Engin Ulukaya - Academia.edu (original) (raw)

Papers by Engin Ulukaya

Veterinary Research Communications

Cells

Cholangiocarcinoma (CCA) is a poorly treatable type of cancer and its incidence is dramatically i... more Cholangiocarcinoma (CCA) is a poorly treatable type of cancer and its incidence is dramatically increasing. The lack of understanding of the biology of this tumor has slowed down the identification of novel targets and the development of effective treatments. Based on next generation sequencing profiling, alterations in DNA damage response (DDR)-related genes are paving the way for DDR-targeting strategies in CCA. Based on the notion of synthetic lethality, several DDR-inhibitors (DDRi) have been developed with the aim of accumulating enough DNA damage to induce cell death in tumor cells. Observing that DDRi alone could be insufficient for clinical use in CCA patients, the combination of DNA-damaging regimens with targeted approaches has started to be considered, as evidenced by many emerging clinical trials. Hence, novel therapeutic strategies combining DDRi with patient-specific targeted drugs could be the next level for treating cholangiocarcinoma.

Proceedings of the 2nd International Conference on Natural Products for Cancer Prevention and Therapy, 2017

The exploration of natural products is of importance because the management of cancer is still no... more The exploration of natural products is of importance because the management of cancer is still not satisfactory. Pristimerin is a naturally occurring triterpenoid that has been shown to suppress the proliferation of various cancer cell lines at relatively lower concentrations, of which the IC50 values are around 0.5-4 μM. Its cytotoxic potential on particularly cancer stem cells (CSCs) should be much more important due to the CSCs' recent role in recurrence of cancer. Although pristimerin exerted growth inhibitory activity in various cancer cells, the mechanisms is still debatable. Its antigrowth effect seems to involve the blockage of autophagic process as well. In our studies, pristimerin showed an anti-growth effect on cancer cells and cancer stem cells with IC50 values ranging at 0.38-1.75 μM. Apoptosis was induced in MCF-7 and MCF-7s (CSCs) cells. It also resulted in an incompleted autophagy as evidenced by the increase of autophagy-related proteins (P62 and LC3-II) as well as an unfolded protein response (UPR). Moreover, it inhibited the growth of xenografts in NOD/SCID mice. Taken together, pristimerin deserves further attention in terms of its use for the treatment of breast cancer. In this talk, quite an unusal cytotoxic potential of pristimerin will be discussed.

Medicina, 2021

Tumor chemosensitivity assays (TCAs), also known as drug response assays or individualized tumor ... more Tumor chemosensitivity assays (TCAs), also known as drug response assays or individualized tumor response tests, have been gaining attention over the past few decades. Although there have been strong positive correlations between the results of these assays and clinical outcomes, they are still not considered routine tests in the care of cancer patients. The correlations between the assays’ results (drug sensitivity or resistance) and the clinical evaluations (e.g., response to treatment, progression-free survival) are highly promising. However, there is still a need to design randomized controlled prospective studies to secure the place of these assays in routine use. One of the best ideas to increase the value of these assays could be the combination of the assay results with the omics technologies (e.g., pharmacogenetics that gives an idea of the possible side effects of the drugs). In the near future, the importance of personalized chemotherapy is expected to dictate the use of ...

Prostate cancer is among the leading causes of death worldwide because its metastatic form is a d... more Prostate cancer is among the leading causes of death worldwide because its metastatic form is a deadly disease. Therefore, the development of new chemotherapeutics is of immense importance. Nanoparticle technology seems to provide diverse options in this regard. Therefore, poly(N‐isopropylacrylamide) (PNIPAM) coated superparamagnetic iron oxide nanoparticles (SPION) loaded with Etoposide were prepared in small sizes (57 nm) and with 3.5 % drug content to improve the efficiency of Etoposide in prostate cancer therapy. Sustained release of the drug was achieved, which found to be sensitive to low pH and high temperature. The anti‐growth activity of SPION‐PNIPAM‐Etoposide formulation against metastatic prostate cancer cells (PC‐3, LNCaP) were investigated by SRB assay, then, confirmed by ATP assay. Mode of cell death was evaluated by using flow cytometry analyses. A significant improvement of nanoformulated drug was observed at 5–10 μg/ml doses of the drug in both cell lines. More impo...

Antioxidants, 2020

Hybrid compounds combine fragments with complementary targets to achieve a common pharmacological... more Hybrid compounds combine fragments with complementary targets to achieve a common pharmacological goal. This approach represents an increasingly popular strategy for drug discovery. In this work, we aimed to design antitumor hybrid compounds based on an inhibitor of ataxia-telangiectasia and Rad3-related protein (ATR)-dependent signaling, protoapigenone, and a pro-oxidant ferrocene or chalcone fragment. Four new triazole-coupled hybrids were prepared. The compounds were cytotoxic against human breast cancer cell lines in vitro, showing IC50 values in the sub-micromolar range. The nature of interactions between relevant fragments of the hybrids was evaluated by the Chou–Talalay method. Experimental combination treatment with the fragments showed additive effects or slight/moderate synergism, while strong synergism was observed when the fragments were virtually combined into their hybrids, suggesting a relevant pharmacological benefit of the coupling. All hybrids were strong inhibitor...

Bioorganic & Medicinal Chemistry, 2021

Being one of the leading causes of cancer death among women, various chemotherapeutic agents isol... more Being one of the leading causes of cancer death among women, various chemotherapeutic agents isolated from natural compounds are used in breast cancer treatment and consequently studies to develop new drugs still continue. There are several studies on 18βH-glycyrrhetinic acid, a secondary metabolite which is found in Glycyrrhiza glabra (liquorice roots), as a potential anticancer agent. In this study, the cytotoxic and apoptotic effects of Soloxolone methyl compound, a semisynthetic derivative of 18βH-glycyrrhetinic acid were investigated on breast cancer cells (MCF-7, MDA-MBA-231). Soloxolone methyl is found to be cytotoxic on both MCF-7 and MDA-MBA-231 breast cancer cells by inducing apoptosis. Especially in MDA-MB-231 cells apoptosis is detected to be triggered by ER stress. The antigrowth effects of Soloxolone methyl were determined using MTT and ATP assays. To identify the mode of cell death (apoptosis/necrosis), fluorescent staining (Hoechst 33342 and Propidium iodide) and caspase-cleaved cytokeratin 18 (M30-antigen) analyses were used. In addition, apoptosis was investigated on gene and protein levels by PCR and Western Blotting. Soloxolone methyl decreased cell viability on cells in a dose and time-dependent manner and induced apoptosis markers. An increase on apoptotic proteins related to endoplasmic reticulum stress (IRE1-α, Bip, CHOP) was also determined in MDA-MB-231 cells. Moreover, an increase of apoptotic gene expressions was determined in both cells treated with Soloxolone methyl. Advance analyses should be performed to elucidate the potential of Soloxolone methyl as an anticancer agent in breast cancer treatment.

JBIC Journal of Biological Inorganic Chemistry, 2019

In this work, mixed ligand complexes of Co(II) Ni(II) and Cu(II) were synthesized using quercetin... more In this work, mixed ligand complexes of Co(II) Ni(II) and Cu(II) were synthesized using quercetin and diimine (1,10-phenanthroline or 2,2′-bipyiridine) ligands. The obtained Ni(II) and Co(II) complexes are new and the Cu(II) complexes are synthesized by different method from the literature. The characterization of complexes was performed by elemental analysis, thermogravimetric analysis, ESI-MS, UV-visible and infrared spectral analyses, magnetic susceptibility and molar conductivity measurements. It was found that quercetin, diimine and metal(II) ion form 1:1:1 complexes. Resulting data supported octahedral geometry for Ni(II) and Co(II) complexes and square pyramidal geometry for Cu(II) complexes. The proposed compositions are [Co(queH-1)Cl(phen)(H 2 O)]•2H 2 O (1, queH = quercetin, phen = 1,10-phenanthroline), [Ni(queH-1) Cl(phen)(H 2 O)]•2H 2 O (2), [Cu(queH-1)Cl(phen)]•2.5H 2 O (3) and [Cu(queH-1)Cl(bpy)]•2H 2 O (4, bpy = 2,2′-bipyiridine). Antioxidant capacity and total phenolic content of complexes measured by Folin-Ciocalteu and ABTS methods. Anti-cancer effect of these compounds were tested against different cancer cells (A549, PC-3, HeLa and MCF-7). Apoptosis identified by the fluorescence imaging, caspase cleaved cytokeratin-18 and flow cytometry analysis (annexin V, caspase 3/7, mitochondria membrane potential and oxidative stress). As a result, Cu(II) complexes are more effective than the other compounds and Complex 3 is a promising anti-cancer compound against breast cancer MCF-7 and MDA-MB-231 cells (IC 50 values are 2.4 and 5.4 µM for 48 h, respectively). Flow cytometry analysis exhibited that Complex 3 caused apoptosis in MCF-7 cells. These results support that Complex 3 has anticancer activity and can be a potential anticancer agent especially in breast cancer.

TURKISH JOURNAL OF BIOLOGY, 2017

Synthetic Communications, 2019

1,4-Naphthoquinones (1,4-NQ) have been reported to possess a variety of pharmacological propertie... more 1,4-Naphthoquinones (1,4-NQ) have been reported to possess a variety of pharmacological properties including antibacterial, antifungal, antiviral, anti-inflammatory, anti-artherosclerotic, and anticancer effects. In this study, new Nand S,S-substituted-1,4-NQ derivatives were synthesized in excellent yields and were completely characterized by spectroscopic analysis IR, NMR (1 H and 13 C), MS and microanalysis. The cytotoxic activities of 1,4-NQ derivatives were examined against to A-549, DU145, HCT-116 and MDA-MB-231 cancer cells. Among these compounds, 2-[4-(2-furoyl)piperazine-1-yl]-3-chloro-1,4-NQ 5 and 2,3-bis(cyclobuthylsulfanyl)-1,4-NQ 17 were identified as the most potent anticancer agents with cytotoxic activity against three cell lines (breast (MDA-MB-231), prostate (DU145), colorectal (HCT-116).

TURKISH JOURNAL OF BIOLOGY, 2019

Breast cancer is the most-diagnosed cancer type among women. The triple-negative subtype is an es... more 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.

Nanomedicine, 2019

Aim: N-acetyl-L-cysteine (NAC) is a free radical scavenger. We developed NAC-coated Ag2S (NAC-Ag2... more Aim: N-acetyl-L-cysteine (NAC) is a free radical scavenger. We developed NAC-coated Ag2S (NAC-Ag2S) quantum dot (QD) as an optical imaging and therapeutic agent. Materials & methods: QDs were synthesized in water. Their optical imaging potential and toxicity were studied in vitro. Results: NAC-Ag2S QDs have strong emission, that is tunable between 748 and 840 nm, and are stable in biologically relevant media. QDs showed significant differences both in cell internalization and toxicity in vitro. QDs were quite toxic to breast and cervical cancer cells but not to lung derived cells despite the higher uptake. NAC-Ag2S reduces reactive oxygen species (ROS) but causes cell death via DNA damage and apoptosis. Conclusion: NAC-Ag2S QDs are stable and strong signal-generating theranostic agents offering selective therapeutic effects.

Journal of Cancer Research and Therapeutics, 2018

Context: The natural products derived from plants are the important sources that can be used for ... more Context: The natural products derived from plants are the important sources that can be used for breast cancer treatment. Salvia species and their derived products were recommended as potential antitumor substances. Aim: The potential cytotoxic and genotoxic effects of Salvia kronenburgii have been investigated on breast cancer cell lines, MCF-7 and MDA-MB-231. Materials and Methods: Determination of chemical compounds of S. kronenburgii was done using a gas chromatography coupled to time-of-flight mass spectrometry system and a dual-stage commercial thermal desorption injector. Growth inhibition of the S. kronenburgii was measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and ATP viability assays. The cell death mode was detected by fluorescent dyes. Genotoxic effect of S. kronenburgii was measured by comet assay. Results: S. kronenburgii showed antiproliferative effect in a dose-dependent manner on MCF-7 and MDA-MB-231 cell lines by inducing apoptosis-like cell death. The pyknotic cell nuclei were observed at the cell lines in response to S. kronenburgii. Furthermore, significant increase was shown in genetic damage index and frequencies in the damaged cells. Conclusion: S. kronenburgii might be a promising natural source for cancer therapy. Further experiments need to be done in vivo to understand of the anticancer effects of this plant.

Experimed, 2018

Amaç: Bu çalışmada amacımız, belirli bir dozun üzerinde kardiyak yan etkileri oldukça fazla olan ... more Amaç: Bu çalışmada amacımız, belirli bir dozun üzerinde kardiyak yan etkileri oldukça fazla olan ve meme kanseri tedavisinde kullanılan kemoterapötiklerden doksorubisinin, tedavide kullanım miktarlarını azaltmayı ve etkinliğini arttırmayı sağlayan bir maddeyi saptamaktı. Etken madde olarak anti proliferatif etkisi olduğu düşünülen vitamin D analoglarından biri olan kalsitriol seçilmiş ve doksorubisin ile kombine tedavisinin, insan meme kanseri hücre hattı MCF-7 üzerine sitotoksik etkisinin saptanması amaçlanmıştır. Gereç ve Yöntem: MCF-7 insan meme kanseri hücre hattı kalsitriol ile muamele edilerek, gerçek zamanlı olarak, x-CELLigence cihazında 72 saat inkübasyona bırakıldı ve kalsitriolün anti-proliferatif optimum doz tespiti zamana bağlı hücre indeksi grafiği The xCELLigence Real-Time Cell Analysis (RTCA) software programı kullanılarak yapıldı. Kalsitriol optimum dozu ve doksorubisinin farklı dozlarının kombinasyonu MCF-7 hücre kültürü ile muamele edilerek sitotoksisite tayini için Sulforhodamine-B (SRB) uygulaması ve spektrofotometrik ölçüm uygulandı. Spektrofotometrik ölçüm sonuçları anlamlılık sonuçları için Student's t-Testi ile değerlendirildi.

Anticancer Research, 2018

Background: The inhibition of autophagy using pharmacological inhibitors such as chloroquine may ... more Background: The inhibition of autophagy using pharmacological inhibitors such as chloroquine may be an effective strategy to overcome chemotherapy or resistance to anti-angiogenic therapy. Materials and Methods: The cytotoxic effect of doxorubicin (0.1-1 μM), chloroquine (0.25-32 μM) and their combination were investigated by employing ATP assay in human umbilical vein endothelial cells (HUVECs). The effect of doxorubicin and chloroquine combination was also measured using tube formation assay on Matrigel. The anti-angiogenic activities of doxorubicin (2.5 μg/pellet) and chloroquine (15 μg/pellet), their combination, and standards (50 μg/pellet) were tested in vivo using the chick embryo chorioallantoic membrane (CAM) assay. Results: The combination of doxorubicin and chloroquine significantly had a stronger anti-angiogenic effect than the positive control (±)-thalidomide and doxorubicin alone in the CAM assay and in vitro tube-formation assay. Conclusion: Chloroquine enhanced the anti-angiogenic effect of doxorubicin on CAM at the tested concentrations.

European journal of medicinal chemistry, Jan 16, 2018

A series of new Pt(II) saccharinate complexes containing PR ligands (PPh, PPhCy, PPhCy and PCy) w... more A series of new Pt(II) saccharinate complexes containing PR ligands (PPh, PPhCy, PPhCy and PCy) with progressive phenyl (Ph) replacement by cyclohexyl (Cy) were synthesized and structurally characterized by IR, NMR, ESI-MS and X-ray diffraction. The anticancer activity of the complexes was tested against human breast (MCF-7), lung (A549), colon (HCT116), and prostate (DU145) cancer cell lines as well as against normal bronchial epithelial (BEAS-2B) cells. Trans-configured complexes 1, 3 and 5 emerged as potential anticancer drug candidates. The mechanism of action of the potent complexes was then investigated in detail. The three complexes interacted with DNA by groove binding and with HSA via hydrophobic IIA subdomain. Furthermore, the complexes cleaved plasmid DNA efficiently. Cellular uptake studies in MCF-7 cells showed that the biologically active complexes were mainly localized in cytoplasm. The cytotoxic activity was a function of the lipophilicity and cellular accumulation o...

Journal of proteomics, 2018

The prognosis of pancreatic ductal adenocarcinoma (PDAC), the eighth most lethal cancer for men a... more The prognosis of pancreatic ductal adenocarcinoma (PDAC), the eighth most lethal cancer for men and ninth for women worldwide, remains dismal. The increasing rates of deaths by PDAC indicate that the overall management of the disease in 21st century is still insufficient. Thus it is obvious that there is an unmet need to improve management of PDAC by finding new biomarkers to screen high risk patients, confirm diagnosis, and predict response to treatment as well more efficacious and safer treatments. Patient Derived Xenografts (PDX) have been developed as a new promising tool in an effort to mirror genetics, tumor heterogeneity and cancer microenvironment of the primary tumor. Herein we aim to give an updated overview of the current status and the perspectives of PDX in the search for the identification of novel biomarkers and improved therapeutic outcomes for PDAC but also their use as a valuable tool towards individualized treatments to improve the outcome of the disease. Furtherm...

Pharmacological research, 2017

Several natural products have been suggested as effective agents for the treatment of cancer. Giv... more Several natural products have been suggested as effective agents for the treatment of cancer. Given the important role of CSCs (Cancer Stem Cells) in cancer, which is a trendy hypothesis, it is worth investigating the effects of pristimerin on CSCs as well as on the other malignant cells (MCF-7 and MDA-MB-231) of breast cancer. The anti-growth activity of pristimerin against MCF-7 and MCF-7s (cancer stem cell enriched population) cells was investigated by real time viability monitorization (xCELLigence System®) and ATP assay, respectively. Mode of cell death was evaluated using electron and fluorescence microscopies, western blotting (autophagy, apoptosis and ER-stress related markers) and flow cytometry (annexin-V staining, caspase 3/7 activity, BCL-2 and PI3K expressions). Pristimerin showed an anti-growth effect on cancer cells and cancer stem cells with IC50 values ranging at 0.38-1.75μM. It inhibited sphere formation at relatively lower doses (<1.56μM). Apoptosis was induced...