Browsing by Author "Cengiz, E"

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    Overcoming drug resistance in hormone- and drug-refractory prostate cancer cell line, PC-3 by docetaxel and gossypol combination
    Cengiz, E; Karaca, B; Kucukzeybek, Y; Gorumlu, G; Gul, MK; Erten, C; Atmaca, H; Uzunoglu, S; Karabulut, B; Sanli, UA; Uslu, R
    Drug resistance is a significant challenge of daily oncology practice. Docetaxel and gossypol both have antitumoral activity in hormone-refractory prostate cancer (HRPC). Our results revealed that docetaxel and gossypol were synergistically cytotoxic and apoptotic in PC-3 cells in a dose- and time-dependent manner. We further investigated the expression profiles of genes involved in drug resistance and metabolism with a Human Cancer Drug Resistance and Metabolism PCR Array(A (R)) (SuperArray). Six of the 84 genes that are known to regulate drug resistance, metabolism, cell cycle, DNA repair and oncogenesis were downregulated a parts per thousand yen3-fold change by the combination treatment. These results may be important in devising mechanism-based and targeted therapeutic strategies for prostate cancer, especially in devising combination therapy for drug resistant prostate cancers.
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    Targeting apoptosis in the hormone- and drug-resistant prostate cancer cell line, DU-145, by gossypol/zoledronic acid combination
    Sanli, UA; Gorumlu, G; Erten, C; Gul, MK; Cengiz, E; Kucukzeybek, Y; Karaca, B; Atmaca, H; Uzunoglu, S; Karabulut, B; Uslu, R
    Possible synergistic cytotoxic and apoptotic effects of gossypol with zoledronic acid on DU-145 cells were explored, along with the rationale behind any observed synergism due to the different apoptotic proteins involved. XTT cell proliferation assay was used to assess the cytotoxicity, and DNA fragmentation and caspase 3/7 activity were measured to verify apoptosis. Human Apoptosis Array was used to evaluate apoptotic proteins. The synergistic cytotoxic combination treatment had a versatile effect on apoptotic proteins, through inhibition of anti-apoptotic proteins (including cIAP-1, cIAP-2, survivin, livin, claspin, p53, p21, PON-2 and heat shock proteins) and concurrently the induction of pro-apoptotic proteins (Bad, Bax, Fas, FADD, cleaved caspase-3 and p27). Both drugs had a minimal toxicity profile comparing to cytotoxic agents. Combination treatments targeting many pivotal apoptosis-related proteins may be a rationale option for treatment of prostate cancer. (C) 2009 International Federation for Cell Biology. Published by Elsevier Ltd. All rights reserved.
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    Regulation of growth factors in hormone- and drug-resistant prostate cancer cells by synergistic combination of docetaxel and octreotide
    Erten, C; Karaca, B; Kucukzeybek, Y; Gorumlu, G; Cengiz, E; Gul, MK; Atmaca, H; Uzunoglu, S; Karabulut, B; Sanli, UA; Uslu, R
    OBJECTIVE To evaluate the effects of combined treatment with docetaxel and octreotide, a somatostatin analogue, on human hormone- and drug-refractory prostate cancer cell lines, PC-3 and DU-145, and on some growth factors related to tumour growth and angiogenesis in prostate cancer. MATERIALS AND METHODS A cell proliferation assay was used to assess the cytotoxicity of the drugs. To verify apoptosis, both DNA fragmentation (by enzyme-linked immunosorbent assay) and caspase 3/7 activity were measured. We also investigated the effect of combined docetaxel and octreotide on growth factors secreted from prostate cancer cells using a human growth factor antibody array. RESULTS The combination of docetaxel and octreotide resulted in significant synergistic cytotoxic activity and apoptosis, which was dose- and time-dependent. The combined treatment also resulted in significantly less secretion of stem cell factor and platelet-derived growth factor-AB in PC-3 cells, and transforming growth factor-beta and basic fibroblast growth factor in DU-145 cells, than in untreated controls. CONCLUSION Octreotide, a somatostatin analogue, combined with docetaxel might provide a rationale treatment option for hormone-refractory prostate cancer cells, not only by direct inhibition of cell proliferation but also by inhibiting the secretion of growth factors.
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    Enhancement of docetaxel-induced cytotoxicity and apoptosis by all-trans retinoic acid (ATRA) through downregulation of survivin (BIRC5), MCL-1 and LTbeta-R in hormone- and drug resistant prostate cancer cell line, DU-145
    Kucukzeybek, Y; Gul, MK; Cengiz, E; Erten, C; Karaca, B; Gorumlu, G; Atmaca, H; Uzunoglu, S; Karabulut, B; Sanli, UA; Uslu, R
    Background: The management of hormone-refractory prostate cancer (HRPC) still remains as an important challenge of daily oncology practice. Docetaxel has proved to be a first line treatment choice. All-trans retinoic acid (ATRA) could potently inhibit the growth of prostate cancer cells in vitro and its combination with various anticancer agents results in increased cytotoxicity. Based on these data, our aim was to examine the synergistic/additive cytotoxic and apoptotic effects of combination of docetaxel and ATRA, in hormone- and drug refractory human DU-145 prostate cancer cells. Furthermore, we have searched for the underlying mechanisms of apoptosis by demonstrating apoptosis-related genes. Methods: XTT cell proliferation assay was used for showing cytotoxicity. For verifying apoptosis, both DNA Fragmentation by ELISA assay and caspase 3/7 activity measurement were used. For detecting the mechanism of apoptosis induced by docetaxel-ATRA combination, OligoGeArray (R) which consists of 112 apoptosis related genes was used. Results: Our results revealed that docetaxel and ATRA were synergistically cytotoxic and apoptotic in DU-145 cells, in a dose- and time dependent manner. It was also shown by our studies that apoptosis was induced in DU-145 prostate carcinoma cells with significant cytotoxicity, no matter which agent applied first. We have found out that docetaxel-ATRA combination significantly downregulates survivin (BIRC5), myeloid cell leukemia-1 (MCL-1) and lymphotoxin beta-receptor (LT beta R) genes, which all three have pivotal roles in regulation of apoptosis and cell cycle progression. Conclusion: In conclusion, we strongly suggest that docetaxel and ATRA combination is a good candidate for this challenging era of daily oncologic practice. Also, the combination of docetaxel and ATRA might allow a reduction in docetaxel doses and by this way may diminish docetaxel adverse effects while maintaining the therapeutic effect in patients with HRPC.
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    Profiling of angiogenic cytokines produced by hormone- and drug-refractory prostate cancer cell lines, PC-3 and DU-145 before and after treatment with gossypol
    Karaca, B; Kucukzeybek, Y; Gorumlu, G; Erten, C; Gul, MK; Cengiz, E; Atmaca, H; Uzunoglu, S; Sanli, UA; Karabulut, B; Uslu, R
    In this study, we aimed to investigate the angiogenic cytokine profiles of hormone- and drug-refractory prostate carcinoma cell lines, PC-3 and DU-145. We also studied the effect of gossypol, a natural polyphenolic cotton-seed extract, on the angiogenic cytokine profile of these cell lines. XTT cell proliferation assay was used for the assessment of cytotoxicity. For apoptosis, both histone-DNA fragmentation by ELISA assay and caspase 3/7 activity measurement were used. Angiogenic cytokine profiles of supernatants from both cell lines, before and after treatment with gossypol, were investigated using the human angiogenesis antibody array I (R). It was shown that the two different hormone- and drug-resistant prostate cancer cell lines, PC-3 and DU-145, constitutively express some important angiogenic cytokines, which are known to regulate tumorigenicity and angiogenesis in hormone- refractory prostate cancer. However, PC-3 and DU-145 cells have distinct angiogenic cytokine profiles. In addition, these two cells lines respond differently to gossypol treatment in terms of cytotoxicity and angiogenic cytokine secretion. After treatment with 10 mu M of gossypol, there was a 1.5-fold decrease in angiogenin and IL-8 levels and a 1.7- and 1.8-fold decrease in ENA-78 and GRO-alpha levels respectively, in DU-145 cells. For PC-3 cells, there were 1.6- and 1.8-fold decreases in IL-8 and VEGF levels, respectively. We conclude that PC-3 and DU-145 cells secrete significant amounts of different angiogenic cytokines that may explain their aggressive nature and metastatic potential. Gossypol treatment affects angiogenic cytokine secretion from these two cell lines in a different manner. By expanding our knowledge of the heterogeneous biological behavior of these two cell lines, novel treatment approaches can be developed for the treatment of prostate cancer.
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    Animals and Justice: An Examination in Context of Rawls and Nussbaum
    Cengiz, E; Gökalp, N
    Humanity shares the world with other creatures, and species relate to each other. In the relationship between humans and animals, which has a long history, from time to time, negativities are also striking. There are cases where animals are exposed to people's abuse. In the history of philosophy, the moral status of animals, their rights, and people's duty to animals are often discussed. Rawls, one of the influential figures of the 20th century, considers that animals are not the subject of political life in the discussion of the possibility of a fair society, but argue that people must treat them only with compassion. Nussbaum, on the other hand, states that, unlike his mentor, animals and humans have common characteristics and that the relationship between them should be regulated within the framework of justice. According to her, Rawlsian theory does not see animals as subjects of justice and is insufficient in resolving the injustices they are subjected to. In this study, the contractual and Kantian elements, which are the reasons for the situation of animals to remain a dead-end in Rawls' theory, and Nussbaum's criticisms within the framework of the capabilities approach will be expressed. Nussbaum, who strives to create a world that protects animals and their habitats as well as humans, will explain in general terms her suggestions for solutions to animal problems and her views. To create a world that protects animals and their habitats as well as humans, Nussbaum's suggestions for solutions to animal-related problems and her views will be explained in general terms.
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    Apoptosis-mediated Cytotoxic Effects of Ibandronic Acid on Hormone- and Drug-refractory Prostate Cancer Cells and Human Breast Cancer Cells
    Kucukzeybek, Y; Gorumlu, G; Cengiz, E; Karabulut, B; Sezgin, C; Atmaca, H; Sanli, UA; Uzunoglu, S; Uslu, R
    Over 80% of patients with advanced breast and prostate cancer ultimately develop bone metastases. Ibandronic acid has proven efficacy for treatment of bone metastasis secondary to breast cancer. This study was designed to investigate the cytotoxic and apoptotic effects of ibandronic acid on hormone- and drug-refractory prostate carcinoma DU-145 and human breast cancer MCF-7 cell lines. Cytotoxicity was evaluated using an XTT cell proliferation kit, and apoptosis was assessed by enzyme-linked immunosorbent assay (histone-DNA fragmentation) and measurement of caspase 3/7 activity. With increasing concentrations of ibandronic acid there was a dose- and time-dependent decrease in cell numbers. MCF-7 cells were more resistant than DU-145 cells (half maximal inhibitory concentrations of 122 and 90 mu M, respectively). Ibandronic acid induced apoptosis in both cell lines. The study showed an apoptosis-mediated cytotoxic effect for ibandronic acid (in addition to the already known osteoclast inhibiting effect) in breast cancer patients with bone metastases; which was also observed in prostate cancer cells. Further clinical studies involving breast and prostate cancer patients with bone metastases are warranted to confirm these findings.
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    Docetaxel/zoledronic acid combination triggers apoptosis synergistically through downregulating antiapoptotic Bcl-2 protein level in hormone-refractory prostate cancer cells
    Karabulut, B; Erten, C; Gul, MK; Cengiz, E; Karaca, B; Kucukzeybek, Y; Gorumlu, G; Atmaca, H; Uzunoglu, S; Sanli, UA; Baran, Y; Uslu, R
    Docetaxel, a semi-synthetic taxane analogue, is used effectively in the treatment of metastatic prostate cancer. Zoledronic acid, the most potent member of bisphosphonates, has shown pleiotropic anti-tumoral effects on prostate cancer cells. We have explored the possible additive/synergistic effects and the apoptotic pathways induced by combination treatment of docetaxel and zoledronic acid in hormone and drug refractory, PC-3 and DU-145 prostate cancer cells. Combination of docetaxel and zoledronic acid synergistically inhibits cell growth in PC-3 and DU-145 cells. Moreover, this effect was due to downregulation of antiapoptotic protein Bcl-2 in PC-3 and DU-145 cells. In conclusion, docetaxel/zoledronic acid combination is potentially a novel and effective approach for the treatment of prostate cancer. (C) 2008 International Federation for Cell Biology. Published by Elsevier Ltd. All rights reserved.