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Öğe Apoptotic effect of thymoquinone on OVCAR3 cells via the P53 and CASP3 activation(Sociedade Brasileira para o Desenvolvimento da Pesquisa em Cirurgia, 2024) Karaosmanoğlu, Özge; Kamalak, Zeynep; Özdemir, İlhan; Tuncer, Mehmet Cudi; Öztürk, ŞamilPurpose: The limitations in cancer treatment and the inadequacy of classical methods have made it necessary to discover therapeutics in cancer treatment. The cytotoxicity of thymoquinone, which has quite different properties in terms of biological activities, in ovarian cancer cells, and the changes in the expression levels of apoptotic genes (p53/caspase-3 (casp-3)) were investigated. Methods: In the study, thymoquinone (5, 50, 100, 250 and 500 µM and 24, 48, 72 hours) were applied to ovarian adenocarcinoma cancer cell line (OVCAR3), at different concentrations. Cytotoxic effect of thymoquinone on OVCAR-3 cells were analyzed by MTT method, and apoptotic and pro-apoptotic gene expression levels (p53, Casp-3) of thymoquinone in cancer cells were analyzed by quantitative real-time polymerase chain reaction. Results: Thymoquinone, whose effect has been revealed in many types of cancer, was shown to significantly reduce the viability of OVCAR3 cancer cells depending on the dose and time (p < 0.05). It was also determined that Casp-3 and p53 gene expressions increased in OVCAR3 cells. Conclusions: Considering the in-vitro cytotoxic activity and apoptotic gene expressions of thymoquinone, an important treatment agent, since it is a promising agent for the future of cancer treatment, more comprehensive studies may pave the way for its clinical use.Öğe Boswellic Acid Enhances Gemcitabine's Inhibition of Hypoxia-Driven Angiogenesis in Human Endometrial Cancer(Mdpi, 2025) Alkan Akalin, Senem; Afsin, Yasemin; Ozdemir, Ilhan; Tuncer, Mehmet Cudi; Ozturk, SamilBackground and Objectives: Endometrial carcinoma is among the most common gynecological malignancies, with recurrence and chemoresistance remaining major clinical challenges. This study aimed to evaluate the combined effects of Boswellic acid (BA), a natural pentacyclic triterpene, and Gemcitabine (GEM), a nucleoside analog chemotherapeutic, on hypoxia, angiogenesis, and apoptosis in human endometrial cancer cells. Materials and Methods: ECC-1 cells were treated with BA, GEM, or their combination under normoxic and hypoxic conditions. Cell viability (MTT assay); nuclear morphology (NucBlue staining); cell cycle distribution (PI flow cytometry); angiogenesis (VEGF ELISA expression); apoptosis (Caspase-3/7 activity; Bax; Bcl-2 expression); inflammatory cytokines (IL-1 beta; IL-6; TNF-alpha); and gene ontology enrichment were analyzed. Results: Both BA and GEM reduced cell viability in a dose- and time-dependent manner, with the combination producing synergistic cytotoxicity and lower IC50 values. Hypoxia enhanced drug sensitivity, particularly in combination therapy. BA and GEM significantly suppressed HIF-1 alpha and VEGF expression, with maximal inhibition observed in the combination group. Apoptotic induction was confirmed by increased Bax and Caspase-3 and decreased Bcl-2 expression, together with elevated Caspase-3/7, -8, and -9 activity. Pro-inflammatory cytokine levels were markedly reduced, and gene ontology analysis revealed enrichment of apoptotic, anti-proliferative, and anti-angiogenic pathways. Conclusions: BA + GEM combination synergistically suppresses hypoxia-driven angiogenesis and promotes apoptosis in endometrial cancer cells. These findings support its potential as an adjuvant therapeutic approach, warranting further preclinical and clinical validation.Öğe Combined Hesperidin and Doxorubicin Treatment Induces Apoptosis and Modulates Inflammatory Cytokines in HeLa Cervical Cancer Cells(Mdpi, 2025) Ozdemir, Ilhan; Afsin, Yasemin; Tuncer, Mehmet Cudi; Ozturk, SamilCervical cancer is a major gynecological malignancy linked to hormonal dysregulation and genetic alterations. Chemotherapy is standard but limited by toxicity and chemoresistance, prompting interest in plant-derived adjuncts. This study examined the anticancer and immunomodulatory effects of Hesperidin (Hes), a citrus flavonoid, with Doxorubicin (DX) in HeLa cervical cancer cells. Cell viability was assessed by MTT assay, apoptotic markers (Bcl-2, Caspase-3) by RT-qPCR, and inflammatory cytokines (IL-1 beta, IL-6, TNF-alpha, IFN-gamma) by ELISA. Cytokine levels were normalized to 10(4) viable cells, and mRNA expression of all four cytokines was quantified by RT-qPCR, confirming protein-level changes and showing the strongest IL-6 suppression with Hes+DX. Chou-Talalay combination index (CI) analysis demonstrated synergistic interactions (CI < 1.0) between Hes and DX across all tested concentrations, with strong synergism (CI < 0.7) at medium and high doses, particularly at 48 and 72 h. Hes alone showed dose-dependent cytotoxicity, while the combination markedly increased Caspase-3, reduced Bcl-2, and decreased IL-1 beta, IL-6, and TNF-alpha, indicating enhanced intrinsic apoptosis and complementary immunomodulation. These results suggest that Hes augments DX's pro-apoptotic and anti-inflammatory effects, potentially allowing lower chemotherapy doses and reduced systemic toxicity in cervical cancer treatment.Öğe Combined Hesperidin and Gemcitabine Therapy Modulates Apoptosis and Angiogenesis Pathways in ISHIKAWA Human Endometrial Adenocarcinoma Cells(Mdpi, 2025) Afsin, Yasemin; Ozdemir, Ilhan; Toprak, Veysel; Tuncer, Mehmet Cudi; Ozturk, SamilBackground and Objectives: Endometrial adenocarcinoma is among the most prevalent malignancies of the female reproductive system, and therapeutic options remain limited, particularly in advanced stages. In recent years, natural agents, especially flavonoids, have gained considerable interest for their capacity to enhance the effectiveness of chemotherapeutic drugs and modulate tumor-related molecular mechanisms. Hesperidin, a citrus-derived flavonoid, is recognized for its antioxidant and anti-inflammatory effects, while Gemcitabine, a nucleoside analog, is widely used in cancer treatment. Investigating their combined effects on endometrial carcinoma cells could yield novel insights into multimodal therapeutic development. This current study aimed to assess the impact of Hesperidin (Hes) and Gemcitabine (Gem) on ISHIKAWA cells, a human endometrial adenocarcinoma model, with particular attention to pathways associated with hypoxia, angiogenesis, apoptosis, and oxidative stress. Materials and Methods: ISHIKAWA cells were treated with varying concentrations of Hes (50-200 mu M) and Gem (10-50 nM), either individually or together, for 24 and 48 h. Cell viability was determined using the MTT assay, while apoptosis was measured by Caspase-3/7 activity and NucBlue nuclear staining. Intracellular reactive oxygen species (ROS) generation was quantified via DCFH-DA fluorescence. Expression levels of HIF-1 alpha, VEGF, Bax, Bcl-2, and Caspase-3 were examined by RT-qPCR. Synergistic interactions were analyzed with the Chou-Talalay combination index. Biological enrichment was further explored using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Results: Both Hes and Gem significantly decreased ISHIKAWA cell viability in a concentration- and time-dependent manner (p < 0.001). The combined treatment induced stronger apoptotic effects, as reflected by increased Caspase-3/7 activity and nuclear morphological changes. RT-qPCR demonstrated upregulation of Bax and Caspase-3, together with downregulation of Bcl-2, HIF-1 alpha, and VEGF. While Hes reduced intracellular ROS, Gem elevated it; their combination produced a balanced oxidative response. All dose combinations displayed strong synergism (CI < 1). GO and KEGG enrichment confirmed the involvement of apoptosis-, angiogenesis-, and hypoxia-related pathways. Conclusions: Co-treatment with Hes and Gem exhibits synergistic anticancer activity in endometrial cancer cells by promoting apoptosis, suppressing angiogenesis- and hypoxia-related gene expression, and modulating oxidative stress. This combined therapeutic approach highlights its potential as a promising adjuvant option, warranting further evaluation in in vivo and translational studies.Öğe Effects of Curcumin and Doxorubicin on the Viability of Neuroblastoma Cancer Cell Line(2024) Ünlü, İlker; Özdemir, İlhan; Öztürk, Şamil; Tuncer, Mehmet CudiAim: Neuroblastoma has a very important place among childhood diseases, and despite all the methods used in treatment, it is very difficult to prevent neuroblastoma invasion. The number of studies showing that curcumin, the most active component of turmeric, is not toxic, is increasing day by day. In this study, the anticancer activities of curcumin (Cur), one of the important active compounds, were demonstrated in the Neuroblastoma cancer cell line (Na2B). Method: Neuroblastoma cell line was used in the study. To determine the IC50 doses of Dox and Cur, Na2B cells line were cultivated with an automatic pipette. MTT analysis was performed to analyze cell survival (viability). Inhibition levels in the cells were determined at 24 and 48 hours. Results: While the IC50 of Na2B cell proliferation was approximately 124.5 uM at the 48th hour in Dox-treated cells, the IC50 value of Cur at the 48th hour was found to be 224.6 uM. Conclusion: These results showed that Cur could be an alternative agent in the treatment of neuroblastoma, and its fewer side effects compared to other chemotherapeutic agents such as Dox would increase its preferability.Öğe Gallic Acid Induces HeLa Cell Lines Apoptosis via the P53/Bax Signaling Pathway(Mdpi, 2024) Sarı, Umut; Zaman, Fuat; Özdemir, İlhan; Öztürk, Şamil; Tuncer, Mehmet CudiBackground: Cervical cancer is a type of cancer that originates from the endometrium and is more common in developed countries and its incidence is increasing day by day in developing countries. The most commonly prescribed chemotherapeutic drugs limit their use due to serious side effects and the development of drug resistance. For this reason, interest in new active ingredients obtained from natural products is increasing. This study aimed to reveal the apoptotic and antiproliferative effects of gallic acid and doxorubicin combination therapy against the HeLa cell line. Methods: We investigated the anti-cancer effects of doxorubicin and gallic acid in the human HeLa cervical cell line by using the MTT test, Nucblue staining for the identification of apoptotic cells due to nuclear condensation using fluorescent substance, and apoptotic markers P53 and Bax for the RT-PCR test. Results: The highest cytotoxic effect obtained in the study, the highest increase in apoptotic induction, and a significant difference in P53/Bax levels were seen in the gallic acid/doxorubicin combination. Additionally, it was determined that gallic acid exhibited an effective cytotoxic effect on HeLa and HaCat cells within 48 and 72 h of application. Conclusions: The obtained findings show that the gallic acid/doxorubicin combination applied to HeLa cells may be an alternative treatment against both the cytotoxic effect size and the side effects of the chemotherapy agent.Öğe Histopathological Changes in The Spinal Cord Tissue of Rats Administered an Experimental Mussel Diet(Dicle University, 2024) Ünlü, İlker; Özdemir, İlhan; Tuncer, Mehmet Cudi; Öztürk, ŞamilAim: Regional eating habits show that it causes neurodegenerative problems due to heavy metals that can accumulate in consumed foods and affect tissues such as the nervous system. Since crustaceans such as mussels feed by filtering the water, they are exposed to toxic plankton and various chemicals, especially heavy metals. Due to the limitations of experimental studies on this subject, the effects of mussel consumption on the spinal cord were investigated. Methods: In this study, histopathological changes in the spinal cord tissue of rats fed with shellfish collected from the Dardanelles were determined. The subjects were divided into two groups, and the first group was fed standard rat food for 4 weeks, and the second group was fed a mussel diet. At the end of the study, spinal cord tissue samples taken from rats were subjected to routine histopathological procedures and evaluated under a light microscope. Results: In the experimental group, a decrease in the number of neurons in the medulla spinalis and an increase in the number of astrocytes were noted. TUNEL staining showed that apoptosis occurred intensively in glial cells, but did not occur in anterior and posterior horn motor neurons. Conclusion: The findings showed that long-term mussel consumption can cause axonal damage in motor and sensory neurons and degeneration in glial cells. For this reason, it is important for health that marine diets in coastal areas are made with healthy and hygienic products.Öğe Inhibitory effect of Curcumin on a cervical cancer cell line via the RAS/RAF signaling pathway(F Hernandez, 2025) Özdemir, İlhan; Zaman, Fuat; Doğan Baş, Dilek; Sarı, Umut; Öztürk, Şamil; Tuncer, Mehmet CudiObjective. Cervical cancer has a very important place in female infertility and ranks fourth among cancers affecting women. Curcumin (CUR) is closely associated with the expression and activity of various regulatory proteins. It is also known that curcumin has preventive and therapeutic effects on various types of cancer. In this study, the anticancer activities of curcumin were demonstrated in the human cervical cancer cell line (HeLa). Methods. qRT-PCR and western blot analyses were used to evaluate mRNA and protein expression of curcumin in HeLa and immortalized human skin keratinocyte cell lines (HaCaT) (proliferation and apoptosis regulatory markers of the RAS/RAF signaling pathway). MTT analysis was performed, showing HeLa and HaCaT cell proliferation depending on the dose and duration of curcumin and doxorubicin. A wound scratch healing assay was applied to examine cell migration and invasion of HeLa after curcumin application. To determine the role of curcumin and doxorubicin in the apoptosis of HeLa cells, the mRNA levels of caspase-3 were examined by qRT-PCR. The results were analyzed with a one-way ANOVA SPSS 20.0 program. Results. CUR (IC50: 242.8 mu M) and DOX (IC50: 92.1 mu M) were determined to have the ability to inhibit the proliferation of HeLa cells and induce apoptosis over a 72-hour period and dose- dependently. Moreover, the results revealed that the mRNA and protein expression levels of RAF and RAS in HeLa cells were downregulated by CUR and DOX. Conclusions. The findings show that an alternative treatment method for cervical cancer can be developed with the application of CUR and DOX. Alternative methods for cervical cancer treatment may be developed using different methods in future studies.Öğe Integrated Molecular Analysis of Thymoquinone-Methotrexate Synergy in Breast Cancer Cells: Apoptosis, Oxidative Stress, and Pathway Modulation(Mdpi, 2025) Akalin, Senem Alkan; Afsin, Yasemin; Ozdemir, Ilhan; Tuncer, Mehmet Cudi; Ozturk, SamilBackground/Objectives: Breast cancer remains one of the leading causes of cancer-related mortality in women worldwide, highlighting the urgent need for effective and less toxic therapeutic strategies. Thymoquinone (TQ), a bioactive phytochemical derived from Nigella sativa, possesses antioxidant and anticancer activities. Methotrexate (MTX), a widely used folate antagonist, is an established chemotherapeutic agent but is limited by toxicity and resistance. This study aimed to investigate the potential synergistic effects of TQ and MTX in estrogen receptor-positive MCF-7 breast cancer cells. Methods: MCF-7 cells were exposed to TQ (0-100 mu M), MTX (0-10 mu M), and their combinations for 24-72 h. Cell viability was assessed by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and drug interactions were evaluated using the Chou-Talalay method. Apoptosis was quantified by Annexin V/Propidium Iodide (PI) flow cytometry, and cell cycle distribution was analyzed by PI staining. Intracellular reactive oxygen species (ROS) generation was measured using a 2 ',7 '-Dichlorofluorescin diacetate (DCFH-DA) assay, while antioxidant enzyme (superoxide dismutase (SOD), catalase (CAT)) activities were quantified spectrophotometrically. Gene expression of Bax, Bcl-2, NF-kappa B, MMP-2, and MMP-9 was determined by Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR). Results: TQ and MTX each reduced cell viability in a dose- and time-dependent manner, while combination treatment significantly enhanced cytotoxicity compared with single agents (p < 0.01). Combination Index (CI) values < 1 confirmed a synergistic interaction, particularly at 50 mu M TQ + 5 mu M MTX and 100 mu M TQ + 10 mu M MTX. Combination therapy increased total apoptosis up to 83.6%, markedly elevated the Bax/Bcl-2 ratio, and enhanced caspase-3 activation. Cell cycle analysis revealed pronounced G2/M arrest. ROS levels increased approximately six-fold, accompanied by significant suppression of SOD and CAT activities. qRT-PCR results demonstrated upregulation of pro-apoptotic Bax and downregulation of anti-apoptotic B-cell lymphoma 2 (Bcl-2), nuclear factor kappa B (NF-kappa B), matrix metalloproteinase (MMP)-2, and MMP-9. Conclusions: TQ potentiates the anticancer activity of MTX in MCF-7 breast cancer cells by synergistically inducing apoptosis, oxidative stress, and cell cycle arrest while suppressing metastasis-related genes. This combination may represent a promising therapeutic strategy for breast cancer, warranting further validation in in vivo and clinical studies.Öğe Modulation of FOXP3 Gene Expression in OVCAR3 Cells Following Rosmarinic Acid and Doxorubicin Exposure(Mdpi, 2024) Toprak, Veysel; Özdemir, İlhan; Öztürk, Şamil; Yanar, Orhan; Kızıldemir, Yusuf Ziya; Tuncer, Mehmet CudiBackground/Objectives: Ovarian cancer has the highest mortality rate in the world. Treatment methods are listed as surgery, chemotherapy, and radiotherapy, depending on the stage of cancer, but developing resistance to chemotherapy increases the need for alternative agents that act on the same pathways. The effects of rosmarinic acid (RA) and doxorubicin (DX) on the activation of FOXP3, an important tumor suppressor gene, in OVCAR3 cells were examined. Materials and Methods: In this study, a human ovarian adenocarcinoma cell line was used. MTT analysis was performed to reveal the result of RA and DX on ovarian cancer cell proliferation. Expression levels of FOXP3 for cell proliferation and Capase-3 for apoptosis were determined by RT-qPCR. The wound healing model was applied to determine cell migration rates. The results were evaluated with one-way ANOVA in an SPSS 20.0 program as p <= 0.05. Results: It was determined that RA and DX alone and in combination inhibited the proliferation of OVCAR3 cells in different doses for 24, 48, and 72 h, and caused the cells to die by causing them to undergo apoptosis. Caspase-3 expression increased approximately tenfold in OVCAR3 cells, while FOXP3 expression was upregulated only in RA treatment and was downregulated in DX and RA + DX treatments. Conclusions: According to the results of our study, it was determined that the FOXP3 signaling pathway related to apoptosis, and proliferation was affected by the combination treatment of RA and DX in the OVCAR3 cancer cell line. This shows that RA will gain an important place in cancer treatment with more comprehensive study.Öğe Rosmarinic acid inhibits the proliferation of ovarian carcinoma cells by activating the p53/BAX signaling pathway(F Hernandez, 2025) Ozdemir, Ilhan; Bas, Dilek Dogan; Ozturk, Samil; Karaosmanoglu, Ozge; Tuncer, Mehmet CudiObjective. While chemotherapeutic agents stop the development of cancer cells, they also kill healthy cells. This study aimed to increase anticancer effects and reduce side effects by combining a phytotherapeutic compound with a chemotherapeutic drug. Methods. This study examined the effects of nine concentrations of rosmarinic acid (RA) and doxorubicin (DOX) on human ovarian adenocarcinoma (OVCAR3) and skin keratinocyte (HaCaT) cell lines. Their cytotoxic effects were assessed based on cell viability, evaluated using the MTT assay, and apoptotic activity, evaluated using NucBlue staining and the gene and protein expression of tumor protein p53 (TP53) and BCL2 associated X, apoptosis regulator (BAX) quantified by qRT-PCR and western blots, respectively. Results. The half-maximal inhibitory concentration after 48 hours was 880.4 mu M for RA and 2.26 mu M for DOX. The cytotoxicity analysis revealed that cell viability decreased with the RA concentration. RA increased apoptosis in OVCAR3 cells by activating the p53/BAX pathway. Western blots showed that RA and DOX upregulated p53 and BAX protein levels in OVCAR3 cells. Conclusions. The RA and DOX combination inhibited cell proliferation by inducing apoptosis in OVCAR3 cells. These results suggest that RA may reduce the side effects of DOX toxicity.Öğe Synergistic Anticancer Effects of Metformin and Doxorubicin in Ovarian Cancer Cells Through Dual Apoptotic Pathway Activation and Oxidative Stress Enhancement(Mdpi, 2025) Alkan Akalin, Senem; Afsin, Yasemin; Toprak, Veysel; Ozdemir, Ilhan; Tuncer, Mehmet Cudi; Ozturk, SamilThis study aimed to evaluate the antiproliferative, apoptotic, and oxidative stress-inducing effects of the combination of metformin and doxorubicin (adriamycin) in OVCAR3 and SKOV3 ovarian cancer cell lines and to investigate the potential synergistic interactions between the two agents. Cell viability was assessed using the MTT assay. Apoptosis was quantified via Annexin V/PI staining followed by flow cytometry. Caspase-8 and caspase-9 activities were measured using colorimetric assays. Oxidative stress parameters, including reactive oxygen species (ROS) and nitric oxide (NO), were determined using DCFH-DA fluorescence and the Griess assay, respectively. The mRNA expression levels of apoptosis-related genes (Bcl-2, Survivin, Bax, and Caspase-3) were analyzed by qRT-PCR. Drug interaction and synergy were evaluated using the Chou-Talalay combination index (CI) model and the highest single agent (HSA) model. Prognostic relevance of target genes and protein interaction networks was examined through TCGA and STRING databases. The metformin-doxorubicin combination demonstrated strong synergistic antiproliferative effects in both cell lines (CI < 0.7 in OVCAR3). The combination significantly increased apoptosis compared with single-agent treatments, yielding a total apoptotic rate of 62.5 +/- 4.2% in OVCAR3. Caspase-8 and caspase-9 activities were elevated by 5.6 +/- 0.7-fold and 7.3 +/- 0.8-fold, respectively. Combination treatment also induced marked oxidative stress, increasing NO levels to 12.4 +/- 1.1 M and ROS levels to 412 +/- 25% in OVCAR3 cells. qRT-PCR analyses revealed downregulation of anti-apoptotic Bcl-2 (0.28 +/- 0.04-fold) and Survivin (0.25 +/- 0.03-fold), along with upregulation of pro-apoptotic Bax (5.8 +/- 0.6-fold) and Caspase-3 (6.5 +/- 0.7-fold). Bioinformatic analyses indicated that high Bcl-2 and Survivin expression correlated with poorer overall survival in ovarian cancer patients. Metformin enhances the anticancer efficacy of doxorubicin through synergistic activation of intrinsic and extrinsic apoptotic pathways, induction of oxidative and nitrosative stress, and transcriptional regulation of key apoptotic markers. These findings support the potential use of metformin as an adjuvant agent to strengthen doxorubicin-based chemotherapy in ovarian cancer.
