{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T01:21:53Z","timestamp":1779931313338,"version":"3.53.1"},"reference-count":77,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2025,1,13]],"date-time":"2025-01-13T00:00:00Z","timestamp":1736726400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004281","name":"National Science Center","doi-asserted-by":"publisher","award":["2019\/35\/B\/NZ7\/01165"],"award-info":[{"award-number":["2019\/35\/B\/NZ7\/01165"]}],"id":[{"id":"10.13039\/501100004281","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Although curcumin is a well-known natural polyphenol with many biological activities, its clinical application has been limited by low aqueous solubility and stability. Therefore, curcumin derivatives have been proposed to overcome these limitations and increase anticancer activity. This study tested curcumin derivatives with modified feruloyl moieties (2a and 2a-B) and the \u03b2-diketo moiety (2a-B) to better understand their anticancer mechanism against human bladder cancer cells. The anticancer activity of 2a and 2a-B was determined using MTT (hypoxic conditions) and LDH (normoxic conditions) assays. An ELISA-based protein panel was used to find the potential molecular targets, while flow cytometric, colorimetric, fluorescent, and luminescent assays were used to investigate the cell death mechanism. It was shown that compound 2a exerted a more potent cytotoxic effect under hypoxic conditions, while compound 2a-B demonstrated a comparable effect in normoxic and hypoxic conditions. The potential molecular targets modified by 2a and 2a-B depending on oxygen concentration were also proposed. Both compounds alter cell cycle progression by blocking the cell cycle in the G2\/M phase and decreasing the percentage of cells in the G0\/G1 phase. Compound 2a-B led to phosphatidylserine translocation, increased caspase 3\/7 activity, and decreased mitochondrial membrane potential, suggesting a mitochondrial apoptosis pathway. We found that the Akt signaling pathway may modulate the activity of compound 2a-B, as evidenced by enhanced cytotoxic activity in combination with MK-2206, an Akt 1\/2\/3 inhibitor. Thus, our results provide new insights into the anticancer activity of compounds 2a and 2a-B; however, further studies are needed to better understand their therapeutic potential.<\/jats:p>","DOI":"10.3390\/molecules30020295","type":"journal-article","created":{"date-parts":[[2025,1,13]],"date-time":"2025-01-13T09:49:17Z","timestamp":1736761757000},"page":"295","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Insights into the Mode of Action of Novel Morpholinated Curcumin Derivatives Exhibiting Potent Antitumor Activity in Bladder Cancer Cells In Vitro"],"prefix":"10.3390","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3105-8144","authenticated-orcid":false,"given":"Paulina","family":"Kobylka","sequence":"first","affiliation":[{"name":"Department of Toxicology, Poznan University of Medical Sciences, Rokietnicka 3 Street, 60-806 Poznan, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0831-2856","authenticated-orcid":false,"given":"Pawel","family":"Bakun","sequence":"additional","affiliation":[{"name":"Department of Chemical Technology of Drugs, Poznan University of Medical Sciences, Rokietnicka 3 Street, 60-806 Poznan, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8514-5238","authenticated-orcid":false,"given":"Joanna","family":"Kuzminska","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Poznan University of Medical Sciences, Rokietnicka 3 Street, 60-806 Poznan, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5705-5414","authenticated-orcid":false,"given":"Tomasz","family":"Goslinski","sequence":"additional","affiliation":[{"name":"Department of Chemical Technology of Drugs, Poznan University of Medical Sciences, Rokietnicka 3 Street, 60-806 Poznan, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2903-4912","authenticated-orcid":false,"given":"Marek","family":"Murias","sequence":"additional","affiliation":[{"name":"Department of Toxicology, Poznan University of Medical Sciences, Rokietnicka 3 Street, 60-806 Poznan, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3606-3623","authenticated-orcid":false,"given":"Malgorzata","family":"Kucinska","sequence":"additional","affiliation":[{"name":"Department of Toxicology, Poznan University of Medical Sciences, Rokietnicka 3 Street, 60-806 Poznan, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Fu, Y.-S., Chen, T.-H., Weng, L., Huang, L., Lai, D., and Weng, C.-F. (2021). Pharmacological Properties and Underlying Mechanisms of Curcumin and Prospects in Medicinal Potential. Biomed. Pharmacother., 141.","DOI":"10.1016\/j.biopha.2021.111888"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Islam, M.R., Rauf, A., Akash, S., Trisha, S.I., Nasim, A.H., Akter, M., Dhar, P.S., Ogaly, H.A., Hemeg, H.A., and Wilairatana, P. (2024). Targeted Therapies of Curcumin Focus on Its Therapeutic Benefits in Cancers and Human Health: Molecular Signaling Pathway-Based Approaches and Future Perspectives. Biomed. Pharmacother., 170.","DOI":"10.1016\/j.biopha.2023.116034"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Wang, H., Zhang, K., Liu, J., Yang, J., Tian, Y., Yang, C., Li, Y., Shao, M., Su, W., and Song, N. (2021). Curcumin Regulates Cancer Progression: Focus on ncRNAs and Molecular Signaling Pathways. Front. Oncol., 11.","DOI":"10.3389\/fonc.2021.660712"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1007\/978-3-030-56153-6_2","article-title":"Turmeric and Curcumin: From Traditional to Modern Medicine","volume":"1291","author":"Akaberi","year":"2021","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Liu, Z., Huang, P., Law, S., Tian, H., Leung, W., and Xu, C. (2018). Preventive Effect of Curcumin Against Chemotherapy-Induced Side-Effects. Front. Pharmacol., 9.","DOI":"10.3389\/fphar.2018.01374"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"111699","DOI":"10.1016\/j.fct.2020.111699","article-title":"Curcumin as a Preventive or Therapeutic Measure for Chemotherapy and Radiotherapy Induced Adverse Reaction: A Comprehensive Review","volume":"145","author":"Akbari","year":"2020","journal-title":"Food Chem. Toxicol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Tan, B.L., and Norhaizan, M.E. (2019). Curcumin Combination Chemotherapy: The Implication and Efficacy in Cancer. Molecules, 24.","DOI":"10.3390\/molecules24142527"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1007\/s13765-014-4077-1","article-title":"Curcumin as a Cancer Chemotherapy Sensitizing Agent","volume":"57","author":"Kwon","year":"2014","journal-title":"J. Korean Soc. Appl. Biol. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Xie, L., Ji, X., Zhang, Q., and Wei, Y. (2022). Curcumin Combined with Photodynamic Therapy, Promising Therapies for the Treatment of Cancer. Biomed. Pharmacother., 146.","DOI":"10.1016\/j.biopha.2021.112567"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Dytrych, P., Kej\u00edk, Z., Hajduch, J., Kapl\u00e1nek, R., Vesel\u00e1, K., Ku\u010dnirov\u00e1, K., Skali\u010dkov\u00e1, M., Venhauerov\u00e1, A., Hoskovec, D., and Mart\u00e1sek, P. (2023). Therapeutic Potential and Limitations of Curcumin as Antimetastatic Agent. Biomed. Pharmacother., 163.","DOI":"10.1016\/j.biopha.2023.114758"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.ejmech.2019.04.058","article-title":"Developments in the Anticancer Activity of Structurally Modified Curcumin: An up-to-Date Review","volume":"177","author":"Rodrigues","year":"2019","journal-title":"Eur. J. Med. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Kuzminska, J., Szyk, P., Mlynarczyk, D.T., Bakun, P., Muszalska-Kolos, I., Dettlaff, K., Sobczak, A., Goslinski, T., and Jelinska, A. (2024). Curcumin Derivatives in Medicinal Chemistry: Potential Applications in Cancer Treatment. Molecules, 29.","DOI":"10.3390\/molecules29225321"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Tabanelli, R., Brogi, S., and Calderone, V. (2021). Improving Curcumin Bioavailability: Current Strategies and Future Perspectives. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13101715"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"10713","DOI":"10.1021\/acsomega.2c07326","article-title":"Curcumin Formulations for Better Bioavailability: What We Learned from Clinical Trials Thus Far?","volume":"8","author":"Hegde","year":"2023","journal-title":"ACS Omega"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"105489","DOI":"10.1016\/j.phrs.2021.105489","article-title":"The Potency of Heterocyclic Curcumin Analogues: An Evidence-Based Review","volume":"166","author":"Rodrigues","year":"2021","journal-title":"Pharmacol. Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1618","DOI":"10.1039\/C3OB42201A","article-title":"Syntheses and Photophysical Properties of BF2 Complexes of Curcumin Analogues","volume":"12","author":"Bai","year":"2014","journal-title":"Org. Biomol. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2264","DOI":"10.3762\/bjoc.13.223","article-title":"Curcuminoid\u2013BF2 Complexes: Synthesis, Fluorescence and Optimization of BF2 Group Cleavage","volume":"13","author":"Weiss","year":"2017","journal-title":"Beilstein J. Org. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"103528","DOI":"10.1016\/j.arabjc.2021.103528","article-title":"Synthetic Approaches for BF2-Containing Adducts of Outstanding Biological Potential. A Review","volume":"15","author":"Delgado","year":"2022","journal-title":"Arab. J. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.jfluchem.2016.09.009","article-title":"Fluoro-Curcuminoids and Curcuminoid-BF2 Adducts: Synthesis, X-Ray Structures, Bioassay, and Computational\/Docking Study","volume":"191","author":"Laali","year":"2016","journal-title":"J. Fluor. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Lazewski, D., Kucinska, M., Potapskiy, E., Kuzminska, J., Popenda, L., Tezyk, A., Goslinski, T., Wierzchowski, M., and Murias, M. (2023). Enhanced Cytotoxic Activity of PEGylated Curcumin Derivatives: Synthesis, Structure\u2013Activity Evaluation, and Biological Activity. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24021467"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"944","DOI":"10.1007\/s00044-024-03233-z","article-title":"Morpholinated Curcuminoids Against Urinary Bladder Cancer Cells: Synthesis and Anticancer Evaluation","volume":"33","author":"Bakun","year":"2024","journal-title":"Med. Chem. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"135269","DOI":"10.1016\/j.molstruc.2023.135269","article-title":"Novel Fluorocurcuminoid-BF2 Complexes and Their Unlocked Counterparts as Potential Bladder Anticancer Agents\u2014Synthesis, Physicochemical Characterization, and In Vitro Anticancer Activity","volume":"1283","author":"Wierzchowski","year":"2023","journal-title":"J. Mol. Struct."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Sultana, S., Munir, N., Mahmood, Z., Riaz, M., Akram, M., Rebezov, M., Kuderinova, N., Moldabayeva, Z., Shariati, M.A., and Rauf, A. (2021). Molecular Targets for the Management of Cancer Using Curcuma longa Linn. Phytoconstituents: A Review. Biomed. Pharmacother., 135.","DOI":"10.1016\/j.biopha.2020.111078"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"120984","DOI":"10.1016\/j.lfs.2022.120984","article-title":"Curcumin in the Treatment of Urological Cancers: Therapeutic Targets, Challenges and Prospects","volume":"309","author":"Hashemi","year":"2022","journal-title":"Life Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"15173","DOI":"10.3390\/ijms150915173","article-title":"Curcumin Promotes KLF5 Proteasome Degradation through Downregulating YAP\/TAZ in Bladder Cancer Cells","volume":"15","author":"Gao","year":"2014","journal-title":"Int. J. Mol. Sci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3530","DOI":"10.1016\/j.fct.2012.06.045","article-title":"Curcumin-Induced Heme Oxygenase-1 Expression Plays a Negative Role for Its Anti-Cancer Effect in Bladder Cancers","volume":"50","author":"Wu","year":"2012","journal-title":"Food Chem. Toxicol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1007\/s10495-022-01735-y","article-title":"Programmed Cell Death Detection Methods: A Systematic Review and a Categorical Comparison","volume":"27","author":"Kari","year":"2022","journal-title":"Apoptosis"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"9214","DOI":"10.7150\/thno.45125","article-title":"Targeting Phosphatidylserine for Cancer Therapy: Prospects and Challenges","volume":"10","author":"Chang","year":"2020","journal-title":"Theranostics"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1023\/B:APPT.0000031452.75162.75","article-title":"Phosphatidylserine Exposure during Early Primary Necrosis (Oncosis) in JB6 Cells as Evidenced by Immunogold Labeling Technique","volume":"9","author":"Krysko","year":"2004","journal-title":"Apoptosis"},{"key":"ref_30","first-page":"1205","article-title":"Internucleosomal DNA Cleavage Triggered by Plasma Membrane Damage during Necrotic Cell Death. Involvement of Serine but Not Cysteine Proteases","volume":"151","author":"Dong","year":"1997","journal-title":"Am. J. Pathol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e2216531120","DOI":"10.1073\/pnas.2216531120","article-title":"Cell Survival Following Direct Executioner-Caspase Activation","volume":"120","author":"Nano","year":"2023","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Sivandzade, F., Bhalerao, A., and Cucullo, L. (2019). Analysis of the Mitochondrial Membrane Potential Using the Cationic JC-1 Dyeas a Sensitive Fluorescent Probe. Bio Protoc., 9.","DOI":"10.21769\/BioProtoc.3128"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2078","DOI":"10.1016\/j.freeradbiomed.2010.10.691","article-title":"Thioredoxin 1 as a Subcellular Biomarker of Redox Imbalance in Human Prostate Cancer Progression","volume":"49","author":"Shan","year":"2010","journal-title":"Free Radic. Biol. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"9291683","DOI":"10.1155\/2019\/9291683","article-title":"Increased Thioredoxin-1 Expression Promotes Cancer Progression and Predicts Poor Prognosis in Patients with Gastric Cancer","volume":"2019","author":"Shang","year":"2019","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1007\/s00345-021-03900-5","article-title":"Thioredoxin 1 (Trx1) Is Associated with Poor Prognosis in Clear Cell Renal Cell Carcinoma (ccRCC): An Example for the Crucial Role of Redox Signaling in ccRCC","volume":"40","author":"Ribback","year":"2022","journal-title":"World J. Urol."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Liu, X., Dong, X., Hu, Y., and Fang, Y. (2023). Identification of Thioredoxin-1 as a Biomarker of Lung Cancer and Evaluation of Its Prognostic Value Based on Bioinformatics Analysis. Front. Oncol., 13.","DOI":"10.3389\/fonc.2023.1080237"},{"key":"ref_37","first-page":"4293","article-title":"Cellular Levels of Thioredoxin Associated with Drug Sensitivity to Cisplatin, Mitomycin C, Doxorubicin, and Etoposide1","volume":"55","author":"Yokomizo","year":"1995","journal-title":"Cancer Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"e1660","DOI":"10.1038\/cddis.2015.40","article-title":"Akt Phosphorylates Prohibitin 1 to Mediate Its Mitochondrial Localization and Promote Proliferation of Bladder Cancer Cells","volume":"6","author":"Jiang","year":"2015","journal-title":"Cell Death Dis."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Bakun, P., Wysocki, M., Stachowiak, M., Musielak, M., Dlugaszewska, J., Mlynarczyk, D.T., Sobotta, L., Suchorska, W.M., and Goslinski, T. (2024). Quaternized Curcumin Derivative\u2014Synthesis, Physicochemical Characteristics, and Photocytotoxicity, Including Antibacterial Activity after Irradiation with Blue Light. Molecules, 29.","DOI":"10.3390\/molecules29194536"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1016\/j.clon.2021.03.001","article-title":"Hypoxia and Its Modification in Bladder Cancer: Current and Future Perspectives","volume":"33","author":"Lodhi","year":"2021","journal-title":"Clin. Oncol."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Lazewski, D., Kucinska, M., Potapskiy, E., Kuzminska, J., Tezyk, A., Popenda, L., Jurga, S., Teubert, A., Gdaniec, Z., and Kujawski, J. (2022). Novel Short PEG Chain-Substituted Porphyrins: Synthesis, Photochemistry, and In Vitro Photodynamic Activity against Cancer Cells. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms231710029"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1158\/2159-8290.CD-21-1059","article-title":"Hallmarks of Cancer: New Dimensions","volume":"12","author":"Hanahan","year":"2022","journal-title":"Cancer Discov."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2786","DOI":"10.1111\/jcmm.16372","article-title":"A Literature Review on Function and Regulation Mechanism of DKK4","volume":"25","author":"Lou","year":"2021","journal-title":"J. Cell. Mol. Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1186\/s13045-020-00990-3","article-title":"Targeting the Wnt\/\u03b2-Catenin Signaling Pathway in Cancer","volume":"13","author":"Zhang","year":"2020","journal-title":"J. Hematol. Oncol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2249","DOI":"10.1080\/01635581.2020.1856895","article-title":"Targeting Major Signaling Pathways of Bladder Cancer with Phytochemicals: A Review","volume":"73","author":"Chestnut","year":"2021","journal-title":"Nutr. Cancer"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1186\/s13058-019-1097-0","article-title":"HER2 Regulates HIF-2\u03b1 and Drives an Increased Hypoxic Response in Breast Cancer","volume":"21","author":"Jarman","year":"2019","journal-title":"Breast Cancer Res."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Shin, J.W., Kim, S., Ha, S., Choi, B., Kim, S., Im, S.-A., Yoon, T.-Y., and Chung, J. (2019). The HER2 S310F Mutant Can Form an Active Heterodimer with the EGFR, Which Can Be Inhibited by Cetuximab but Not by Trastuzumab as Well as Pertuzumab. Biomolecules, 9.","DOI":"10.3390\/biom9100629"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1002\/cyto.b.21877","article-title":"Evaluation of HER2 Expression in Urothelial Carcinoma Cells as a Biomarker for Circulating Tumor Cells","volume":"98","author":"Nini","year":"2020","journal-title":"Cytom. Part B Clin. Cytom."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Infantino, V., Santarsiero, A., Convertini, P., Todisco, S., and Iacobazzi, V. (2021). Cancer Cell Metabolism in Hypoxia: Role of HIF-1 as Key Regulator and Therapeutic Target. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22115703"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1038\/s41392-023-01332-8","article-title":"Hypoxic Microenvironment in Cancer: Molecular Mechanisms and Therapeutic Interventions","volume":"8","author":"Chen","year":"2023","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Nakayama, K., and Kataoka, N. (2019). Regulation of Gene Expression under Hypoxic Conditions. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20133278"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1038\/s41392-022-01080-1","article-title":"Hypoxia Signaling in Human Health and Diseases: Implications and Prospects for Therapeutics","volume":"7","author":"Luo","year":"2022","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1186\/s12943-019-1089-9","article-title":"Role of Hypoxia in Cancer Therapy by Regulating the Tumor Microenvironment","volume":"18","author":"Jing","year":"2019","journal-title":"Mol. Cancer"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Rakotomalala, A., Escande, A., Furlan, A., Meignan, S., and Lartigau, E. (2021). Hypoxia in Solid Tumors: How Low Oxygenation Impacts the \u201cSix Rs\u201d of Radiotherapy. Front. Endocrinol., 12.","DOI":"10.3389\/fendo.2021.742215"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"100787","DOI":"10.1016\/j.drup.2021.100787","article-title":"Hypoxia as a Driver of Resistance to Immunotherapy","volume":"59","author":"Kopecka","year":"2021","journal-title":"Drug Resist. Updates"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"2103978","DOI":"10.1002\/adma.202103978","article-title":"Conquering the Hypoxia Limitation for Photodynamic Therapy","volume":"33","author":"Wan","year":"2021","journal-title":"Adv. Mater."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"63138","DOI":"10.18632\/oncotarget.11257","article-title":"Hypoxia Enhances the Malignant Nature of Bladder Cancer Cells and Concomitantly Antagonizes Protein O-Glycosylation Extension","volume":"7","author":"Peixoto","year":"2016","journal-title":"Oncotarget"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"616","DOI":"10.7150\/ijbs.24329","article-title":"Role of DKK4 in Tumorigenesis and Tumor Progression","volume":"14","author":"Cai","year":"2018","journal-title":"Int. J. Biol. Sci."},{"key":"ref_59","first-page":"e70700","article-title":"Hypoxia-Inducible Factor 1-Alpha (HIF-1\u03b1) and Cancer: Mechanisms of Tumor Hypoxia and Therapeutic Targeting","volume":"16","author":"Basheeruddin","year":"2024","journal-title":"Cureus"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1089\/ars.2014.5837","article-title":"Oxidative Stress, Redox Signaling, and Autophagy: Cell Death Versus Survival","volume":"21","author":"Burns","year":"2014","journal-title":"Antioxid. Redox Signal."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"80","DOI":"10.3892\/ol.2022.13200","article-title":"Revisiting Therapeutic Strategies for Ovarian Cancer by Focusing on Redox Homeostasis (Review)","volume":"23","author":"Kobayashi","year":"2022","journal-title":"Oncol. Lett."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.semcdb.2020.03.009","article-title":"Mammalian Cell Cycle Cyclins","volume":"107","author":"Malumbres","year":"2020","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"2868","DOI":"10.1002\/1873-3468.13635","article-title":"Triggering Mitosis","volume":"593","author":"Crncec","year":"2019","journal-title":"FEBS Lett."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1186\/s13008-024-00115-z","article-title":"CIP\/KIP and INK4 Families as Hostages of Oncogenic Signaling","volume":"19","year":"2024","journal-title":"Cell Div."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Bitar, S.A., and Gali-Muhtasib, H. (2019). The Role of the Cyclin Dependent Kinase Inhibitor P21cip1\/Waf1 in Targeting Cancer: Molecular Mechanisms and Novel Therapeutics. Cancers, 11.","DOI":"10.3390\/cancers11101475"},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Kreis, N.-N., Louwen, F., and Yuan, J. (2019). The Multifaceted P21 (Cip1\/Waf1\/CDKN1A) in Cell Differentiation, Migration and Cancer Therapy. Cancers, 11.","DOI":"10.3390\/cancers11091220"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.dnarep.2018.07.008","article-title":"Multiple Functions of P27 in Cell Cycle, Apoptosis, Epigenetic Modification and Transcriptional Regulation for the Control of Cell Growth: A Double-Edged Sword Protein","volume":"69","author":"Abbastabar","year":"2018","journal-title":"DNA Repair"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"3451","DOI":"10.1158\/0008-5472.CAN-19-3663","article-title":"P27 as a Transcriptional Regulator: New Roles in Development and Cancer","volume":"80","author":"Razavipour","year":"2020","journal-title":"Cancer Res."},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Mart\u00ednez-Lim\u00f3n, A., Joaquin, M., Caballero, M., Posas, F., and Nadal, E. (2020). de The P38 Pathway: From Biology to Cancer Therapy. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21061913"},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Whitaker, R.H., and Cook, J.G. (2021). Stress Relief Techniques: P38 MAPK Determines the Balance of Cell Cycle and Apoptosis Pathways. Biomolecules, 11.","DOI":"10.3390\/biom11101444"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.3892\/ol.2017.6205","article-title":"Antitumor Effects of Curcumin in Human Bladder Cancer In Vitro","volume":"14","author":"Shi","year":"2017","journal-title":"Oncol. Lett."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Shi, J., Wang, Y., Jia, Z., Gao, Y., Zhao, C., and Yao, Y. (2017). Curcumin Inhibits Bladder Cancer Progression via Regulation of \u03b2-Catenin Expression. Tumour Biol., 39.","DOI":"10.1177\/1010428317702548"},{"key":"ref_73","first-page":"DDT01-1","article-title":"Abstract #DDT01-1: MK-2206: A Potent Oral Allosteric AKT Inhibitor","volume":"69","author":"Yan","year":"2009","journal-title":"Cancer Res."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1956","DOI":"10.1158\/1535-7163.MCT-09-1012","article-title":"MK-2206, an Allosteric Akt Inhibitor, Enhances Antitumor Efficacy by Standard Chemotherapeutic Agents or Molecular Targeted Drugs In Vitro and In Vivo","volume":"9","author":"Hirai","year":"2010","journal-title":"Mol. Cancer Ther."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1002\/ajh.24762","article-title":"Akt Inhibitor MK-2206 in Combination with Bendamustine and Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia: Results from the N1087 Alliance Study","volume":"92","author":"Larsen","year":"2017","journal-title":"Am. J. Hematol."},{"key":"ref_76","first-page":"2943","article-title":"Downregulation of Glucose-Regulated Protein 78 Enhances the Cytotoxic Effects of Curcumin on Human Nasopharyngeal Carcinoma Cells","volume":"42","author":"Yu","year":"2018","journal-title":"Int. J. Mol. Med."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1131","DOI":"10.1111\/bph.13765","article-title":"Curcuminoid EF24 Enhances the Anti-Tumour Activity of Akt Inhibitor MK-2206 through ROS-Mediated Endoplasmic Reticulum Stress and Mitochondrial Dysfunction in Gastric Cancer","volume":"174","author":"Chen","year":"2017","journal-title":"Br. J. Pharmacol."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/30\/2\/295\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T10:27:59Z","timestamp":1759919279000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/30\/2\/295"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,13]]},"references-count":77,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2025,1]]}},"alternative-id":["molecules30020295"],"URL":"https:\/\/doi.org\/10.3390\/molecules30020295","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,13]]}}}