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    A Comparative Study on In vitro Anti-cancer and In vivo Anti-angiogenic Effects of TRPC Blockers Pyr-3 and SKF-96365
    (Bentham Science Publ Ltd, 2023) Kiyan, Hulya Tuba; Uvez, Ayca; Erkisa, Merve; Ikitimur-Armutak, Elif Ilkay; Yilmazer, Nadim; Esener, Osman Behzat Burak; Kutucu, Deniz Erol
    Introduction Angiogenesis is involved in many physiological and pathological conditions including cancer. A number of TRP channels induce angiogenesis, promote cell proliferation or induce apoptosis in several types of human cancers. Therefore, TRP channels may be considered potential pharmacological targets for therapeutic options of disorders caused by insufficient angiogenesis or aberrant vascularization. Aims This study aimed to comparatively investigate in vitro anti-cancer and in vivo anti-angiogenic effects of TRPC blockers Pyr-3 and SKF-96365. Methods For anti-cancer effects, four cancer cell lines (MDA-MB-231, A549, PC-3, and HCT-116) were used. In vivo anti-angiogenic effects were investigated by employing in vivo CAM assay of fertilized hen eggs. Results Pyr-3 affected cell viability in a dose-dependent manner, all concentrations of SKF-96365 significantly reduced cell viability in all cell lines. Pyr-3 and SKF-96365 at concentrations of 2.5 & mu;g/pellet and 50 & mu;g/pellet, respectively inhibited in vivo angiogenesis significantly. Conclusion The concentration of 2.5 & mu;g/pellet caused no irritation, whereas 50 & mu;g/pellet produced some slight irritation. Apart from their anti-cancer effects, our findings indicate that Pyr-3 and SKF-96365 may be promising anti-angiogenic agents for the treatment of angiogenesis-related disorders.
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    Pd(II) and Pt(II) saccharinate complexes with two phosphine derivatives: Synthesis, anticancer and antiangiogenic activities
    (Wiley, 2024) Icsel, Ceyda; Yilmaz, Veysel T.; Aygun, Muhittin; Erkisa, Merve; Ulukaya, Engin; Akar, R. Okan
    As clinically used anticancer Pt(II) drugs have severe side effects, there is a growing interest for new metal complexes with great potential for cancer therapy. The current work aimed to prepare and characterize new Pd(II) and Pt(II) saccharinate (sac) complexes bearing pyridyl- and benzyldiphenylphosphines (PPh2Py and PPh2Bz, respectively), cis-[Pd(sac)2(PPh2Py)2] (1), cis-[PtCl(sac)(PPh2Py)2]center dot 0.5DMF (2), cis-[Pd(sac)2(PPh2Bz)2]center dot DMF (3) and trans-[PtCl(sac)(PPh2Bz)2] (4) as promising anticancer and antiangiogenic drugs. The anticancer activity of the complexes was screened against seven cancer cell lines including HCT116 (colon), HepG2 (liver), MDA-MB-231 (breast), PANC-1 (pancreatic), A549 (lung), C6 (glioma), DU145 (prostate) and normal human lung epithelial cells (BEAS-2B). 1 and 2 did not show biological activity below 20 mu M at 48 h, whereas 3 and 4 displayed significant cytotoxic effect on the cancer cells. 4 was the most potent complex (IC50 = 2.2-12.1 mu M) and displayed much greater cytotoxicity than cisplatin in all the cancer cell lines. 4 caused apoptosis in HCT116 cells as evidenced by annexin V positivity and caspase 3/7 activity assays. Furthermore, the inhibition of antiapoptotic Bcl-2 proteins by the complex suggested the intrinsic apoptosis. In addition, 4 greatly enhanced generation of intracellular reactive oxygen species (ROS) and consequently caused remarkable DNA double-strand breaks in HCT116 cells. Moreover, the chick chorioallantoic membrane (CAM) assay was used to evaluate antiangiogenic potential of 4. The complex effectively inhibited angiogenesis at a dose of 50 ng, suggesting it as a promising multi-targeted agent for antiangiogenic cancer treatment. A trans-configured Pt(II) saccharinate complex bearing benzyldiphenylphosphine inhibits both growth of human colorectal carcinoma cells (HCT116) and angiogenesis, acting as a multifunctional anticancer and antiangiogenic agent. image
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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.
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    Water-soluble copper(II) 5-fluorouracil complexes bearing polypyridyl co-ligands: synthesis, structures and anticancer activity
    (Royal Soc Chemistry, 2023) Icsel, Ceyda; Yilmaz, Veysel T.; Aygun, Muhittin; Erkisa, Merve; Ulukaya, Engin
    Five newly synthesized copper(II) 5-fluorouracil (5-FU) complexes of polypyridyl co-ligands with good solubility in water, namely [CuCl(5-FU)(bpy)(DMSO)] (1), [Cu(5-FU)(phen)(2)](5-FU)center dot 4H(2)O (2), [Cu(5-FU)(dpya)(2)](NO3)center dot 2.5H(2)O (3), [Cu(5-FU)(NO3)(bpyma)]center dot H2O (4) and [CuCl(5-FU)(terpy)] (5) (bpy = 2,2 '-bipyridine, phen = 1,10-phenanthroline, dpya = 2,2 '-dipyridylamine, bpyma = bis(2-pyridylmethyl)amine and terpy = 2,2 ';6 ',2 ''-terpyridine), were characterized by elemental analysis and a number of spectrometric methods. The structures of complexes 1-5 were determined by X-ray crystallography and the copper(II) ions were five coordinate. Cytotoxic activity of the complexes in four human cancer cell lines, A549 (lung carcinoma), MDA-MB-231 (breast carcinoma), HCT116 (colon carcinoma) and DU145 (prostate carcinoma), and a normal cell line, BEAS-2B (human lung epithelial), was determined by SRB assay and compared with that of 5-FU and cisplatin. The complexation of 5-FU together with polypyridyl ligands resulted in a significant increase in the cytotoxicity of the complexes, with complex 2 exhibiting the highest anticancer potency against all the cell lines, with HCT116 being the most sensitive. The mode of action of cell death for 2 was investigated using morphological imaging and cytometric analyses, including the capacity for induction of apoptosis, generation of reactive oxygen species, mitochondrial dysfunction and DNA damage.