{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T17:11:06Z","timestamp":1785431466958,"version":"3.56.0"},"reference-count":42,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T00:00:00Z","timestamp":1785110400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Istanbul Aydin University Scientific Research Projects Program","award":["BAP 2023\/17"],"award-info":[{"award-number":["BAP 2023\/17"]}]},{"award":["BAP 2023\/17"],"award-info":[{"award-number":["BAP 2023\/17"]}],"id":[{"id":"https:\/\/ror.org\/00qsyw664","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Curr. Issues Mol. Biol.","CIMB"],"abstract":"<jats:p>Gastric cancer remains a leading cause of cancer-related mortality worldwide, largely due to resistance to platinum-based chemotherapy. Indoleamine 2,3-dioxygenase 1 (IDO1) has been implicated in tumor progression and immune evasion; however, its cell-intrinsic role in chemoresistance remains incompletely understood. This study demonstrates that IDO1 functions as a critical regulator of cisplatin sensitivity in gastric cancer cells through a ROS-mediated mechanism. IDO1 expression was suppressed using siRNA in two gastric cancer cell lines, AGS and MKN45, followed by cisplatin treatment. Cell viability, oxidative stress levels, apoptosis-related gene expression, and caspase-3\/7 activity were assessed to evaluate the functional consequences of IDO1 knockdown. IDO1 silencing significantly enhanced cisplatin-induced cytotoxicity in both cell lines, accompanied by increased intracellular reactive oxygen species (ROS) levels and a marked transcriptional shift toward a pro-apoptotic gene expression profile characterized by upregulation of Bax and p53 and downregulation of anti-apoptotic Bcl-2. Critically, functional apoptosis analysis revealed that combined IDO1 silencing and cisplatin treatment markedly increased caspase-3\/7 activity, confirming activation of the execution phase of apoptosis. These findings establish that IDO1 limits apoptotic susceptibility in a cell-intrinsic manner and contributes to cisplatin sensitivity in gastric cancer cells. The mechanistic basis involves IDO1\u2019s ROS-scavenging function: by suppressing IDO1, cells lose their capacity to neutralize ROS, leading to excessive ROS accumulation that triggers mitochondrial dysfunction and activates p53-dependent apoptotic pathways. In conclusion, this study identifies IDO1 as a key regulator of oxidative stress-associated, caspase-dependent apoptosis in gastric cancer and suggests that targeting IDO1 in combination with platinum-based chemotherapy represents a promising strategy to enhance the efficacy of gastric cancer treatment. These findings provide a rationale for clinical translation and provide a foundation for future preclinical and clinical studies.<\/jats:p>","DOI":"10.3390\/cimb48080762","type":"journal-article","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T14:08:14Z","timestamp":1785161294000},"page":"762","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["IDO1 Silencing Enhances Cisplatin Sensitivity in Gastric Cancer Cells via Modulation of Apoptosis and Oxidative Stress"],"prefix":"10.3390","volume":"48","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3250-1427","authenticated-orcid":false,"given":"Negar","family":"Taghavi Pourianazar","sequence":"first","affiliation":[{"name":"Medical Laboratory Techniques, Vocational School of Health Services, Istanbul Aydin University, 34925 Istanbul, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8134-8847","authenticated-orcid":false,"given":"Narin","family":"Abdullah","sequence":"additional","affiliation":[{"name":"Pathology Laboratory Techniques, Vocational School of Health Services, Istanbul Aydin University, 34925 Istanbul, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmet","family":"Ilvan","sequence":"additional","affiliation":[{"name":"Vocational School of Health Services, Istanbul Aydin University, 34925 Istanbul, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1038\/s41571-023-00747-0","article-title":"Global burden of gastric cancer: Epidemiological trends, risk factors, screening and prevention","volume":"20","author":"Thrift","year":"2023","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_2","first-page":"3477","article-title":"Current treatment and recent progress in gastric cancer","volume":"81","author":"Joshi","year":"2021","journal-title":"Cancer Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1016\/j.ejphar.2014.07.025","article-title":"Cisplatin in cancer therapy: Molecular mechanisms of action","volume":"740","author":"Dasari","year":"2014","journal-title":"Eur. J. Pharmacol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2997","DOI":"10.1073\/pnas.1614430113","article-title":"Cisplatin DNA damage and repair maps of the human genome","volume":"113","author":"Hu","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e478s","DOI":"10.6061\/clinics\/2018\/e478s","article-title":"DNA repair pathways and cisplatin resistance: An intimate relationship","volume":"73","author":"Rocha","year":"2018","journal-title":"Clinics"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"6099","DOI":"10.1111\/febs.16086","article-title":"Indoleamine 2, 3-dioxygenase 1 (IDO1): An up-to-date overview of an eclectic immunoregulatory enzyme","volume":"289","author":"Pallotta","year":"2022","journal-title":"FEBS J."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1038\/cmi.2017.143","article-title":"IDO1 in cancer: A Gemini of immune checkpoints","volume":"15","author":"Zhai","year":"2018","journal-title":"Cell. Mol. Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"200ra116","DOI":"10.1126\/scitranslmed.3006504","article-title":"Up-regulation of PD-L1, IDO, and T regs in the melanoma tumor microenvironment is driven by CD8+ T cells","volume":"5","author":"Spranger","year":"2013","journal-title":"Sci. Transl. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1371","DOI":"10.1038\/s12276-023-01028-7","article-title":"Immune regulation through tryptophan metabolism","volume":"55","author":"Seo","year":"2023","journal-title":"Exp. Mol. Med."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Wang, H., Luo, Y., Ran, R., Li, X., Ling, H., Wen, F., and Yu, T. (2022). IDO1 modulates the sensitivity of epithelial ovarian cancer cells to cisplatin through ROS\/p53-dependent apoptosis. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms231912002"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3889","DOI":"10.1038\/onc.2008.35","article-title":"Immune escape as a fundamental trait of cancer: Focus on IDO","volume":"27","author":"Prendergast","year":"2008","journal-title":"Oncogene"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e2011170118","DOI":"10.1073\/pnas.2011170118","article-title":"IDO1 scavenges reactive oxygen species in myeloid-derived suppressor cells","volume":"118","author":"Ju","year":"2021","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1038\/s41419-022-05021-2","article-title":"IDO1 plays a tumor-promoting role via MDM2-mediated suppression of the p53 pathway in diffuse large B-cell lymphoma","volume":"13","author":"Sun","year":"2022","journal-title":"Cell Death Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1242\/jcs.031682","article-title":"Control of mitochondrial apoptosis by the Bcl-2 family","volume":"122","author":"Brunelle","year":"2009","journal-title":"J. Cell Sci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1158\/1541-7786.MCR-19-0239","article-title":"Targeting the kynurenine pathway for the treatment of cisplatin-resistant lung cancer","volume":"18","author":"Nguyen","year":"2020","journal-title":"Mol. Cancer Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/j.it.2016.01.002","article-title":"IDO in the tumor microenvironment: Inflammation, counter-regulation, and tolerance","volume":"37","author":"Munn","year":"2016","journal-title":"Trends Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1396","DOI":"10.1038\/sj.cdd.4401963","article-title":"Mitochondrial outer membrane permeabilization during apoptosis: The innocent bystander scenario","volume":"13","author":"Chipuk","year":"2006","journal-title":"Cell Death Differ."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1038\/nrm2952","article-title":"Mitochondria and cell death: Outer membrane permeabilization and beyond","volume":"11","author":"Tait","year":"2010","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1016\/S0092-8674(00)81871-1","article-title":"p53, the cellular gatekeeper for growth and division","volume":"88","author":"Levine","year":"1997","journal-title":"Cell"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2831","DOI":"10.1101\/gad.12.18.2831","article-title":"DNA damage activates p53 through a phosphorylation-acetylation cascade","volume":"12","author":"Sakaguchi","year":"1998","journal-title":"Genes Dev."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1016\/j.molcel.2017.05.015","article-title":"ATM, ATR, and DNA-PK: The trinity at the heart of the DNA damage response","volume":"66","author":"Blackford","year":"2017","journal-title":"Mol. Cell"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"6236","DOI":"10.1093\/emboj\/cdf616","article-title":"MDM2-HDAC1-mediated deacetylation of p53 is required for its degradation","volume":"21","author":"Ito","year":"2002","journal-title":"EMBO J."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1669","DOI":"10.1089\/ars.2010.3644","article-title":"p53, oxidative stress, and aging","volume":"15","author":"Liu","year":"2011","journal-title":"Antioxid. Redox Signal."},{"key":"ref_24","first-page":"47","article-title":"Cytoplasmic functions of the tumour suppressor p53","volume":"10","author":"Green","year":"2009","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"632","DOI":"10.1002\/jcb.24709","article-title":"Apoptosis regulation at the mitochondrial outer membrane","volume":"115","author":"Gillies","year":"2014","journal-title":"J. Cell. Biochem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"6332","DOI":"10.4049\/jimmunol.166.10.6332","article-title":"Antioxidants inhibit indoleamine 2,3-dioxygenase in IFN-gamma-activated human macrophages: Posttranslational regulation by pyrrolidine dithiocarbamate","volume":"166","author":"Thomas","year":"2001","journal-title":"J. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"5435","DOI":"10.1158\/0008-5472.CAN-12-0569","article-title":"Tryptophan catabolism in cancer: Beyond IDO and tryptophan depletion","volume":"72","author":"Platten","year":"2012","journal-title":"Cancer Res."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Brentnall, M., Rodriguez-Menocal, L., De Guevara, R.L., Cepero, E., and Boise, L.H. (2013). Caspase-9, caspase-3 and caspase-7 have distinct roles during intrinsic apoptosis. BMC Cell Biol., 14.","DOI":"10.1186\/1471-2121-14-32"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.coi.2020.12.001","article-title":"Tryptophan and indole metabolism in immune regulation","volume":"70","author":"Fiore","year":"2021","journal-title":"Curr. Opin. Immunol."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Kim, M., and Tomek, P. (2021). Tryptophan: A rheostat of cancer immune escape mediated by immunosuppressive enzymes IDO1 and TDO. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.636081"},{"key":"ref_31","first-page":"490","article-title":"Immune-regulated IDO1-dependent tryptophan metabolism","volume":"33","author":"Newman","year":"2021","journal-title":"Cell Metab."},{"key":"ref_32","unstructured":"Stone, T.W., Darlington, L.G., and Stoy, N. (2023). Modulation of T cells by tryptophan metabolites in the context of cancer and neurodegenerative diseases. Front. Immunol., 14."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1038\/nrd2803","article-title":"Targeting cancer cells by ROS-mediated mechanisms: A radical therapeutic approach? Nature reviews","volume":"8","author":"Trachootham","year":"2009","journal-title":"Drug Discov."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1038\/nrd4002","article-title":"Modulation of oxidative stress as an anticancer strategy","volume":"12","author":"Gorrini","year":"2013","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1016\/j.freeradbiomed.2009.12.022","article-title":"Reactive oxygen species, cellular redox systems, and apoptosis","volume":"48","author":"Circu","year":"2010","journal-title":"Free Radic. Biol. Med."},{"key":"ref_36","first-page":"5379","article-title":"IDO1: An important immunotherapy target in cancer treatment","volume":"10","author":"Li","year":"2017","journal-title":"OncoTargets Ther."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1462","DOI":"10.1158\/1078-0432.CCR-18-2882","article-title":"Reimagining IDO pathway inhibition in cancer immunotherapy via downstream focus on the tryptophan\u2013kynurenine\u2013aryl hydrocarbon axis","volume":"25","author":"Labadie","year":"2019","journal-title":"Clin. Cancer Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"e1777625","DOI":"10.1080\/2162402X.2020.1777625","article-title":"Trial watch: IDO inhibitors in cancer therapy","volume":"9","author":"Galluzzi","year":"2020","journal-title":"OncoImmunology"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1186\/s13045-021-01080-8","article-title":"Indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors in clinical trials for cancer immunotherapy","volume":"14","author":"Tang","year":"2021","journal-title":"J. Hematol. Oncol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.1016\/S1470-2045(19)30274-8","article-title":"Epacadostat plus pembrolizumab versus placebo plus pembrolizumab in patients with unresectable or metastatic melanoma (ECHO-301\/KEYNOTE-252): A phase 3, randomised, double-blind study","volume":"20","author":"Long","year":"2019","journal-title":"Lancet Oncol."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Tokito, T., Kolesnik, O., S\u00f8rensen, J., Artac, M., Quintela, M.L., Lee, J.S., Hussein, M., Pless, M., Paz-Ares, L., and Leopold, L. (2024). Epacadostat plus pembrolizumab versus placebo plus pembrolizumab as first-line treatment for metastatic non-small cell lung cancer with high levels of programmed death-ligand 1: A randomized, double-blind phase 2 study. BMC Cancer, 23.","DOI":"10.1186\/s12885-023-11203-8"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Lara, P.N., Villanueva, L., Ibanez, C., Erman, M., Lee, J.L., Heinrich, D., Lipatov, O.N., Gedye, C., Gokmen, E., and Acevedo, A. (2024). A randomized, open-label, phase 3 trial of pembrolizumab plus epacadostat versus sunitinib or pazopanib as first-line treatment for metastatic renal cell carcinoma (KEYNOTE-679\/ECHO-302). BMC Cancer, 23.","DOI":"10.1186\/s12885-023-10971-7"}],"container-title":["Current Issues in Molecular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1467-3045\/48\/8\/762\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T14:40:33Z","timestamp":1785163233000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1467-3045\/48\/8\/762"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,27]]},"references-count":42,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["cimb48080762"],"URL":"https:\/\/doi.org\/10.3390\/cimb48080762","relation":{},"ISSN":["1467-3045"],"issn-type":[{"value":"1467-3045","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,27]]}}}