{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,9]],"date-time":"2026-05-09T21:45:03Z","timestamp":1778363103062,"version":"3.51.4"},"reference-count":96,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T00:00:00Z","timestamp":1767744000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Faculty of medicine, Chaing Mai University","award":["Agree-2568-0143-000743"],"award-info":[{"award-number":["Agree-2568-0143-000743"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background\/Objectives: Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide, and the development of effective therapies with improved safety profiles is urgently needed. The hydrodistillation residue extract of Syzygium aromaticum (SA) is rich in phenolic compounds, including ellagic acid and gallic acid, which are known for their antioxidant and anticancer properties. This study aimed to evaluate the anticancer efficacy, safety, and metabolic effects of SA extract in CRC models. Methods: The anticancer activity of SA was investigated using in vitro and in vivo approaches. Human colorectal cancer HCT116-Red-FLuc cells were used to assess cytotoxicity, selectivity, and dose- and time-dependent effects. In vivo efficacy was evaluated in a CRC xenograft mouse model using tumor volume measurement, micro-ultrasound imaging, and bioluminescence analysis. Hematological and blood biochemical parameters were analyzed to assess systemic safety. Untargeted metabolomic profiling was performed to explore metabolic alterations associated with SA treatment. Results: SA inhibited HCT116-Red-FLuc cell proliferation in a dose- and time-dependent manner and demonstrated selective cytotoxicity toward cancer cells, with a selectivity index of 4.41 at 24 h, although selectivity declined with prolonged exposure. In xenograft mice, SA significantly suppressed tumor growth and reduced metastatic incidence. The 500 mg\/kg dose (SA500) showed the greatest antitumor efficacy while maintaining normal hematological and biochemical profiles, indicating a favorable safety margin compared with 5-fluorouracil (5FU). The 1000 mg\/kg dose (SA1000) induced marked suppression of Ki-67, Bcl-2, and CD31 expression and enhanced apoptosis. Metabolomic analysis identified 44 differential metabolites related to fatty acid, amino acid, and nucleotide metabolism. Conclusions: These findings suggest that SA extract exerts significant antitumor activity against CRC with improved tolerability compared with conventional chemotherapy, supporting its potential as a complementary natural therapeutic candidate.<\/jats:p>","DOI":"10.3390\/pharmaceutics18010079","type":"journal-article","created":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T14:02:51Z","timestamp":1767794571000},"page":"79","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Antitumor Activity of the Ethanolic Extract from Syzygium aromaticum in Colorectal Cancer Xenograft Mice"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5974-7278","authenticated-orcid":false,"given":"Thunyatorn","family":"Yimsoo","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand"},{"name":"Laboratory Animal Center, Office of Advanced Science and Technology, Thammasat University, Pathum Thani 12120, Thailand"},{"name":"Thammasat University Research Unit in Mechanisms of Drug Action and Molecular Imaging, Thammasat University, Pathum Thani 12120, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5547-2230","authenticated-orcid":false,"given":"Weerakit","family":"Taychaworaditsakul","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hathaichanok","family":"Chuntakaruk","sequence":"additional","affiliation":[{"name":"Center for Artificial Intelligence in Medicine, Research Affairs, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand"},{"name":"Center of Excellence in Computational Molecular Biology, Chulalongkorn University, Bangkok 10330, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Worapapar","family":"Treesuppharat","sequence":"additional","affiliation":[{"name":"Thammasat University Research Unit in Mechanisms of Drug Action and Molecular Imaging, Thammasat University, Pathum Thani 12120, Thailand"},{"name":"Drug Discovery and Development Center, Office of Advanced Science and Technology, Pathum Thani 12120, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1116-4636","authenticated-orcid":false,"given":"Sumet","family":"Kongkiatpaiboon","sequence":"additional","affiliation":[{"name":"Drug Discovery and Development Center, Office of Advanced Science and Technology, Pathum Thani 12120, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Apipu","family":"Ariyachayut","sequence":"additional","affiliation":[{"name":"Thammasat University Research Unit in Mechanisms of Drug Action and Molecular Imaging, Thammasat University, Pathum Thani 12120, Thailand"},{"name":"Drug Discovery and Development Center, Office of Advanced Science and Technology, Pathum Thani 12120, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sunee","family":"Chansakaow","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Chiang Mai University, Chiang Mai 50200, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9044-3777","authenticated-orcid":false,"given":"Teera","family":"Chewonarin","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Parirat","family":"Khonsung","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seewaboon","family":"Sireeratawong","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand"},{"name":"Clinical Research Center for Food and Herbal Product Trials and Development (CR-FAH), Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"78","DOI":"10.3393\/ac.2020.01.07","article-title":"Current Colorectal Cancer in Thailand","volume":"36","author":"Lohsiriwat","year":"2020","journal-title":"Ann. Coloproctol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/S1470-2045(24)00600-4","article-title":"Colorectal cancer incidence trends in younger versus older adults: An analysis of population-based cancer registry data","volume":"26","author":"Sung","year":"2025","journal-title":"Lancet Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1386","DOI":"10.1093\/annonc\/mdw235","article-title":"ESMO consensus guidelines for the management of patients with metastatic colorectal cancer","volume":"27","author":"Cervantes","year":"2016","journal-title":"Ann. Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.1056\/NEJMoa1305275","article-title":"Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer","volume":"369","author":"Douillard","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"vi64","DOI":"10.1093\/annonc\/mdt354","article-title":"Early colon cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up","volume":"24","author":"Labianca","year":"2013","journal-title":"Ann. Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1200\/JCO.2005.03.0106","article-title":"OPTIMOX1: A randomized study of FOLFOX4 or FOLFOX7 with oxaliplatin in a stop-and-Go fashion in advanced colorectal cancer\u2014A GERCOR study","volume":"24","author":"Tournigand","year":"2006","journal-title":"J. Clin. Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e27918","DOI":"10.1097\/MD.0000000000027918","article-title":"Synergistic effects of herbal medicines and anticancer drugs: A protocol for systematic review and meta-analysis","volume":"100","author":"Cheon","year":"2021","journal-title":"Medicine"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Delgado-Gonzalez, P., Garza-Trevino, E.N., de la Garza Kalife, D.A., Quiroz Reyes, A., and Hernandez-Tobias, E.A. (2023). Bioactive Compounds of Dietary Origin and Their Influence on Colorectal Cancer as Chemoprevention. Life, 13.","DOI":"10.3390\/life13101977"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Bucciantini, M., Leri, M., Nardiello, P., Casamenti, F., and Stefani, M. (2021). Olive Polyphenols: Antioxidant and Anti-Inflammatory Properties. Antioxidants, 10.","DOI":"10.3390\/antiox10071044"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Mileo, A.M., Nistico, P., and Miccadei, S. (2019). Polyphenols: Immunomodulatory and Therapeutic Implication in Colorectal Cancer. Front. Immunol., 10.","DOI":"10.3389\/fimmu.2019.00729"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"247","DOI":"10.3727\/096504014X13946388748910","article-title":"Clove extract inhibits tumor growth and promotes cell cycle arrest and apoptosis","volume":"21","author":"Liu","year":"2014","journal-title":"Oncol. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2329144","DOI":"10.1080\/19476337.2024.2329144","article-title":"Total phenolic and flavonoid content, antioxidant activity and characteristics of a chocolate beverage incorporated with encapsulated clove bud extract","volume":"22","author":"Indiarto","year":"2024","journal-title":"CyTA\u2014J. Food"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"273","DOI":"10.37349\/etat.2023.00134","article-title":"Anticancer of genus Syzygium: A systematic review","volume":"4","author":"Abdulrahman","year":"2023","journal-title":"Explor. Target. Antitumor Ther."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"6439","DOI":"10.2147\/IJN.S211047","article-title":"Anticancer and antibacterial effects of a clove bud essential oil-based nanoscale emulsion system","volume":"14","author":"Nirmala","year":"2019","journal-title":"Int. J. Nanomed."},{"key":"ref_15","first-page":"1","article-title":"Anti-Tumor, Antioxidant and Antimicrobial and the Phenolic Constituentsof Clove Flower Buds (Syzygium aromaticum)","volume":"2014","author":"Awad","year":"2014","journal-title":"J. Microb. Biochem. Technol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Yimsoo, T., Taychaworaditsakul, W., Chansakaow, S., Kongkiatpaiboon, S., Tayana, N., Chewonarin, T., Khonsung, P., and Sireeratawong, S. (2025). The Effect of the Ethanolic Extracts from Syzygium aromaticum and Syzygium nervosum on Antiproliferative Activity and Apoptosis in HCT116 and HT-29 Cells. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26146826"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"136","DOI":"10.4103\/JMAU.JMAU_51_18","article-title":"In vivo Bioluminescence-Based Monitoring of Liver Metastases from Colorectal Cancer: An Experimental Model","volume":"7","author":"Magistri","year":"2019","journal-title":"J. Microsc. Ultrastruct."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1098\/rsfs.2011.0037","article-title":"Micro-ultrasound for preclinical imaging","volume":"1","author":"Foster","year":"2011","journal-title":"Interface Focus"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"891","DOI":"10.7863\/jum.2010.29.6.891","article-title":"Volume of preclinical xenograft tumors is more accurately assessed by ultrasound imaging than manual caliper measurements","volume":"29","author":"Ayers","year":"2010","journal-title":"J. Ultrasound Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1181","DOI":"10.1080\/004982599238047","article-title":"\u2018Metabonomics\u2019: Understanding the metabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR spectroscopic data","volume":"29","author":"Nicholson","year":"1999","journal-title":"Xenobiotica"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1038\/nrm3314","article-title":"Metabolomics: The apogee of the omics trilogy","volume":"13","author":"Patti","year":"2012","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/s12953-025-00241-8","article-title":"Mass-spectrometry based metabolomics: An overview of workflows, strategies, data analysis and applications","volume":"23","author":"Hajnajafi","year":"2025","journal-title":"Proteome Sci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3675","DOI":"10.1038\/s41467-024-48009-6","article-title":"MetaboAnalystR 4.0: A unified LC-MS workflow for global metabolomics","volume":"15","author":"Pang","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1447","DOI":"10.1016\/j.biopha.2018.08.130","article-title":"Effects of berberine on tumor growth and intestinal permeability in HCT116 tumor-bearing mice using polyamines as targets","volume":"107","author":"Wu","year":"2018","journal-title":"Biomed. Pharmacother."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"180","DOI":"10.3390\/s110100180","article-title":"In vivo bioluminescent imaging (BLI): Noninvasive visualization and interrogation of biological processes in living animals","volume":"11","author":"Close","year":"2011","journal-title":"Sensors"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3698","DOI":"10.1118\/1.4735039","article-title":"SU-E-J-198: Bioluminescence Monitoring of Metastatic Breast Cancer: Quantitative Assessment of Radiation Treatment Effects and Tracking of Tumor Cells","volume":"39","author":"Park","year":"2012","journal-title":"Med. Phys."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"102088","DOI":"10.1016\/j.toxrep.2025.102088","article-title":"Mild and reversible nephrotoxicity following repeated administration of damnacanthal in nude mice","volume":"15","author":"Kotsaouppara","year":"2025","journal-title":"Toxicol. Rep."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"W398","DOI":"10.1093\/nar\/gkae253","article-title":"MetaboAnalyst 6.0: Towards a unified platform for metabolomics data processing, analysis and interpretation","volume":"52","author":"Pang","year":"2024","journal-title":"Nucleic Acids Res."},{"key":"ref_29","unstructured":"Charles River Laboratories (2025, November 01). BALB\/c Nude Mouse Hematology and Clinical Pathology Data. Available online: https:\/\/assets.www.criver.com\/storage-account-container\/resources\/doc_a\/BALBcNudeMouseClinicalPathologyData.pdf."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Irakli, M., Skendi, A., Bouloumpasi, E., Chatzopoulou, P., and Biliaderis, C.G. (2021). LC-MS Identification and Quantification of Phenolic Compounds in Solid Residues from the Essential Oil Industry. Antioxidants, 10.","DOI":"10.3390\/antiox10122016"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"\u010ci\u017em\u00e1rikov\u00e1, M., Michalkov\u00e1, R., Mirossay, L., Moj\u017ei\u0161ov\u00e1, G., Zigov\u00e1, M., Bardel\u010d\u00edkov\u00e1, A., and Moj\u017ei\u0161, J. (2023). Ellagic Acid and Cancer Hallmarks: Insights from Experimental Evidence. Biomolecules, 13.","DOI":"10.3390\/biom13111653"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2077","DOI":"10.1002\/tox.24087","article-title":"Gallic acid attenuates metastatic potential of human colorectal cancer cells through the miR-1247-3p-modulated integrin\/FAK axis","volume":"39","author":"Huang","year":"2024","journal-title":"Environ. Toxicol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/j.jep.2019.02.047","article-title":"Antiproliferative potential from aqueous Viscum album L. preparations and their main constituents in comparison with ricin and purothionin on human cancer cells","volume":"236","author":"Felenda","year":"2019","journal-title":"J. Ethnopharmacol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1016\/j.jff.2016.02.011","article-title":"Turmeric ethanolic extract possesses stronger inhibitory activities on colon tumour growth than curcumin\u2014The importance of turmerones","volume":"22","author":"Yue","year":"2016","journal-title":"J. Funct. Foods"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Wang, W., Wang, S., Liu, Y., Wang, X., Nie, J., Meng, X., and Zhang, Y. (2022). Ellagic Acid: A Dietary-Derived Phenolic Compound for Drug Discovery in Mild Cognitive Impairment. Front. Aging Neurosci., 14.","DOI":"10.3389\/fnagi.2022.925855"},{"key":"ref_36","first-page":"225","article-title":"Pharmacological effects of gallic acid in health and diseases: A mechanistic review","volume":"22","author":"Kahkeshani","year":"2019","journal-title":"Iran. J. Basic Med. Sci."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Abdullah, H., Ismail, I., Suppian, R., and Zakaria, N.M. (2023). Natural Gallic Acid and Methyl Gallate Induces Apoptosis in Hela Cells through Regulation of Intrinsic and Extrinsic Protein Expression. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24108495"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Nouri, Z., Fakhri, S., Nouri, K., Wallace, C.E., Farzaei, M.H., and Bishayee, A. (2020). Targeting Multiple Signaling Pathways in Cancer: The Rutin Therapeutic Approach. Cancers, 12.","DOI":"10.3390\/cancers12082276"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Ling, T., Lang, W.H., Maier, J., Quintana Centurion, M., and Rivas, F. (2019). Cytostatic and Cytotoxic Natural Products against Cancer Cell Models. Molecules, 24.","DOI":"10.3390\/molecules24102012"},{"key":"ref_40","first-page":"659","article-title":"Improvement of the Selectivity Index (SI) and Cytotoxicity Activity of Doxorubicin Drug by Panax ginseng Plant Extract","volume":"76","year":"2021","journal-title":"Arch. Razi Inst."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Rashidi, M., Seghatoleslam, A., Namavari, M., Muhammadi, A., Fahmidehkar, M.A., Ramezani, A., Eftekhar, E., Hosseini, A., Erfani, N., and Fakher, S. (Int. J. Cancer Manag., 2017). Selective Cytotoxicity and Apoptosis-Induction of Cyrtopodion Scabrum Extract Against Digestive Cancer Cell Lines, Int. J. Cancer Manag., in press.","DOI":"10.5812\/ijcm.8633"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3952","DOI":"10.3748\/wjg.v22.i15.3952","article-title":"Gallic acid induced apoptotic events in HCT-15 colon cancer cells","volume":"22","author":"Subramanian","year":"2016","journal-title":"World J. Gastroenterol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"613","DOI":"10.3892\/ijo.2017.3843","article-title":"Multiple effects of ellagic acid on human colorectal carcinoma cells identified by gene expression profile analysis","volume":"50","author":"Zhao","year":"2017","journal-title":"Int. J. Oncol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1007\/s40495-016-0076-8","article-title":"Challenges and Opportunities with Predicting in Vivo Phase II Metabolism via Glucuronidation from in Vitro Data","volume":"2","author":"Ge","year":"2016","journal-title":"Curr. Pharmacol. Rep."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1124\/dmd.110.035873","article-title":"Similarities and differences in the expression of drug-metabolizing enzymes between human hepatic cell lines and primary human hepatocytes","volume":"39","author":"Guo","year":"2011","journal-title":"Drug Metab. Dispos."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Moreau, M., Mallick, P., Smeltz, M., Haider, S., Nicolas, C.I., Pendse, S.N., Leonard, J.A., Linakis, M.W., McMullen, P.D., and Clewell, R.A. (2022). Considerations for Improving Metabolism Predictions for In Vitro to In Vivo Extrapolation. Front. Toxicol., 4.","DOI":"10.3389\/ftox.2022.894569"},{"key":"ref_47","first-page":"90","article-title":"Xenograft Tumor Volume Measurement in Nude Mice: Estimation of 3D Ultrasound Volume Measurements Based on Manual Caliper Measurements","volume":"4","author":"Baris","year":"2020","journal-title":"J. Basic Clin. Health Sci."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1158\/0008-5472.CAN-10-2666","article-title":"Pharmacokinetic modeling of tumor bioluminescence implicates efflux, and not influx, as the bigger hurdle in cancer drug therapy","volume":"71","author":"Sim","year":"2011","journal-title":"Cancer Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1007\/s11418-024-01821-2","article-title":"Urolithin C suppresses colorectal cancer progression via the AKT\/mTOR pathway","volume":"78","author":"Yang","year":"2024","journal-title":"J. Nat. Med."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"638","DOI":"10.3892\/etm.2021.10070","article-title":"Gallic acid suppresses colon cancer proliferation by inhibiting SRC and EGFR phosphorylation","volume":"21","author":"Lin","year":"2021","journal-title":"Exp. Ther. Med."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1002\/iub.572","article-title":"The monocarboxylate transporter family\u2014Role and regulation","volume":"64","author":"Halestrap","year":"2012","journal-title":"IUBMB Life"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"10315","DOI":"10.1158\/0008-5472.CAN-08-1984","article-title":"Overexpression of OATP1B3 confers apoptotic resistance in colon cancer","volume":"68","author":"Lee","year":"2008","journal-title":"Cancer Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1186\/2052-8426-2-15","article-title":"Role of solute carriers in response to anticancer drugs","volume":"2","author":"Li","year":"2014","journal-title":"Mol. Cell. Ther."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"97","DOI":"10.5455\/jice.20160118062127","article-title":"Natural polyphenols: Influence on membrane transporters","volume":"5","author":"Hussain","year":"2016","journal-title":"J. Intercult. Ethnopharmacol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1186\/s12967-025-06640-x","article-title":"The interplay between driver mutation and oxidative stress in colorectal cancer: From pathogenesis to therapeutics","volume":"23","author":"Huang","year":"2025","journal-title":"J. Transl. Med."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1186\/s13045-020-00949-4","article-title":"The MAPK and AMPK signalings: Interplay and implication in targeted cancer therapy","volume":"13","author":"Yuan","year":"2020","journal-title":"J. Hematol. Oncol."},{"key":"ref_57","first-page":"528","article-title":"High expression of organic anion transporter 2 and organic cation transporter 2 is an independent predictor of good outcomes in patients with metastatic colorectal cancer treated with FOLFOX-based chemotherapy","volume":"4","author":"Tashiro","year":"2014","journal-title":"Am. J. Cancer Res."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1158\/1535-7163.MCT-04-0291","article-title":"The multidrug resistance protein 5 (ABCC5) confers resistance to 5-fluorouracil and transports its monophosphorylated metabolites","volume":"4","author":"Pratt","year":"2005","journal-title":"Mol. Cancer Ther."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Marin, J.J.G., Monte, M.J., Macias, R.I.R., Romero, M.R., Herraez, E., Asensio, M., Ortiz-Rivero, S., Cives-Losada, C., Di Giacomo, S., and Gonzalez-Gallego, J. (2022). Expression of Chemoresistance-Associated ABC Proteins in Hepatobiliary, Pancreatic and Gastrointestinal Cancers. Cancers, 14.","DOI":"10.3390\/cancers14143524"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"e11171","DOI":"10.1016\/j.heliyon.2022.e11171","article-title":"P-glycoprotein and cancer: What do we currently know?","volume":"8","author":"Muriithi","year":"2022","journal-title":"Heliyon"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"C699","DOI":"10.1152\/ajpcell.00412.2025","article-title":"Strategies for overcoming ABC transporter-mediated multidrug resistance in colorectal cancer","volume":"329","author":"Reedijk","year":"2025","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_62","first-page":"48","article-title":"Anti-Cancer Therapy: Chlorogenic Acid, Gallic Acid and Ellagic Acid in Synergism","volume":"12","author":"Moon","year":"2017","journal-title":"IOSR J. Pharm. Biol. Sci."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Lee, J., Kim, Y.S., Lee, J., Heo, S.C., Lee, K.L., Choi, S.W., and Kim, Y. (2016). Walnut Phenolic Extract and Its Bioactive Compounds Suppress Colon Cancer Cell Growth by Regulating Colon Cancer Stemness. Nutrients, 8.","DOI":"10.3390\/nu8070439"},{"key":"ref_64","first-page":"401","article-title":"Normal organ weights, serum chemistry, hematology, and cecal and nasopharyngeal bacterial cultures in the gray short-tailed opossum (Monodelphis domestica)","volume":"49","author":"Evans","year":"2010","journal-title":"J. Am. Assoc. Lab. Anim. Sci."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"6493286","DOI":"10.1155\/2019\/6493286","article-title":"Histological, Biochemical, and Hematological Effects of Goniothalamin on Selective Internal Organs of Male Sprague-Dawley Rats","volume":"2019","author":"Kaid","year":"2019","journal-title":"J. Toxicol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1002\/ame2.12041","article-title":"Reference values for selected hematological, biochemical and physiological parameters of Sprague-Dawley rats at the Animal House, Faculty of Medicine, University of Colombo, Sri Lanka","volume":"1","author":"Delwatta","year":"2018","journal-title":"Anim. Model. Exp. Med."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"He, Q., Su, G., Liu, K., Zhang, F., Jiang, Y., Gao, J., Liu, L., Jiang, Z., Jin, M., and Xie, H. (2017). Sex-specific reference intervals of hematologic and biochemical analytes in Sprague-Dawley rats using the nonparametric rank percentile method. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0189837"},{"key":"ref_68","first-page":"e58126","article-title":"Assessing the Hepatotoxic Effects of Fluoropyrimidine Chemotherapy in Male Iraqi Colorectal Cancer Patients","volume":"16","author":"Challoob","year":"2024","journal-title":"Cureus"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"15784","DOI":"10.3390\/ijms131215784","article-title":"Brain metastases from colorectal cancer: Microenvironment and molecular mechanisms","volume":"13","author":"Zang","year":"2012","journal-title":"Int. J. Mol. Sci."},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Jaiswara, P.K., and Shukla, S.K. (2023). Chemotherapy-Mediated Neuronal Aberration. Pharmaceuticals, 16.","DOI":"10.3390\/ph16081165"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"S307","DOI":"10.4103\/0975-7406.100281","article-title":"Applications of immunohistochemistry","volume":"4","author":"Duraiyan","year":"2012","journal-title":"J. Pharm. Bioallied Sci."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"411","DOI":"10.4132\/jptm.2016.08.08","article-title":"Immunohistochemistry for Pathologists: Protocols, Pitfalls, and Tips","volume":"50","author":"Kim","year":"2016","journal-title":"J. Pathol. Transl. Med."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1354\/vp.42-4-405","article-title":"Technical aspects of immunohistochemistry","volume":"42","year":"2005","journal-title":"Vet. Pathol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1177\/002215549804600306","article-title":"TUNEL Apoptotic Cell Detection in Tissue Sections: Critical Evaluation and Improvement","volume":"46","author":"Guillermet","year":"1998","journal-title":"J. Histochem. Cytochem."},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Mirzayans, R., and Murray, D. (2020). Do TUNEL and Other Apoptosis Assays Detect Cell Death in Preclinical Studies?. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21239090"},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Sanchez-Martin, V., Plaza-Calonge, M.D.C., Soriano-Lerma, A., Ortiz-Gonzalez, M., Linde-Rodriguez, A., Perez-Carrasco, V., Ramirez-Macias, I., Cuadros, M., Gutierrez-Fernandez, J., and Murciano-Calles, J. (2022). Gallic Acid: A Natural Phenolic Compound Exerting Antitumoral Activities in Colorectal Cancer via Interaction with G-Quadruplexes. Cancers, 14.","DOI":"10.3390\/cancers14112648"},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Donisi, I., Balestrieri, A., Del Vecchio, V., Bifulco, G., Balestrieri, M.L., Campanile, G., and D\u2019Onofrio, N. (2025). l-Carnitine and Acetyl-l-Carnitine Induce Metabolism Alteration and Mitophagy-Related Cell Death in Colorectal Cancer Cells. Nutrients, 17.","DOI":"10.3390\/nu17061010"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1510","DOI":"10.1093\/jn\/135.6.1510","article-title":"Increased Carnitine-Dependent Fatty Acid Uptake into Mitochondria of Human Colon Cancer Cells Induces Apoptosis","volume":"135","author":"Wenzel","year":"2005","journal-title":"J. Nutr."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"C1278","DOI":"10.1152\/ajpcell.00319.2019","article-title":"The fatty acid derivative palmitoylcarnitine abrogates colorectal cancer cell survival by depleting glutathione","volume":"317","author":"Turnbull","year":"2019","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1792","DOI":"10.1038\/s41467-025-56678-0","article-title":"Ketogenic diet suppresses colorectal cancer through the gut microbiome long chain fatty acid stearate","volume":"16","author":"Tsenkova","year":"2025","journal-title":"Nat. Commun."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1892","DOI":"10.1016\/j.apsb.2024.01.002","article-title":"A medium chain fatty acid, 6-hydroxyhexanoic acid (6-HHA), protects against obesity and insulin resistance","volume":"14","author":"Sebag","year":"2024","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1016\/j.chembiol.2016.04.012","article-title":"Foamy Monocytes Are Enriched in cis-7-Hexadecenoic Fatty Acid (16:1n-9), a Possible Biomarker for Early Detection of Cardiovascular Disease","volume":"23","author":"Guijas","year":"2016","journal-title":"Cell Chem. Biol."},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Scanferlato, R., Bortolotti, M., Sansone, A., Chatgilialoglu, C., Polito, L., De Spirito, M., Maulucci, G., Bolognesi, A., and Ferreri, C. (2019). Hexadecenoic Fatty Acid Positional Isomers and De Novo PUFA Synthesis in Colon Cancer Cells. Int. J. Mol. Sci., 20.","DOI":"10.20944\/preprints201902.0082.v1"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1194\/jlr.M079145","article-title":"Occurrence and biological activity of palmitoleic acid isomers in phagocytic cells","volume":"59","author":"Astudillo","year":"2018","journal-title":"J. Lipid Res."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1016\/j.bbalip.2013.09.007","article-title":"Sphingolipids in colon cancer","volume":"1841","author":"Coant","year":"2014","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1007\/s12602-022-09916-6","article-title":"Effect of a Diet Supplemented with Sphingomyelin and Probiotics on Colon Cancer Development in Mice","volume":"14","author":"Marzo","year":"2022","journal-title":"Probiotics Antimicrob. Proteins"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1221","DOI":"10.1002\/ijc.32146","article-title":"Plasma metabolites associated with colorectal cancer: A discovery-replication strategy","volume":"145","author":"Geijsen","year":"2019","journal-title":"Int. J. Cancer"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"2361","DOI":"10.3892\/or.2015.3868","article-title":"Preclinical assessment of early tumor response after irradiation by positron emission tomography with 2-amino-[3-11C]isobutyric acid","volume":"33","author":"Tsuji","year":"2015","journal-title":"Oncol. Rep."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"372509","DOI":"10.1155\/2011\/372509","article-title":"The Clinical Value of PET with Amino Acid Tracers for Gliomas WHO Grade II","volume":"2011","author":"Smits","year":"2011","journal-title":"Int. J. Mol. Imaging"},{"key":"ref_90","first-page":"1448206","article-title":"A Metabolomic Investigation of Eugenol on Colorectal Cancer Cell Line HT-29 by Modifying the Expression of APC, p53, and KRAS Genes","volume":"2021","author":"Hosseini","year":"2021","journal-title":"Evid. Based Complement. Altern. Med."},{"key":"ref_91","doi-asserted-by":"crossref","unstructured":"Rushing, B.R., Wiggs, A., Molina, S., Schroder, M., and Sumner, S. (2023). Metabolomics Analysis Reveals Novel Targets of Chemosensitizing Polyphenols and Omega-3 Polyunsaturated Fatty Acids in Triple Negative Breast Cancer Cells. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24054406"},{"key":"ref_92","first-page":"2441","article-title":"Changes in amino acid pool and utilization during apoptosis in HL-60 cells induced by epigallocatechin gallate or gallic acid","volume":"21","author":"Sakagami","year":"2001","journal-title":"Anticancer. Res."},{"key":"ref_93","first-page":"3","article-title":"Global serum metabolomics profiling of colorectal cancer","volume":"11","author":"Hashim","year":"2019","journal-title":"Mol. Clin. Oncol."},{"key":"ref_94","doi-asserted-by":"crossref","unstructured":"Hasegawa, K., Saiura, A., Takayama, T., Miyagawa, S., Yamamoto, J., Ijichi, M., Teruya, M., Yoshimi, F., Kawasaki, S., and Koyama, H. (2016). Adjuvant Oral Uracil-Tegafur with Leucovorin for Colorectal Cancer Liver Metastases: A Randomized Controlled Trial. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0162400"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1177\/1758834012441049","article-title":"Tegafur-uracil is a safe alternative for the treatment of colorectal cancer in patients with partial dihydropyrimidine dehydrogenase deficiency: A proof of principle","volume":"4","author":"Cubero","year":"2012","journal-title":"Ther. Adv. Med. Oncol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1007\/s00280-014-2553-2","article-title":"Pretherapeutic uracil and dihydrouracil levels in saliva of colorectal cancer patients are associated with toxicity during adjuvant 5-fluorouracil-based chemotherapy","volume":"74","author":"Carlsson","year":"2014","journal-title":"Cancer Chemother. Pharmacol."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/18\/1\/79\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T05:27:19Z","timestamp":1767936439000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/18\/1\/79"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,7]]},"references-count":96,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,1]]}},"alternative-id":["pharmaceutics18010079"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics18010079","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,7]]}}}