{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T22:32:03Z","timestamp":1789425123750,"version":"build-2803163510"},"reference-count":73,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2025,9,9]],"date-time":"2025-09-09T00:00:00Z","timestamp":1757376000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001807","name":"FAPESP","doi-asserted-by":"publisher","award":["2022\/07090-4"],"award-info":[{"award-number":["2022\/07090-4"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Overcoming resistance to temozolomide (TMZ) chemotherapy is a major challenge in glioma treatment. Polyunsaturated fatty acids (PUFAs) can interfere with drug resistance in glioma but their mechanism of action is poorly understood. Eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) effects were assessed using proliferation and clonogenic assays, adhesion and migration assays, glucose and lactate metabolism, detection of lipid droplets, acidic vesicles, reactive oxygen species, and phosphokinase proteome analysis. EPA or DHA caused significant reductions in cell number, colony formation, adhesion, and migration in comparison with TMZ alone, increasing lipid droplet accumulation, reactive oxygen species formation, acidic vesicle number and apoptosis, while also altering glucose and lactate metabolism. TMZ increased phosphorylation of ERK 1\/2, GSK3\u03b1\/\u03b2, AMPK\u03b11, Akt 1\/2\/3, PRAS40, CREB, HSP27, WNK1, and c-Jun in U87MG TMZR cells. EPA in the presence of TMZ reduced the phosphorylation of GSK3\u03b1\/\u03b2, Akt 1\/2\/3, HSP27, and WNK1, while DHA reduced the phosphorylation of ERK 1\/2, GSK3\u03b1\/\u03b2, AMPK\u03b11, Akt 1\/2\/3, and WNK1, thereby leading to additive or synergistic effects of EPA or DHA in combination with TMZ. Overall, the present study highlights the alterations seen in TMZ-resistant glioma cells when exposed to EPA or DHA and demonstrates the therapeutic potential that modulation of lipid metabolism can exert upon important aspects of glioma cell biology.<\/jats:p>","DOI":"10.3390\/ijms26188759","type":"journal-article","created":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T10:27:12Z","timestamp":1757500032000},"page":"8759","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["The Omega-3 Fatty Acids Eicosapentaenoic Acid and Docosahexaenoic Acid Enhance the Effects of Temozolomide Chemotherapy in Glioblastoma Cells"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7896-8893","authenticated-orcid":false,"given":"Jana\u00edna Alessandra","family":"Silva","sequence":"first","affiliation":[{"name":"Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of S\u00e3o Paulo, S\u00e3o Paulo 05508-000, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0691-2364","authenticated-orcid":false,"given":"Alison","family":"Colquhoun","sequence":"additional","affiliation":[{"name":"Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of S\u00e3o Paulo, S\u00e3o Paulo 05508-000, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,9]]},"reference":[{"key":"ref_1","unstructured":"Louis, D.N. (2021). WHO Classification of Tumors of the Central Nervous System, IARC. [5th ed.]."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1093\/neuonc\/noab106","article-title":"The 2021 WHO Classification of Tumors of the Central Nervous System: A summary","volume":"23","author":"Louis","year":"2021","journal-title":"Neuro-Oncology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"iii1","DOI":"10.1093\/neuonc\/noab200","article-title":"CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2014\u20132018","volume":"23","author":"Ostrom","year":"2021","journal-title":"Neuro-Oncology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1093\/neuonc\/nou035","article-title":"GBM\u2019s multifaceted landscape: Highlighting regional and microenvironmental heterogeneity","volume":"16","author":"Vartanian","year":"2014","journal-title":"Neuro-Oncology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1624","DOI":"10.1200\/JCO.2003.05.063","article-title":"Cost of migration: Invasion of malignant gliomas and implications for treatment","volume":"21","author":"Giese","year":"2003","journal-title":"J. Clin. Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1622","DOI":"10.1093\/neuonc\/now117","article-title":"Reactive astrocytes potentiate tumor aggressiveness in a murine glioma resection and recurrence model","volume":"18","author":"Okolie","year":"2016","journal-title":"Neuro-Oncology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1186\/1475-2867-5-30","article-title":"ABC transporters as multidrug resistance mechanisms and the development of chemosensitizers for their reversal","volume":"5","author":"Choi","year":"2005","journal-title":"Cancer Cell Int."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Perazzoli, G., Prados, J., Ortiz, R., Caba, O., Cabeza, L., Berdasco, M., G\u00f3nzalez, B., Melguizo, C., and Alonso, M.M. (2015). Temozolomide Resistance in Glioblastoma Cell Lines: Implication of MGMT, MMR, P-Glycoprotein and CD133 Expression. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0140131"},{"key":"ref_9","first-page":"91","article-title":"Cellular mechanisms of multidrug resistance of tumor cells","volume":"81","author":"Stavrovskaya","year":"2016","journal-title":"Biochemistry"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1885","DOI":"10.1016\/j.juro.2008.11.092","article-title":"Mechanisms of action of eicosapentaenoic acid in bladder cancer cells in vitro: Alterations in mitochondrial metabolism, reactive oxygen species generation and apoptosis induction","volume":"181","author":"Colquhoun","year":"2009","journal-title":"J. Urol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1007\/s12035-010-8134-4","article-title":"Lipids, Mitochondria and Cell Death: Implications in Neuro-oncology","volume":"42","author":"Colquhoun","year":"2010","journal-title":"Mol. Neurobiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1408","DOI":"10.1007\/s10495-016-1298-2","article-title":"Identification of cytotoxic mediators and their putative role in the signaling pathways during docosahexaenoic acid (DHA)-induced apoptosis of cancer cells","volume":"21","author":"Das","year":"2016","journal-title":"Apoptosis"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1002\/iub.154","article-title":"Gamma-linolenic Acid Alters Ku80, E2F1, and Bax Expression and Induces Micronucleus Formation in C6 Glioma Cells In Vitro","volume":"61","author":"Benadiba","year":"2009","journal-title":"IUBMB Life"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Zahid, S., El Dahan, M.S., Iehl, F., Fernandez-Varela, P., Le Du, M.-H., Ropars, V., and Charbonnier, J.B. (2021). The Multifaceted Roles of Ku70\/80. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22084134"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Yuan, Y., Shah, N., Almohaisin, M.I., Saha, S., and Lu, F. (2021). Assessing fatty acid-induced lipotoxicity and its therapeutic potential in glioblastoma using stimulated Raman microscopy. Sci. Rep., 11.","DOI":"10.1038\/s41598-021-86789-9"},{"key":"ref_16","first-page":"239","article-title":"\u03c93-polyunsaturated fatty acids induce cell death through apoptosis and autophagy in glioblastoma cells: In vitro and in vivo","volume":"39","author":"Kim","year":"2018","journal-title":"Oncol. Rep."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1186\/1476-511X-10-173","article-title":"MicroRNA profile of polyunsaturated fatty acid treated glioma cells reveal apoptosis-specific expression changes","volume":"10","author":"Kitajka","year":"2011","journal-title":"Lipids Health Dis."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1186\/1476-511X-8-8","article-title":"Gamma-linolenic acid inhibits both tumour cell cycle progression and angiogenesis in the orthotopic C6 glioma model through changes in VEGF, Flt1, ERK1\/2, MMP2, cyclin D1, pRb, p53 and p27 protein expression","volume":"8","author":"Miyake","year":"2009","journal-title":"Lipids Health Dis."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"574","DOI":"10.2174\/1389450122666210901121935","article-title":"Omega-3 Fatty Acid Treatment Combined with Chemotherapy to Prevent Toxicity, Drug Resistance, and Metastasis in Cancer","volume":"23","author":"Soni","year":"2022","journal-title":"Curr. Drug Targets"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"503","DOI":"10.2174\/156652411796268740","article-title":"Docosahexaenoic Acid (DHA) Sensitizes Brain Tumor Cells to Etoposide-Induced Apoptosis","volume":"11","author":"Wang","year":"2011","journal-title":"Curr. Mol. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"547","DOI":"10.3171\/2014.10.JNS14759","article-title":"Enhanced anticancer properties of lomustine in conjunction with docosahexaenoic acid in glioblastoma cell lines","volume":"122","author":"Harvey","year":"2015","journal-title":"J. Neurosurg."},{"key":"ref_22","first-page":"361","article-title":"Eicosapentaenoic acid enhances the sensitivity of glioma cell line U87 to temozolomide via inhibiting endoplasmic reticulum stress","volume":"25","author":"Huang","year":"2017","journal-title":"Chin. J. Clin. Nutr."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Silva, J.A., and Colquhoun, A. (2023). Effect of Polyunsaturated Fatty Acids on Temozolomide Drug-Sensitive and Drug-Resistant Glioblastoma Cells. Biomedicines, 11.","DOI":"10.3390\/biomedicines11030779"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1158\/0008-5472.CAN-08-2356","article-title":"A New model for prediction of drug distribution in tumor and normal tissues: Pharmacokinetics of temozolomide in glioma patients","volume":"69","author":"Rosso","year":"2009","journal-title":"Cancer Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3728","DOI":"10.1158\/1078-0432.CCR-03-0807","article-title":"Plasma and Cerebrospinal Fluid Population Pharmacokinetics of Temozolomide in Malignant Glioma Patients","volume":"10","author":"Ostermann","year":"2004","journal-title":"Clin. Cancer Res."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Beltzig, L., Schwarzenbach, C., Leukel, P., Frauenknecht, K.B.M., Sommer, C., Tancredi, A., Hegi, M.E., Christmann, M., and Kaina, B. (2022). Senescence Is the Main Trait Induced by Temozolomide in Glioblastoma Cells. Cancers, 14.","DOI":"10.3390\/cancers14092233"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/S1388-1981(01)00136-6","article-title":"\u03b3-Linolenic acid and eicosapentaenoic acid induce modifications in mitochondrial metabolism, reactive oxygen species generation, lipid peroxidation and apoptosis in Walker 256 rat carcinosarcoma cells","volume":"1533","author":"Colquhoun","year":"2001","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1002\/glia.10246","article-title":"Protective role of glucose-6-phosphate dehydrogenase activity in the metabolic response of C6 rat glioma cells to polyunsaturated fatty acid exposure","volume":"43","author":"Ramos","year":"2003","journal-title":"Glia"},{"key":"ref_29","first-page":"2050","article-title":"Resveratrol reverses temozolomide resistance by downregulation of MGMT in T98G glioblastoma cells by the NF-\u03baB-dependent pathway","volume":"27","author":"Huang","year":"2012","journal-title":"Oncol. Rep."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1002\/cpdd.84","article-title":"Pharmacokinetics of Eicosapentaenoic Acid in Plasma and Red Blood Cells After Multiple Oral Dosing With Icosapent Ethyl in Healthy Subjects","volume":"3","author":"Braeckman","year":"2013","journal-title":"Clin. Pharmacol. Drug Dev."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"11858","DOI":"10.18632\/oncotarget.24405","article-title":"Effects of the polyunsaturated fatty acids, EPA and DHA, on hematological malignancies: A systematic review","volume":"9","author":"Moloudizargari","year":"2018","journal-title":"Oncotarget"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"von Schacky, C. (2021). Importance of EPA and DHA Blood Levels in Brain Structure and Function. Nutrients, 13.","DOI":"10.3390\/nu13041074"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.prostaglandins.2011.06.003","article-title":"Docosahexaenoic acid (DHA) incorporation into the brain from plasma, as an in vivo biomarker of brain DHA metabolism and neurotransmission","volume":"96","author":"Rapaport","year":"2011","journal-title":"Prostaglandins Other Lipid Mediat."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1186\/1476-511X-7-45","article-title":"The influence of feeding linoleic, gamma-linolenic and docosahexaenoic acid rich oils on rat brain tumor fatty acids composition and fatty acid binding protein 7 mRNA expression","volume":"7","author":"Nasrollahzadeh","year":"2008","journal-title":"Lipids Health Dis."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1186\/s13195-017-0250-1","article-title":"DHA brain uptake and APOE4 status: A PET study with [1-11C]-DHA","volume":"9","author":"Yassine","year":"2017","journal-title":"Alzheimer\u2019s Res. Ther."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.plefa.2017.07.003","article-title":"DHA, EPA and their combination at various ratios differently modulated A\u03b225-35-induced neurotoxicity in SH-SY5Y cells","volume":"136","author":"Zhang","year":"2018","journal-title":"Prostaglandins Leukot. Essent. Fat. Acids"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1016\/j.clnesp.2024.06.053","article-title":"Role of Omega-3 fatty acids eicosapentaenoic (EPA) and docosahexaenoic (DHA) as modulatory and anti-inflammatory agents in noncommunicable diet-related diseases\u2014Reports from the last 10 years","volume":"63","author":"Banaszak","year":"2024","journal-title":"Clin. Nutr. ESPEN"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1194\/jlr.M500415-JLR200","article-title":"Docosahexaenoic acid facilitates cell maturation and beta-adrenergic transmission in astrocytes","volume":"47","author":"Joardar","year":"2006","journal-title":"J. Lipid Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1155","DOI":"10.1111\/jnc.13510","article-title":"Docosahexaenoic acid (DHA) prevents corticosterone-induced changes in astrocyte morphology and function","volume":"136","author":"Hennebelle","year":"2016","journal-title":"J. Neurochem."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Zgorzynska, E., Dziedzic, B., Markiewicz, M., and Walczewska, A. (2021). Omega-3 PUFAs Suppress IL-1\u03b2-Induced Hyperactivity of Immunoproteasomes in Astrocytes. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22115410"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Serafim, R.B., da Silva, P., Cardoso, C., Di Cristofaro, L.F.M., Netto, R.P., de Almeida, R., Navegante, G., Storti, C.B., de Sousa, J.F., and de Souza, F.C. (2021). Expression Profiling of Glioblastoma Cell Lines Reveals Novel Extracellular Matrix-Receptor Genes Correlated With the Responsiveness of Glioma Patients to Ionizing Radiation. Front. Oncol., 11.","DOI":"10.3389\/fonc.2021.668090"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"844","DOI":"10.2353\/ajpath.2009.080920","article-title":"Expression of Integrin 6 1 Enhances Tumorigenesis in Glioma Cells","volume":"175","author":"Delamarre","year":"2009","journal-title":"Am. J. Pathol."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Ellert-Miklaszewska, A., Poleszak, K., Pasierbinska, M., and Kaminska, B. (2020). Integrin Signaling in Glioma Pathogenesis: From Biology to Therapy. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21030888"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"5043","DOI":"10.21873\/anticanres.14507","article-title":"Inhibitory Effect of Eicosapentaenoic Acid on the Migration of the Esophageal Squamous Cell Carcinoma Cell Line TE-1","volume":"40","author":"Kubota","year":"2020","journal-title":"Anticancer Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1007\/s10549-013-2703-y","article-title":"DHA is a more potent inhibitor of breast cancer metastasis to bone and related osteolysis than EPA","volume":"141","author":"Rahman","year":"2013","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"9420","DOI":"10.1039\/D4FO02346C","article-title":"Docosahexaenoic acid inhibits the invasion and migration of colorectal cancer by reversing EMT through the TGF-\u03b21\/Smad signaling pathway","volume":"15","author":"Jiang","year":"2024","journal-title":"Food Funct."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2416","DOI":"10.1002\/jcb.29464","article-title":"Docosahexaenoic acid suppresses migration of triple-negative breast cancer cell through targeting metastasis-related genes and microRNA under normoxic and hypoxic conditions","volume":"121","author":"Javadian","year":"2020","journal-title":"J. Cell. Biochem."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"49961","DOI":"10.18632\/oncotarget.10266","article-title":"Docosahexaenoic acid suppresses breast cancer cell metastasis by targeting matrix-metalloproteinases","volume":"7","author":"Yun","year":"2016","journal-title":"Oncotarget"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"9706","DOI":"10.1039\/D1NR02128A","article-title":"Super resolution microscopy reveals DHA-dependent alterations in glioblastoma membrane remodelling and cell migration","volume":"13","author":"Xu","year":"2021","journal-title":"Nanoscale"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.3892\/ijo.2015.3101","article-title":"High-capacity glycolytic and mitochondrial oxidative metabolisms mediate the growth ability of glioblastoma","volume":"47","author":"Kim","year":"2015","journal-title":"Int. J. Oncol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"32843","DOI":"10.1074\/jbc.M111.260935","article-title":"Metabolic Alterations in Highly Tumorigenic Glioblastoma Cells","volume":"286","author":"Zhou","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Cheng, S.-Y., Chen, N.-F., Wen, Z.-H., Yao, Z.-K., Tsui, K.-H., Kuo, H.-M., and Chen, W.-F. (2021). Glutathione S-Transferase M3 Is Associated with Glycolysis in Intrinsic Temozolomide-Resistant Glioblastoma Multiforme Cells. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22137080"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Martins, F., van der Kellen, D., Gon\u00e7alves, L.G., and Serpa, J. (2023). Metabolic Profiles Point Out Metabolic Pathways Pivotal in Two Glioblastoma (GBM) Cell Lines, U251 and U-87MG. Biomedicines, 11.","DOI":"10.3390\/biomedicines11072041"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Caragher, S., Miska, J., Shireman, J., Park, C.H., Muroski, M., Lesniak, M.S., and Ahmed, A.U. (2020). Temozolomide Treatment Increases Fatty Acid Uptake in Glioblastoma Stem Cells. Cancers, 2.","DOI":"10.3390\/cancers12113126"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"C1120","DOI":"10.1152\/ajpcell.00304.2020","article-title":"Docosahexaenoic and eicosapentaenoic fatty acids differentially regulate glucose and fatty acid metabolism in L6 rat skeletal muscle cells","volume":"319","author":"Katsnelson","year":"2020","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"974","DOI":"10.5114\/aoms.2020.92293","article-title":"Arachidonic and eicosapentaenoic acids induce oxidative stress to suppress proliferation of human glioma cells","volume":"16","author":"Hari","year":"2020","journal-title":"Arch. Med. Sci."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"105136","DOI":"10.1016\/j.neuint.2021.105136","article-title":"Antioxidant responses related to temozolomide resistance in glioblastoma","volume":"149","author":"Alonso","year":"2021","journal-title":"Neurochem. Int."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1007\/7651_2024_571","article-title":"Assessing Autophagy Flux in Glioblastoma Temozolomide Resistant Cells","volume":"2879","author":"Clark","year":"2025","journal-title":"Methods Mol. Biol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"e2885","DOI":"10.1038\/cddis.2017.248","article-title":"Connective tissue growth factor promotes temozolomide resistance in glioblastoma through TGF-\u03b21-dependent activation of Smad\/ERK signaling","volume":"8","author":"Zeng","year":"2017","journal-title":"Cell Death Dis."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"5732","DOI":"10.3892\/mmr.2016.5964","article-title":"Temozolomide inhibits cellular growth and motility via targeting ERK signaling in glioma C6 cells","volume":"14","author":"Wang","year":"2016","journal-title":"Mol. Med. Rep."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.jns.2016.05.054","article-title":"Akt and \u03b2-catenin contribute to TMZ resistance and EMT of MGMT negative malignant glioma cell line","volume":"367","author":"Yi","year":"2016","journal-title":"J. Neurol. Sci."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"5057","DOI":"10.18632\/oncotarget.13789","article-title":"MiR-433-3p suppresses cell growth and enhances chemosensitivity by targeting CREB in human glioma","volume":"8","author":"Sun","year":"2017","journal-title":"Oncotarget"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"8701","DOI":"10.1007\/s11033-022-07714-5","article-title":"Temozolomide increases heat shock proteins in extracellular vesicles released from glioblastoma cells","volume":"49","year":"2022","journal-title":"Mol. Biol. Rep."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1186\/1476-4598-13-31","article-title":"WNK1-OSR1 kinase-mediated phospho-activation of Na+-K+-2Cl- cotransporter facilitates glioma migration","volume":"13","author":"Zhu","year":"2014","journal-title":"Mol. Cancer"},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Luo, L., Wang, J., Ding, D., Hasan, N., Yang, S.-S., Lin, S.-H., Schreppel, P., Sun, B., Yin, Y., and Erker, T. (2020). Role of NKCC1 Activity in Glioma K+ Homeostasis and Cell Growth: New Insights With the Bumetanide-Derivative STS66. Front. Physiol., 11.","DOI":"10.3389\/fphys.2020.00911"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"e1145","DOI":"10.1038\/cddis.2014.111","article-title":"Temozolomide resistance in glioblastoma cells occurs partly through epidermal growth factor receptor-mediated induction of connexin 43","volume":"5","author":"Munoz","year":"2014","journal-title":"Cell Death Dis."},{"key":"ref_67","first-page":"1901","article-title":"Novel Ruthenium\u2014Gamma-linolenic Acid Complex Inhibits C6 Rat Glioma Cell Proliferation In Vitro and in the Orthotopic C6 Model In Vivo After Osmotic Pump Infusion","volume":"34","author":"Miyake","year":"2014","journal-title":"Anticancer Res."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1367","DOI":"10.3892\/ijo_00000621","article-title":"Gene expression profiling predicts response to temozolomide in malignant gliomas","volume":"36","author":"Yoshino","year":"2010","journal-title":"Int. J. Oncol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1186\/1748-717X-8-65","article-title":"Evaluation of poly (ADP-ribose) polymerase inhibitor ABT-888 combined with radiotherapy and temozolomide in glioblastoma","volume":"8","author":"Barazzuol","year":"2013","journal-title":"Radiat. Oncol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"824","DOI":"10.1038\/s41416-022-01865-9","article-title":"Selective cell cycle arrest in glioblastoma cell lines by quantum molecular resonance alone or in combination with temozolomide","volume":"127","author":"Catanzaro","year":"2022","journal-title":"Br. J. Cancer"},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Souza, F.D.C., Ferreira, M.T., and Colquhoun, A. (2020). Influence of Lipoxygenase Inhibition on Glioblastoma Cell Biology. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21218395"},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Ferreira, M.T., Miyake, J.A., Gomes, R.N., Feitoza, F., Stevannato, P.B., da Cunha, A.S., Serachi, F.d.O., Panagopoulos, A.T., and Colquhoun, A. (2021). Cyclooxygenase Inhibition Alters Proliferative, Migratory, and Invasive Properties of Human Glioblastoma Cells In Vitro. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22094297"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1002\/cbf.1626","article-title":"The novel ruthenium-\u03b3-linolenic complex [Ru2(aGLA)4Cl] inhibits C6 rat glioma cell proliferation and induces changes in mitochondrial membrane potential, increased reactive oxygen species generation and apoptosis in vitro","volume":"28","author":"Ribeiro","year":"2010","journal-title":"Cell Biochem. Funct."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/18\/8759\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:42:24Z","timestamp":1760035344000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/18\/8759"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,9]]},"references-count":73,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2025,9]]}},"alternative-id":["ijms26188759"],"URL":"https:\/\/doi.org\/10.3390\/ijms26188759","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,9]]}}}