Browsing by Author "Karaca, B"

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    Paclitaxel in combination with AT-101 induces apoptosis via supressing Bcl-2, bcl-XL, mcl-1 proteins in human breast cancer cells.
    Cakar, B; Gursoy, P; Atmaca, H; Kisim, A; Bozkurt, E; Uzunoglu, S; Sezgin, C; Sanli, UA; Karabulut, B; Uslu, R; Karaca, B
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    FIBROBLAST GROWTH FACTOR RECEPTOR 2 (FGFR2) POLYMORPHISM STATUS OF TURKISH BREAST CANCER PATIENTS
    Uslu, R; Karaca, B; Atmaca, H; Kisim, A; Cakar, B; Karabulut, B; Sezgin, C; Uzunoglu, S
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    SYNERGISTIC EFFECT OF GOSSYPOL, A COTTON-PLANT SEED, WITH CONVENTIONAL CHEMOTHERAPEUTICS IN MCF-7 CELLS
    Karaca, B; Atmaca, H; Eniseler, AG; Unuvar-Purcu, D; Kisim, A; Karabulut, B; Uzunoglu, S; Uslu, R
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    Trabectedin to induce mitochondrial membrane potential dissipation and reactive oxygen species generation in breast cancer cells.
    Atmaca, H; Bozkurt, E; Cakar, B; Surmeli, ZG; Uzunoglu, S; Uslu, R; Karaca, B
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    Effects of exercise on angiogenesis and apoptosis-related molecules, quality of life, fatigue and depression in breast cancer patients
    Ergun, M; Eyigor, S; Karaca, B; Kisim, A; Uslu, R
    The aim of this study was to explore the effects of exercise on angiogenesis and apoptosis-related molecules, quality of life, fatigue and depression in patients who completed breast cancer treatment. Sixty breast cancer patients were randomised into three groups, as supervised exercise group, home exercise group and education group. Angiogenesis and apoptosis-related cytokine levels and quality of life (EORTC QOL-C30: European Organisation for Research and Treatment of Cancer Quality of Life C30), fatigue (Brief Fatigue Inventory) and depression (BDI: Beck Depression Inventory) scores were compared before and after a 12-week exercise programme. After the exercise programme, statistically significant decreases were found in interleukin-8 and neutrophil activating protein-78 levels in the home exercise group (P < 0.05). The education group showed a statistically significant increase in monocyte chemoattractant protein-1 level (P < 0.05). Functional score and global health score of EORTC QOL-C30 in the supervised exercise group and functional score of EORTC QOL-C30 in the home exercise group increased significantly after exercise programme (P < 0.05). BDI score was significantly lower in the supervised exercise group after the exercise programme (P < 0.05). Changes in angiogenesis and apoptosis-related molecules in the study groups suggest a possible effect of exercise on these parameters. Exercise programmes are safe and effective on quality of life and depression in breast cancer patients whose treatments are complete.
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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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    Combined gossypol and zoledronic acid treatment results in synergistic induction of cell death and regulates angiogenic molecules in ovarian cancer cells
    Atmaca, H; Gorumlu, G; Karaca, B; Degirmenci, M; Tunali, D; Cirak, Y; Purcu, DU; Uzunoglu, S; Karabulut, B; Sanli, UA; Uslu, R
    In the present study, we aimed to evaluate the possible synergistic, cytotoxic effects of combination treatment of gossypol and zoledronic acid, in human ovarian cancer cell lines, OVCAR-3 and MDAH-2774, and to elucidate the role of this novel combination treatment on angiogenesis-related molecules in ovarian cancer. The XTT cell viability assay was used for showing cytotoxicity. Both DNA fragmentation by ELISA assay and caspase 3/7 activity measurement were used for demonstrating apoptosis. To elucidate the angiogenic molecules affected by combination treatment, mRNA levels of angiogenic molecules were measured using the Human Angiogenesis RT2 Profiler (TM) PCR Array (SuperArray, Frederick, MD) in ovarian cancer cell lines, OVCAR-3 and MDAH-2774. The combined treatment resulted in significant, synergistic cytotoxicity, and induced apoptosis. This effect was observed to happen in a dose- and time-dependent manner. Moreover, the combination treatment of 10 mu M gossypol and 5 mu M zoledronic acid resulted in significant down-regulation (>= thee-fold) in mRNA levels of some pivotal angiogenic molecules in OVCAR-3 and MDAH-2774 cells as compared to the untreated control. However, this effect was different in the two ovarian cancer cell lines observed. Gossypol, in combination with zoledronic acid, may provide a rational treatment option for ovarian cancer, not only by direct inhibition of cell proliferation, but also inhibition of angiogenesis-related molecules.
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    Enhancing cytotoxic and apoptotic effect in OVCAR-3 and MDAH-2774 cells with all-trans retinoic acid and zoledronic acid: a paradigm of synergistic molecular targeting treatment for ovarian cancer
    Karabulut, B; Karaca, B; Varol, U; Muslu, U; Cakar, B; Atmaca, H; Kisim, A; Uzunoglu, S; Uslu, R
    Background: Ovarian cancer is the most fatal gynecologic malignancies in the world. Although, platinum based treatments are widely used, the disease becomes treatment refractory within two years, and novel treatment options should be searched. All-trans retinoic acid (ATRA) induces growth arrest, differentiation and cell death in some types of cancer cells and its combination with various anticancer agents results in enhanced cytotoxicity. Zoledronic acid is a common bisphosphonate known for its anticancer effects beyond its current use in the treatment of cancer-induced bone disease. We aimed to investigate the possible additive/synergistic effect of both agents in OVCAR-3 and MDAH-2774 ovarian cancer cell lines, since both agents show superiority to conventional cytotoxics in terms of adverse events. 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. OligoGeArray (R) which consists of 112 apoptosis related genes was used to elucidate the genetic changes within cancer cells. To validate our oligoarray results, quantitative real-time PCR was performed on four selected genes that were maximally effected by the combination treatment: lymphotoxin beta receptor (LTBR), myeloid cell leukemia-1 (MCL-1), tumor necrosis factor receptor superfamily, member 1A (TNFRSF1A), TNFRSF1A-associated death domain protein (TRADD). Results: We demonstrated that a novel combination of ATRA and zoledronic acid is a strong inducer of apoptotic related cell death in both ovarian cancer cells. While the combination therapy significantly induced proapoptotic genes such as tumor necrosis factor receptor superfamily (TNFRSF), TRADD and caspase 4, some of the antiapoptotic genes such as members of MCL-1, LTBR, BAG3 and Bcl-2 family members were inhibited. Conclusions: These are the preliminary molecular results of a novel combination treatment of ATRA and zoledronic acid, with fewer side effects as compared to conventional cytotoxic agents. With additional experimental analysis, it may serve as a good option for the treatment of refractory and elderly ovarian cancer patients, for whom there exists very limited choice of treatment.
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    Comparison of XTT and Alamar blue assays in the assessment of the viability of various human cancer cell lines by AT-101 (-/- gossypol)
    Uzunoglu, S; Karaca, B; Atmaca, H; Kisim, A; Sezgin, C; Karabulut, B; Uslu, R
    This study compared the two different commercially available in vitro viability assays: XTT and Alamar blue (AB), to detect anti-proliferative effects of AT-101, a cotton plant extract, on six different human carcinoma cell lines including: prostate (PC-3 and DU-145), breast (MCF-7 and MDA-MB-231), and ovary (OVCAR-3 and MDAH 2774) in a time- and dose-dependent manner. Cells were exposed to AT-101 in the concentration range of 2.5-40 mu M for 24, 48, and 72 h. The AB assay was slightly more sensitive than the XTT assay in the evaluation of AT-101 at 24 h, suggesting that the AB assay might be used for detecting early changes in cell viability as compared to the XTT assay. Moreover, the AB assay showed less intra-assay variability as compared to the XTT. The non-toxic, non-radioactive AB metabolism assay allows rapid assessment of large numbers of samples, with simple equipment and at reduced cost for continuous monitoring of cancer cell viability, and, thus, should be accepted as a suitable alternative viability method.
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    Zoledronic acid in combination with serine/threonine phosphatase inhibitors induces enhanced cytotoxicity and apoptosis in hormone-refractory prostate cancer cell lines by decreasing the activities of PP1 and PP2A
    Cirak, Y; Varol, U; Atmaca, H; Kisim, A; Sezgin, C; Karabulut, B; Uzunoglu, S; Uslu, R; Karaca, B
    OBJECTIVES To investigate if the cytotoxic and apoptotic effect of zoledronic acid (ZA) can be enhanced by the addition of the serine/threonine protein phosphatase inhibitors calyculin A (CA) and okadaic acid (OA) in hormone and drug refractory prostate cancer cells, PC-3 and DU-145. To discover the effect of these combination treatments on phosphatase 1 (PP1) and PP2A protein expression levels in prostate cancer cells. MATERIALS AND METHODS An XTT cell viability assay was used to determine cytotoxicity. Apoptosis was evaluated by enzyme-linked immunosorbent assay (ELISA) using a Cell Death Detection ELISA Plus Kit and verified by measuring caspase 3/7 enzyme activity. The PP1 and PP2A enzyme activities were evaluated by serine/threonine phosphatase ELISA and expression levels of PP1 and PP2A proteins were then re-assessed by Western blot analysis. RESULTS Combination of ZA with either CA or OA showed synergistic cytotoxicity and apoptosis compared with any agent alone in both PC-3 and DU-145 prostate cancer cells. The combination of ZA with phosphatase inhibitors resulted in enhanced suppression of both PP1 and PP2A enzyme activity and protein levels, which was more overt with the ZA/CA combination. CONCLUSION Results from our study increase the translational potential of our in vitro findings and offer the basic rationale for the design of new combinatory strategies with ZA and phosphatase inhibitors for the treatment of prostate cancer, which may become resistant to conventional therapy.
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    Trastuzumab in combination with AT-101 induces cytotoxicity and apoptosis in Her2 positive breast cancer cells
    Bulut, G; Atmaca, H; Karaca, B
    Aim: AT-101 is a polyphenolic compound with potent anti-apoptotic effects in various cancers. In this study, the possible synergistic cytotoxic and apoptotic effect of trastuzumab/AT-101 combination was investigated in HER2-positive breast cancer cell lines. Materials & methods: SKBR-3, MDA-MB-453 and MCF-10A cell lines were treated with a trastuzumab/AT-101 combination. Synergistic cytotoxicity and apoptosis effects were shown and then PI3K and Akt protein levels were studied. Result: The trastuzumab/AT-101 combination induced synergistic cytotoxicity and apoptosis in both breast cancer cells but not in MCF-10A cells. Combination treatment induced cytotoxicity via inhibiting PI3K/AKT but not the MAPK/ERK pathway. Conclusion: The trastuzumab/AT-101 combination may be a good candidate for patients with trastuzumab-resistant Her2-positive breast cancer and inhibition of the PI3K/AKT pathway may be one of the underlying mechanisms.
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    Pretreatment with AT-101 enhances tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis of breast cancer cells by inducing death receptors 4 and 5 protein levels
    Kisim, A; Atmaca, H; Cakar, B; Karabulut, B; Sezgin, C; Uzunoglu, S; Uslu, R; Karaca, B
    Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily and has been shown to induce extrinsic pathway of apoptosis in many types of cancer cells. AT-101, an (-)-enantiomer of gossypol, is a potent anticancer agent that is shown to be an inhibitor of Bcl-2/Bcl-XL. In this study, we searched whether pretreatment with either of these drugs would result in the enhancement of apoptosis through induction of death receptors and activation of mitochondrial pathways within breast cancer cells. Human breast cancer (MCF-7 and MDA-MB-231) and normal breast cells (MCF-10A) were treated with drugs alone/in combination/sequentially. XTT cell viability assay was used to evaluate cytotoxicity. For showing apoptosis, both DNA Fragmentation and caspase 3/7 activity measurements were done. ELISA and Western blot analysis were done to assess DR4 and DR5 protein levels. The expression levels of apoptotic proteins were assessed by human apoptosis antibody array. The sequential treatment of AT-101 followed by TRAIL resulted in significant synergistic cytotoxicity and apoptosis. Moreover, pretreatment of breast cancer cells with AT-101 and then with TRAIL caused enhancement of the expression levels of DR4 and DR5 in both cancer cell lines, suggesting that these cells were under strong apoptotic stimuli. These findings all together, strongly suggest that pretreatment with AT-101 enhances TRAIL-induced death-inducing signaling complex resulting in the engagement of the mitochondrial pathway to apoptosis in breast cancer cells. These promising, preliminary results make AT-101 and TRAIL a novel combination treatment candidate for breast cancer.
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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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    Combination of AT-101/cisplatin overcomes chemoresistance by inducing apoptosis and modulating epigenetics in human ovarian cancer cells
    Karaca, B; Atmaca, H; Bozkurt, E; Kisim, A; Uzunoglu, S; Karabulut, B; Sezgin, C; Sanli, UA; Uslu, R
    We investigated the effects of AT-101/cisplatin combination treatment on the expression levels of apoptotic proteins and epigenetic events such as DNA methyltransferase (DNMT) and histone deacetylase (HDAC) enzyme activities in OVCAR-3 and MDAH-2774 ovarian cancer cells. XTT cell viability assay was used to evaluate cytotoxicity. For showing apoptosis, both DNA Fragmentation and caspase 3/7 activity measurements were performed. The expression levels of apoptotic proteins were assessed by human apoptosis antibody array. DNMT and HDAC activities were evaluated by ELISA assay and mRNA levels of DNMT1 and HDAC1 genes were quantified by qRT-PCR. Combination of AT-101/cisplatin resulted in strong synergistic cytotoxicity and apoptosis in human ovarian cancer cells. Combination treatment reduced some pivotal anti-apoptotic proteins such as Bcl-2, HIF-1A, cIAP-1, XIAP in OVCAR-3 cells, whereas p21, Bcl-2, cIAP-1, HSP27, Clusterin and XIAP in MDAH-2774 cells. Among the pro-apoptotic proteins, Bad, Bax, Fas, phospho-p53 (S46), Cleaved caspase-3, SMAC/Diablo, TNFR1 and Cytochrome c were induced in OVCAR-3 cells, whereas, Bax, TRAILR2, FADD, p27, phospho-p53 (S46), Cleaved caspase-3, Cytochrome c, SMAC/Diablo and TNFR1 were induced in MDAH-2774 cells. Combination treatment also inhibited both DNMT and HDAC activities and also mRNA levels in both ovarian cancer cells. AT-101 exhibits great potential in sensitization of human ovarian cancer cells to cisplatin treatment in vitro, suggesting that the combination of AT-101 with cisplatin may hold great promise for development as a novel chemotherapeutic approach to overcome platinum-resistance in human ovarian cancer.