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Öğe Chloroquine used in combination with chemotherapy synergistically suppresses growth and angiogenesis in vitro and in vivo(Int Inst Anticancer Research, 2018) Gürel-Gürevin, Ebru; Kıyan, Hülya Tuba; Esener, Osman Behzat Burak; Aydınlık, Şeyma; Üvez, Ayça; Ulukaya, Engin; Dimas, Konstantinos; Armutak, Elif İlkayBackground: 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 mu M), chloroquine (0.25-32 ,mu M) 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 mu g/pellet) and chloroquine (15 mu g/pellet), their combination, and standards (50 mu g/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.Öğe Evidence for heterogeneity in response to treatment in mammary tumors of dogs as happens in humans(NCI CPTAC Assay Portal, 2022) Turna, Özge; Üvez, Ayça; Baykal, Aslıhan; Develi, Elif Sedef; Dıramalı, Murat; Sönmez, Kıvılcım; Karakaş, Didem; Kaşıkçı, Güven; Armutak, Elif İlkay; Ulukaya, EnginTumors are formed by various clones developed over a long time. This gives rise to a heterogeneous nature. This heterogeneity is the hardest challenge in the treatment of cancers because it is the main reason for drug resistance. This is a well-known fact in human cancer. Therefore, we have reasoned that if the tumor heterogeneity in canine mammary gland tumors (CMGTs) could be shown by an ex vivo assay, which will be used first time in veterinary oncology practice, this could be used further in clinics. To achieve this, twenty-six patients were included in the study. Tumor tissues were obtained from animals during routine surgery. Tumor cells were isolated and seeded ex vivo. The cells were exposed to anticancer drugs that are clinically used. Seven days after the treatment, chemosensitivity has luminometrically been assayed by ATP-tumor chemosensitivity assay (ATP-TCA). It has clearly been shown that all the tumor tissues have responded to treatment differently, implying that heterogeneity exists in mammary tumors. There has also been found that there was a weak to moderate statistically significant correlation between tumor size and drug index. However, there has been no correlation between drug index and metastasis to lymph nodes. Hyperplasic areas had relatively higher PCNA values. The results of our study demonstrate the heterogeneity in responses to in vitro drugs. Clinical trials based on test results and follow-up studies with large numbers of animals are needed to prove that such chemotherapeutic activity assessment tests can be clinically useful in predicting drug responses in CMGTs.Öğe Palladium (II) complex and thalidomide intercept angiogenic signaling via targeting FAK/Src and Erk/Akt/PLC gamma dependent autophagy pathways in human umbilical vein endothelial cells(Elsevier, 2021) Aydınlık, Şeyma; Üvez, Ayça; Kıyan, Hülya Tuba; Gürel-Gürevin, Ebru; Yılmaz, Veysel Turan; Ulukaya, EnginThe current study assessed the effects of the thalidomide and palladium (II) saccharinate complex of terpyridine on the suppression of angiogenesis-mediated cell proliferation. The viability was assessed after treatment with palladium (II) complex (1.56–100 ?M) and thalidomide (0.1-400 µM) alone by using ATP assay for 48h. Palladium (II) complex was found to inhibit growth statistically significant in a dose-dependent manner in HUVECs and promoted PARP-1 cleavage through the production of ROS. On the other hand, thalidomide did not cause any significant change in cell viability. Moreover, cell death was observed to be manifested as late apoptosis due to Annexin V/SYTOX staining after palladium (II) complex treatment however, thalidomide did not demonstrate similar results. Thalidomide and palladium (II) complex also suppressed HUVEC migration and capillary-like structure tube formation in vitro in a time-dependent manner. Palladium (II) complex (5 mg/ml) treatment showed a strong antiangiogenic effect similar to positive control thalidomide (5mg/ml) and successfully disrupted the vasculature and reduced the thickness of the vessels compared to control (agar). Furthermore, suppression of autophagy enhanced the cell death and antiangiogenic effect of thalidomide and palladium (II) complex. We also showed that being treated with thalidomide and palladium (II) complex inhibited phosphorylation of the signaling regulators downstream of the VEGFR2. These results provide evidence for the regulation of endothelial cell functions that are relevant to angiogenesis through the suppression of the FAK/Src/Akt/ERK1/2 signaling pathway. Our results also indicate that PLC-?1 phosphorylation leads to activation of p-Akt and p-Erk1/2 which cause stimulation on cell proliferation at lower doses. Hence, we demonstrated that palladium (II) and thalidomide can induce cell death via the Erk/Akt/PLC? signaling pathway and that this pathway might be a novel mechanism.Öğe A promising natural product, pristimerin, results in cytotoxicity against breast cancer stem cells in vitro and xenografts in vivo through apoptosis and an incomplete autopaghy in breast cancer(Academic Press Ltd- Elsevier Science Ltd, 2018) Cevatemre, Buse; Erkısa Genel, Merve; Aztopal, Nazlıhan; Karakaş Zeybek, Didem; Alper, Pınar; Tsimplouli, Chrisiida; Sereti, Evangelia; Dimas, Konstantinos; Armutak, Elif I. İkitimur; Gürevin, Ebru Gürel; Üvez, Ayça; Mori, Mattia; Berardozzi, Simone; Ingallina, Cinzia; D'Acquarica, Ilaria; Botta, Bruno; Özpolat, Bülent; Ulukaya, EnginSeveral 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 (R)) 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 0.38-1.75 mu M. It inhibited sphere formation at relatively lower doses (<1.56 mu M). Apoptosis was induced in MCF-7 and MCF-7s cells. In addition, extensive cytoplasmic vacuolation was observed, implying an incompleted autophagy as evidenced by the increase of autophagy-related proteins (p62 and LC3-II) with an unfolded protein response (UPR). Pristimerin inhibited the growth of MCF-7 and MDA-MB-231-originated xenografts in NOD.CB17-Prkdc(scid)/J mice. In mice, apoptosis was further confirmed by cleavage of PARP, activation of caspase 3 and/or 7 and TUNEL staining. Taken together, pristimerin shows cytotoxic activity on breast cancer both in vitro and in vivo. It seems to represent a robust promising agent for the treatment of breast cancer. Pristimerin's itself or synthetic novel derivatives should be taken into consideration for novel potent anticancer agent(s). (C) 2017 Elsevier Ltd. All rights reserved.
