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Öğe Boswellic Acid Enhances Gemcitabine's Inhibition of Hypoxia-Driven Angiogenesis in Human Endometrial Cancer(Mdpi, 2025) Alkan Akalin, Senem; Afşin, Yasemin; Özdemir, İlhan; Tuncer, Mehmet Cudi; Öztürk, ŞamilBackground 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 Gemcitabine Therapy Modulates Apoptosis and Angiogenesis Pathways in ISHIKAWA Human Endometrial Adenocarcinoma Cells(Mdpi, 2025) Afşin, Yasemin; Özdemir, İlhan; Toprak, Veysel; Tuncer, Mehmet Cudi; Öztürk, ŞamilBackground 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 Gallik Asidin Rahim Ağzı Kanseri Hücre Hattına (HeLa) Karşı Antikanser Etkisi(Dicle Üniversitesi, 2023) Sarı, Umut; Afşin, Yasemin; Özdemir, İlhan; Mutlu Özçelik, Serap; Öztürk, ŞamilAmaç: Servikal kanser, kadın infertilitesinde oldukça önemli yer teşkil eden ve dünya çapında kadınları en çok etkileyen dördüncü kanser olarak karşımıza çıkmaktadır. Doxorubicin (Dox), yumurtalık ve meme kanseri tedavisinde en sık reçete edilen kemoterapötiklerdendir. Kemoterapötik ilaçlar çok etkili tedavi sonuçları ile yanıt oluştursalar da, ciddi yan etkileri oluşturmakta ve ilaç direnci gelişmesi bu ilaçların kullanımına kısıtlama getirmektedir. Antikanser aktiviteye sahip doğal ürünlerin kullanılması bu sorunların kısmen üstesinden gelinmesine yardımcı olabilir. Gallik asit (GA), çeşitli bitki ve gıdalarda yaygın olarak bulunur ve çeşitli biyolojik etkilere sahip olduğu bildirilmiştir. Bu çalışmada GA'in ve güçlü bir kemoterapi ajanı olan Dox’in HeLa hücreleri ve insan deri keratinosit hücre hattı (HaCaT) üzerindeki hücre büyümesinin inhibisyonu ve ölümü ile ilgili etkileri MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide) yöntemi ile belirlenmesi amaçlanmıştır. Yöntemler: Çalışmada serviks adenokarsinoma hücre serisi HeLa (CCL-2™) ve sağlıklı hücre serisi olarak insan deri keratinosit hücre serisi HaCat (RRID: CVCL_0038) kullanılmıştır. Dox ve GA’in IC50 (inhibitory concentration) dozlarının belirlenmesi için HeLa ve HaCaT hücre hattı otomatik multipipet yardımı ile ekimi yapılmıştır. Daha sonra hücre sağkalım (viyabilite) analizini yapmak için MTT testi uygulanmıştır. Bulgular: HeLa hücre büyümesi, Dox ile muamele edilen hücrelerde 48. saatte yaklaşık IC50 137.6 uM iken, GA'in 48. saatteki IC50 değeri 239.2 uM bulunmuştur. Sonuç: Bu sonuçlar, GA’in Dox’nun etkisini güçlendirdiğini ve Dox/GA asit kombinasyonunun, rahim ağzı kanseri tedavisinde diğer kemoterapötik kombinasyonları için daha düşük yan etkilerle umut verici bir alternatif olabileceğini göstermektedir.Öğe Integrated Molecular Analysis of Thymoquinone-Methotrexate Synergy in Breast Cancer Cells: Apoptosis, Oxidative Stress, and Pathway Modulation(Mdpi, 2025) Alkan Akalın, Senem; Afşin, Yasemin; Özdemir, İlhan; Tuncer, Mehmet Cudi; Öztürk, ŞamilBackground/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 Synergistic Anticancer Effects of Metformin and Doxorubicin in Ovarian Cancer Cells Through Dual Apoptotic Pathway Activation and Oxidative Stress Enhancement(Mdpi, 2025) Alkan Akalın, Senem; Afşin, Yasemin; Toprak, Veysel; Özdemir, İlhan; Tuncer, Mehmet Cudi; Öztürk, ŞamilThis 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.
