakta görevli genlerin anlamlı ekspresyon değişikliğinin olması hastalığın moleküler patolojisinin aydınlatılmasına ve alternatif tedavi hedefi olabilecek genlerin belirlenmesine katkı sağlayabilir.
Gene, Jan 20, 2018
Acute promyelocytic leukemia (APL) is a subtype of AML that is a mixture of hematological maligna... more Acute promyelocytic leukemia (APL) is a subtype of AML that is a mixture of hematological malignancy, characterized by a specific translocation t(15;17). The using of all-trans retinoic acid (ATRA) with arsenic trioxide (ATO) or chemotherapeutic agents or both of these agents, composes main treatment strategy of APL. While it is possible to achieve success in treatment of low-risk APL with current treatment regimens, such success is not mentioned in high-risk APL. So, it may develop new approaches for treatment regimens for high-risk APL. In the present study, we aimed to investigate the effects of combinational of a classic anticancer agent paclitaxel and antidiabetic agent metformin on HL-60 APL cell line. The combination dose of paclitaxel and metformin was determined by WST-1 analysis. The effect of combinational dose on apoptosis was assessed in fluorescence microscope after using AnnexinV-EGFP Apoptosis and JC-1 Assay Kit. The effect of combinational dose on cell cycle, apopto...
Turkish journal of haematology : official journal of Turkish Society of Haematology, Jan 5, 2007
Hypericin is the main active component of Hypericium perforatum (St. John's Wort). Hypericin ... more Hypericin is the main active component of Hypericium perforatum (St. John's Wort). Hypericin has been proven to have antitumoral effect in in vitro condition against solid tumors by deteriorating the mitochondrial functions. It has also anti-leukemic effect in in vitro conditions. However, there has not been any comparative study with hypericin and extract obtained from Hypericium perforatum L. In this study, it has been aimed to investigate the potential cytotoxic role of the extract obtained from Hypericium perforatum grown in Ege region on leukemic cell line, to compare the cytotoxic effects of both extract and hypericin in HL-60 cells, and to clarify the underlying mechanism(s) of this cytotoxicity. Hypericium perforatum extract was used in dilutions as 1/1000, 1/5000, 1/10.000, 1/50.000 and the IC50 value was found to be as 1/10.000 dilution. Hypericin was found to have cytotoxicity in HL-60 cells in time and dose dependent manner between the doses of 1nM to 100 μM with IC5...
EJNMMI Radiopharmacy and Chemistry, 2016
Background: The arginine-glycine-aspartic (RGD) peptide sequence serves as a high-affinity antago... more Background: The arginine-glycine-aspartic (RGD) peptide sequence serves as a high-affinity antagonist of the integrin α v β 3 receptor that plays an important role in tumor angiogenesis. Recently we reported [ 68 Ga]FSC(succ-RGD) 3 , a trimeric RGD peptide, exhibited excellent targeting properties for α v β 3 integrin expression and significant improved tumor uptake compared to monomeric [ 68 Ga]NODAGA-RGD.(1) Here we report the PET imaging properties of [ 68 Ga]FSC(succ-RGD) 3 in different xenograft tumor model and compared them with [ 68 Ga]NODAGA-RGD. Materials and methods: The PET imaging properties of [ 68 Ga]FSC(succ-RGD) 3 were studied in nude mice bearing M21 human melanoma xenografts and human glioblastoma U87MG xenograft tumor. A parallel PET imaging of 68 GaNODAGA-RGD in same mouse bearing U87MG xenograft tumor was performed as a comparison. Results: The static PET image of [ 68 Ga]FSC(succ-RGD) 3 in nude mice showed highly visualized tumors of M21 (positive) whereas nonvisualized tumor of M21-L (negative) tumor xenografts 1 h post injection confirming receptor-specific activity accumulation. The dynamic PET images of [ 68 Ga]FSC(succ-RGD) 3 showed rapid clearance of [ 68 Ga]FSC(succ-RGD) 3 from the circulation while the tumor remained clearly visible. A direct comparison of [ 68 Ga]FSC(succ-RGD) 3 with [ 68 Ga]NODAGA-RGD in nude mice bearing U87MG xenograft tumor using PET/CT resulted comparable target/background ratio (tumor/kidneys ratio = 1.3 and 1.6, tumor/ muscle ratio = 4.9, 5, respectively, 90 min post injection). The time activity curves from dynamic PET data showed an increase of the activity concentration of [ 68 Ga]FSC(succ-RGD) 3 in tumor firstly, then remained almost constant whereas that of [ 68 Ga]NO-DAGA-RGD decreased quickly. The significant enhanced tumor uptake (3.8 vs. 1.6 % ID/g) in addition to the slower washout rate from tumor for [ 68 Ga]FSC(succ-RGD) 3 not only allows the PET EJNMMI Radiopharmacy and Chemistry
European Journal of Cancer, 2015
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Papers by Çığır Biray Avci