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    Highly promising antitumor agent of a novel Platinum(II) complex bearing a tetradentate chelating ligand
    (Amer Chemical Soc, 2020) Yılmaz, İsmail; Akar, Remzi Okan; Erkısa Genel, Merve; Selvi, Selin; Şengül, Abdurrahman; Ulukaya, Engin
    A new mononuclear cationic platinum(II) coordination compound with 6,6'-bis(NH-benzimidazol-2-yl)-2,2'-bipyridine (L) ligand having N-4-tetradentate binding pocket [Pt(L)]-Cl-2.2H(2)O (Complex 1) was synthesized and characterized by FTIR(ATR), UV-vis, H-1 NMR, APCI and MALDI MS, and CHN analysis. The antigrowth effect of Complex 1 was tested in breast cancer (MDA-MB-231), lung cancer (A549), colorectal cancer (HCT-116), prostate cancer (PC-3) cell lines, and bronchial epithelial cell line (BEAS-2B) by the SRB and ATP cell viability assays. Apoptosis was detected with Annexin V, mitopotential, BCL-2 inactivation, and gamma H2AX assays by flow cytometry. Complex 1 was found to have cytotoxic activity of MDA-MB-231, A549, HCT-116, and PC-3 cancer cell lines in a dose-dependent manner for 48 h. Complex 1 has been found to cause cell death through different mechanisms depending on the type of cancer. The findings indicated that complex induced intrinsic apoptosis with the increased mitochondrial membrane depolarization level, Bcl-2 inactivation, and DNA damage in PC-3 and A549 cell lines.
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    Key actors in cancer therapy: epigenetic modifiers
    (Tubitak Scientific & Technical Research Council Turkey, 2019) Akar, Remzi Okan; Selvi, Selin; Ulukaya, Engin; Aztopal, Nazlıhan
    Epigenetic reprogramming plays a crucial role in the tumorigenicity and maintenance of tumor-specific gene expression that especially occurs through DNA methylation and/or histone modifications. It has well-defined mechanisms. It is known that alterations in the DNA methylation pattern and/or the loss of specific histone acetylation/methylation markers are related to several hallmarks of cancer, such as drug resistance, sternness, epithelial-mesenchymal transition, and metastasis. It has also recently been highlighted that epigenetic alterations are critical for the regulation of the stemlike properties of cancer cells (tumor-initiating cells; cancer stem cells). Cancer stem cells are thought to be responsible for the recurrence of cancer which makes the patient return to the clinic with metastatic tumor tissue. Hence, the dysregulation of epigenetic machinery represents potential new therapeutic targets. Therefore, compounds with epigenetic activities have become crucial for developing new therapy regimens (e.g., antimetastatic agents) in the fight against cancer. Here, we review the epigenetic modifiers that have already been used in the clinic and/or in clinical trials, related preclinical studies in cancer therapy, and the smart combination strategies that target cancer stem cells along with the other cancer cells. The emerging role of epitranscriptome (RNA epigenetic) in cancer therapy has also been included in this review as a new avenue and potential target for the better management of cancer-beneficial epigenetic machinery.
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    Naftakinon türevli yeni sentez bileşiklerin kanser hücre hatları üzerine etkisinin incelenmesi
    (İstinye Üniversitesi / Sağlık Bilimleri Enstitüsü, 2020) Akar, Remzi Okan
    Prostat kanseri dünyada ikinci, İskandinavya da dahil gelişmiş ülkelerde ise en sık rastlanan birinci kanser türüdür. Hormon ve/veya kemoterapi tedavisi sonrası hücrelerde meydana gelen direnç kanser kaynaklı ölümlerin başlıca sebeplerindendir. Bu nedenle, prostat kanseri tedavisine yönelik yeni ilaç ve tedavi stratejilerinin araştırılmasının yanında, bu ilaç adaylarının etkilediği moleküler yolaklarının aydınlatılması araştırmacıların önemli çalışma sahalarındandır. Naftakinon türevli bileşiklerle yapılan çalışmalarda kanser tedavisinde umut verici etkilerinden ve klinikte kullanılan türevleri olmasından dolayı ilaç olarak kullanımının yaygınlaştığını görülmektedir. Naftakinon türevli ilaçlar topoizomeraz II inhibisyonu ve hücre içi ROS düzeylerinin arttırılması ile hücre ölümünü tetiklemektedir. Dolayısıyla bu tez çalışmasında, yeni sentez naftakinon türevli bir bileşiğin (K13) insan prostat kanseri hücre hatları (PC-3, DU 145 ve LNCaP) üzerine sitotoksik etkileri araştırılmıştır. Naftakinon türevli bileşiğin hücre canlılığı üzerine etkileri SRB canlılık testi ile incelenmiştir. K13 bileşiğinin belirlenen dozlarında söz konusu hücre hatlarında ölüm mekanizmasının belirlenmesi amacıyla akım sitometrisi kullanılmıştır. Son olarak naftakinon türevli bileşiğin etki edebileceği sinyal yolakları ile ilişkili proteinlerin ifade düzeyleri immunoblotlama yöntemi ile belirlenmiştir. Sonuç olarak, yeni sentezlenen naftakinon türevli bileşiğinin üç kanser hücre hattında da hücre ölümünü tetiklediği, fakat mekanizma olarak farklılık gösterdiği bulunmuştur. K13 bileşiğinin prostat kanserinde umut vaad eden bir tedavi seçeneği olabileceği öngörüsüyle farklı kanser türleri de dahil in vitro deneylerin yapılması gerektiği sonucuna varılmıştır.
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    A novel 1,4-naphthoquinone-derived compound induces apoptotic cell death in breast cancer cells
    (TR- Dizin, 2019) Karakaş Zeybek, Didem; Akar, Remzi Okan; Gökmen, Zeliha; Ulukaya, Engin; Deniz, Nahide Gülsah
    Abstract: Breast cancer is the most-diagnosed cancer type among women. The triple-negative subtype is an especially aggressive type of breast cancer. Although chemotherapy is almost the only option for the treatment of triple-negative breast cancer (TNBC), currently used chemotherapeutics are not effective enough, considering the poor survival rate of patients. Therefore, novel compounds need to be developed to improve survival rates. It has been known that quinonic compounds, which are found in nature, have antibacterial, antifungal, and antitumorigenic properties. Naphthoquinones are members of the quinone family and are widely used in research due to their promising properties. In this study, we evaluated the cytotoxic activity of a novel naphthoquinone-derived compound (1,4-naphthoquinone (1,4-NQ)) against two different breast cancer cells: a hormone-responsive cell line (MCF-7) and a triple-negative cell line (MDA-MB-231). As a result, 1,4-NQ decreased cell viability in both tested cell lines in a dose-dependent manner. Increased apoptotic markers (presence of pyknotic nuclei, annexin-V positivity, caspase 3/7 activity, and decreased mitochondrial membrane potential) and DNA damage were especially observed in MDA-MB-231 cells after treatment with the compound. Considering the promising cytotoxic effect of the compound, 1,4-NQ needs further evaluation as a potential candidate for the treatment of TNBC.
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    A promising therapeutic combination for metastatic prostate cancer: Chloroquine as autophagy inhibitor and palladium(II) barbiturate complex
    (Elsevier B.V., 2020) Erkısa Genel, Merve; Aydınlık, Şeyma; Cevatemre, Buse; Aztopal, Nazlıhan; Akar, Remzi Okan; Çelikler, Serap; Yılmaz, Veysel Turan; Ari, Ferda; Ulukaya, Engin
    Autophagy is a catabolic process for cells that can provide energy sources and allows cancer cells to evade cell death. Therefore, studies on the combination of autophagy inhibitors with drugs are increasing as a new treatment modality in cancer. Previously, we reported the anti-tumor activity of a Palladium (Pd)(II) complex against different types of cancer in vitro and in vivo. Chloroquine (CQ), the worldwide used anti-malarial drug, has recently been focused as a chemosensitizer in cancer treatment. The aim of this study was to investigate the efficacy of a combined treatment of these agents that work through different mechanisms to provide an effective treatment modality for metastatic prostate cancer that is certainly fatal. Metastatic prostate cancer cell lines (PC-3 and LNCaP) were treated with Pd (II) complex, CQ, and their combination. The combination enhanced apoptosis by increasing phosphatidylserine translocation and pro-apoptotic proteins. Apoptosis was confirmed by the use of apoptosis inhibitor. The formation of acidic vesicular organelles (AVOs) was observed by acridine orange staining in fluorescence microscopy. The Pd (II) complex increased AVOs formation in prostate cancer cells and CQ-pretreatment has potentiated this effect. Importantly, treatment with CQ suppressed the pro-survival function of autophagy, which might have contributed to enhanced cytotoxicity. In addition, PI3K/AKT/mTOR-related protein expressions were altered after the combination of treatments. Our results suggest that combination treatment enhances apoptotic cell death possibly via the inhibition of autophagy, and may therefore be regarded as a novel and better approach for the treatment of metastatic prostate cancer. © 2020 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM)
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    Synthesis, DNA binding and cytotoxic activity of newcopper(II) complexes of trisubstituted imidazoles
    (Springer, 2022) Gerçek, Zuhal; Yıldız, Ufuk; Ulukaya, Engin; Akar, Remzi Okan
    This study was aimed to synthesize and characterize two new copper(II) complexes, [Cu(phen)(Br-impi)]2+ (1) and [Cu(phen)(M-impi)]2+ (2) (where phen is 1,10-phenanthroline; Br-impi is 2-(2-(4-bromophenyl)-4- (pyridin-2-yl)-4,5-dihydro-1H-imidazol-5-yl)pyridine, andM-impi is 2-(2-(4-methoxyphenyl)-4-(pyridin- 2-yl)-4,5-dihydro-1H-imidazol-5-yl)pyridine), and to study their DNAbinding activity and cytotoxic activity. The interaction of complexes with ds-DNA has been investigated by spectroscopic methods, viscosity measurements, and agarose gel electrophoresis. The results indicate that complex 1 can bind to ds-DNA better than doescomplex 2 with binding constants 1.9 × 105M-1 and 3.9 × 104M-1, respectively.According to the UV titration method, complex 1 is capable of extractingethidium bromide molecules from DNA base pairs at lower concentrations than complex 2. In oxidative medium, both complexes produce complete degradationof plasmid DNA. Thecomplexes were screened against five human cell lines, namely A 549, PC-3, BEAS-2B, HCT-116 and MDZ-MB-231, and it was found that copper(II) complexes of trisubstituted imidazoleexhibited cytotoxic activity. © 2022, Springer Science+Business Media, LLC, part of Springer Nature.
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    Targeting Periostin Expression Makes Pancreatic Cancer Spheroids More Vulnerable to Natural Killer Cells
    (Mdpi, 2023) Karakas, Didem; Erkisa, Merve; Akar, Remzi Okan; Akman, Gizem; Senol, Ezgi Yudum; Ulukaya, Engin
    Pancreatic cancer (PaCa) characteristically has a dense tumor microenvironment, which results in poor patient prognosis. Pancreatic stellate cells (PSCs) are the most abundant cells in the PaCa microenvironment and the principal source of collagen. Periostin, a matricellular protein, is produced specifically by PSCs and promotes the aggressiveness of PaCa cells by facilitating extracellular collagen assembly. Here, we aimed to decrease extracellular collagen assembly by suppressing periostin, thereby increasing the cytotoxic activity of natural killer (NK) cells. Periostin expression was suppressed in PSCs (called PSC-P) using CRISPR-Cas9. PaCa cells (BxPC-3) were co-cultured with PSC and PSC-P cells in a 3D environment to form tumor spheroids mimicking the tumor microenvironment. The extracellular collagen production of spheroids was evaluated by Masson's trichrome staining. The cytotoxic activity of NK-92 cells was analyzed by flow cytometry and confocal microscopy via CD107a staining. Cell death in BxPC-3 cells was evaluated by measuring Annexin-V and PI positivity using flow cytometry. As a result, periostin suppression decreased extracellular collagen and increased the infiltration of NK-92 cells into spheroids, and induced cell death in PaCa cells. In conclusion, we suggest that periostin might be a therapeutic target for PaCa and further analysis is warranted using in vivo models for proof-of-concept.