Browsing by Author "Varol U."

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    The effect of racemic gossypol and AT-101 on angiogenic profile of OVCAR-3 cells: A preliminary molecular framework for gossypol enantiomers
    (2009) Varol U.; Karaca B.; Tunali D.; Degirmenci M.; Cirak Y.; Purcu D.U.; Uzunoglu S.; Sezgin C.; Karabulut B.; Sanli U.A.; Uslu R.
    Aim: To compare the effect of racemic gossypol with its (-)/(-) enantiomer (AT-101) on expression profiles of angiogenic molecules by mRNA levels in human ovarian cancer cell line OVCAR-3. Methods: Cell viability assay (2,3-bis (2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino) carbonyl]-2H-tetrazolium hydroxide) was used to detect cytotoxicity of gossypol enantiomers. DNA fragmentation by an enzyme-linked immunosorbent (ELISA) assay was used to evaluate the rate of apoptosis. The mRNA expression levels of angiogenic molecules were investigated by Human Angiogenesis RT2 Profiler™ PCR Array (SuperArray, Frederick, MD). Results: Both racemic form and AT-101 resulted in a significant cytotoxicity and induced apoptosis. This effect was observed in a dose- and time dependent manner. However, AT-101 was much more potent. In addition, the treatment of 10 μM of racemic gossypol alone and 3 μM of AT-101 alone resulted in significant down-regulation (≥ 3 fold) in mRNA levels of some pivotal angiogenic molecules in OVCAR-3, but altered gene profiles were different by the treatment of each enantiomer. Conclusion: The efficacy of two gossypol enantiomers in OVCAR-3 cells showed distinction. AT-101 was much more potent than racemic gossypol, not only by means of cell death and apoptosis, but also by modulation of angiogenic molecules released from OVCAR-3 cells. Further studies with endothelial cells should be done to verify the anti-angiogenic effect of gossypol enantiomers in cancer treatment.
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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
    (2010) Karabulut B.; Karaca B.; Varol U.; Muslu U.; Cakar B.; Atmaca H.; Ksm 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® 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. © 2010 Karabulut et al; licensee BioMed Central Ltd.
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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
    (2012) 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 enzymelinked immunosorbent assay (ELISA) using a Cell Death Detection ELISA Plus Kit and verifi ed 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 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 andprotein levels, which was more overt with the ZA/CA combination. CONCLUSION • Results from our study increase the translational potential of our in vitro fi ndings 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. © 2012 B J U I N T E R N A T I O N A L.
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    Enhanced cytotoxicity and apoptosis by thymoquinone in combination with zoledronic acid in hormone- and drugresistant prostate cancer cell lines
    (Zerbinis Publications, 2014) Dirican A.; Erten C.; Atmaca H.; Bozkurt E.; Kucukzeybek Y.; Varol U.; Tarhan M.O.; Karaca B.; Uslu R.
    Purpose: Thymoquinone (TQ), an active ingredient of black seed oil (Nigella Sativa), has been shown to possess cytotoxic activity against a variety of cancer cell lines. Our purpose was to investigate if the cytotoxic and apoptotic effect of zoledronic acid (ZA) can be enhanced by the addition of the TQ in hormone- and drug-refractory prostate cancer cells PC-3 and DU-145. Methods: XTT cell proliferation assay was used to assess cytotoxicity; DNA fragmentation and caspase 3/7 activity were also measured. Results: The combination of TQ and ZA resulted in a significant synergistic cytotoxic activity and DN A fragmentation when compared to any single agent alone, in a dose- and time-dependent manner. In addition, TQ and ZA combination increased the caspase 3/7 activity in PC-3 cell line, while this activity could not be demonstrated in DU-145 cell line. Conclusion: TQ and ZA had minimal hematological and non-hematological toxicity profile compared to cytotoxic agents. So, this combination may be an alternative approach for patients who are unable to be treated by conventional treatments because of poor performance status.
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    Zoledronic acid increases cytotoxicity by inducing apoptosis in hormone and docetaxel-resistant prostate cancer cell lines
    (Kluwer Academic Publishers, 2015) Varol U.; Degirmenci M.; Karaca B.; Atmaca H.; Kisim A.; Uzunoglu S.; Sezgin C.; Sanli U.A.; Uslu R.
    Our aim was to investigate the possible synergistic/additive cytotoxic and apoptotic effects of combination of docetaxel and zoledronic acid (ZA), in PC-3 hormone-refractory prostate cancer cells (HRPC), as well as their docetaxel-resistant sublines. We established a docetaxel-resistant cell line (PC-3R) from PC-3 prostate cancer cells, by intermittent exposure to increasing concentrations of docetaxel in vitro. We then examined the effect of ZA and docetaxel on cell proliferation in both PC-3 and PC-3R prostate cancer cells. XTT cell proliferation assay was used to assess the cytotoxicity, and DNA fragmentation and caspase 3/7 enzyme activity were measured to verify apoptosis. According to our results, docetaxel and ZA were found to be synergistically cytotoxic and apoptotic in both PC-3 and docetaxel-resistant PC-3R cells, in a dose- and time-dependent manner. Combined treatment with docetaxel and ZA synergistically inhibited PC-3 cell growth in vitro through an enhanced induction of cell death, compared with either agent alone; this result was also evident on PC-3R cells. Moreover, we have also demonstrated that apoptosis was induced in prostate cancer cells exposed to these drugs by a concentration-dependent increase in DNA fragmentation and caspase 3/7 enzyme activity. We concluded that ZA, either with docetaxel or not, might still exert some cytotoxicity even in docetaxel-resistant cells. From the clinical perspective, when the clinician decided to change the treatment in the post-docetaxel setting, continuing or combination with ZA may be an effective therapeutic approach for the treatment of HRPC patients. © 2014, International Society of Oncology and BioMarkers (ISOBM).
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    Evaluation of prognostic factors in localized high-grade undifferentiated pleomorphic sarcoma: report of a multi-institutional experience of Anatolian Society of Medical Oncology
    (Springer Science and Business Media B.V., 2016) Ozcelik M.; Seker M.; Eraslan E.; Koca S.; Yazilitas D.; Ercelep O.; Ozaslan E.; Kaya S.; Hacibekiroglu I.; Menekse S.; Aksoy A.; Taskoylu B.Y.; Varol U.; Arpaci E.; Ciltas A.; Oksuzoglu B.; Zengin N.; Gumus M.; Aliustaoglu M.
    Most data on prognostic factors for patients with high-grade undifferentiated pleomorphic sarcoma (HGUPS) is obtained from analyses of soft tissue sarcomas. The purpose of this study was to evaluate the clinicopathologic features and their impact on outcomes specifically in patients diagnosed with HGUPS. In this multicenter trial, we retrospectively analyzed 112 patients who were diagnosed and treated at 12 different institutions in Turkey. We collected data concerning the patients, tumor characteristics, and treatment modalities. There were 69 males (61.6 %) and 43 females (38.4 %). Median age was 56 years (19–90). The most common anatomic site of tumor origin was the upper extremity. Pleomorphic variant was the predominant histological subtype. Median tumor size was 8.2 cm (0.6–30 cm). Tumors were mainly deeply seated (57.1 %). Fifty-seven patients (50.9 %) were stage II and the remainder were stage III at the time of diagnosis. Median follow-up was 30 months (2–160). The primary site of distant metastasis was the lung (73.5 %) and the second most common site was the liver (11.7 %). The 5-year overall survival, distant metastasis-free survival, and local recurrence-free survival rates were 56.3, 53.4, and 67.2 %, respectively. Multivariate analysis showed that Eastern Cooperative Oncology Group (ECOG) performance score of II (p = 0.033), deep tumor location (p = 0.000), and development of distant metastasis (p = 0.004) were negatively correlated with overall survival, and perioperative radiotherapy and negative microscopic margins were significant factors for local control rates (p = 0.000 for each). Deep tumor location (p = 0.003) was the only adverse factor related to distant metastasis-free survival. Deep tumor location, ECOG performance score of II, and development of distant metastasis carry a poor prognostic implication on overall survival. These will aid clinicians in predicting survival and treatment decision. © 2015, International Society of Oncology and BioMarkers (ISOBM).
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    Investigating the Correlation Between Long-Term Response in Patients with Metastatic HER2+ Breast Cancer and the Activity of Regulatory T Cells: A Retrospective Study
    (Dove Medical Press Ltd, 2024) Degirmenci M.; Diniz G.; Kahraman D.S.; Sahbazlar M.; Koral L.; Varol U.; Uslu R.
    Background: Trastuzumab is commonly utilized in the management of metastatic HER2-positive breast cancer. Our main goal was to examine the clinical outcomes and immune markers of patients who received trastuzumab and chemotherapy treatment. Methods: Between 1995 and 2012, a total of 98 patients diagnosed with metastatic HER2-positive breast cancer were retrospectively analyzed at Ege University Hospital and Tepecik Training and Research Hospital. The clinicopathological characteristics and clinical outcomes of the patients were assessed, and the associations between response rates, survival and the immune profiles of tumor infiltrating lymphocytes were statistically evaluated. Results: The average age of patients at the time of diagnosis was 50.1±10.3 (ranging from 30 to 79) years. The mean follow-up period for all patients was 97.9±53.8 months. Among the patients, complete response was observed in 24.5%, partial response in 61.2%, and stable disease in 8.2% of cases. The average progression-free survival was 50.3±26.9 months (ranging from 1 to 163 months), and the average overall survival was 88.8±59.4 months (ranging from 12 to 272 months). After analyzing all cases, it was found that patients who were younger (p=0.006), exhibited higher CD3-positivity (p=0.041), presented with higher FOXP3-positivity (p=0.025), showed complete or at least partial response to treatment (p=0.008), and experienced a long-term response to trastuzumab (and chemotherapy) treatment had longer survival (p=0.001). Conclusion: Patients with HER2-positive breast cancer, who initially respond positively to palliative trastuzumab and chemotherapy treatment, can achieve long-term tumor remission lasting for several years. © 2024 Degirmenci et al.