{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T16:10:21Z","timestamp":1791389421454,"version":"4.3.3"},"reference-count":45,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2025,1,30]],"date-time":"2025-01-30T00:00:00Z","timestamp":1738195200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Science Centre of Poland","award":["2016\/22\/E\/NZ4\/00665"],"award-info":[{"award-number":["2016\/22\/E\/NZ4\/00665"]}]},{"name":"National Science Centre of Poland","award":["ST-40"],"award-info":[{"award-number":["ST-40"]}]},{"name":"National Science Centre of Poland","award":["ST-41"],"award-info":[{"award-number":["ST-41"]}]},{"name":"National Science Centre of Poland","award":["ST-89"],"award-info":[{"award-number":["ST-89"]}]},{"DOI":"10.13039\/501100010609","name":"Medical University of Gdansk","doi-asserted-by":"publisher","award":["2016\/22\/E\/NZ4\/00665"],"award-info":[{"award-number":["2016\/22\/E\/NZ4\/00665"]}],"id":[{"id":"10.13039\/501100010609","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010609","name":"Medical University of Gdansk","doi-asserted-by":"publisher","award":["ST-40"],"award-info":[{"award-number":["ST-40"]}],"id":[{"id":"10.13039\/501100010609","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010609","name":"Medical University of Gdansk","doi-asserted-by":"publisher","award":["ST-41"],"award-info":[{"award-number":["ST-41"]}],"id":[{"id":"10.13039\/501100010609","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010609","name":"Medical University of Gdansk","doi-asserted-by":"publisher","award":["ST-89"],"award-info":[{"award-number":["ST-89"]}],"id":[{"id":"10.13039\/501100010609","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Colorectal cancer (CRC) is recognized as the third most lethal cancer worldwide. While existing treatment options demonstrate considerable efficacy, they are often constrained by non-selectivity and substantial side effects. Recent studies indicate that lipid metabolism significantly influences carcinogenesis, highlighting it as a promising avenue for developing targeted anticancer therapies. The purpose of the study was to see if acyl-coenzyme A: cholesterol acyltransferase 1 (ACAT1), 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), and stearoyl-CoA 9-desaturase (SCD1) are good metabolic targets and whether the use of inhibitors of these enzymes together with 5-fluorouracil (5-FU) would have a synergistic effect on CRC cell viability. To confirm that the correct lipid targets were chosen, the expression levels of ACAT1, HMGCR, and SCD1 were examined in CRC patients and cell models. At first, each compound (Avasimibe, Lovastatin, MF-438, and 5-FU was tested separately, and then each inhibitor was paired with 5-FU to assess the synergistic effect on cell viability. Gene expression of selected enzymes significantly increased in tissue samples obtained from CRC patients and cancer cell lines (HT-29). Inhibition of any of the selected enzymes reduced CRC cell growth in a dose-dependent manner. More importantly, the combination of 5-FU + Avasimibe (an ACAT1 inhibitor) and 5-FU + MF-438 (an SCD1 inhibitor) produced a stronger antiproliferative effect than the inhibitors alone. 5-FU combined either with Avasimibe or MF-438 showed a synergistic effect with an HSA score of 47.00 at a dose of 0.3 + 30 \u00b5M, respectively (2.66% viability rate vs. 46%; p &lt; 0.001), and 39.34 at a dose of 0.3 + 0.06 \u00b5M (46% vs. 10.33%; p &lt; 0.001), respectively. The association of 5-FU with Lovastatin (HMGCR inhibitor) did not significantly impact CRC cell viability in a synergistic manner. Inhibition of lipid metabolism combined with standard chemotherapy is a promising strategy that reduces CRC cell viability and allows for the use of a lower drug dose. The combination of 5-FU and Avasimibe has the greatest therapeutic potential among studied compounds.<\/jats:p>","DOI":"10.3390\/ijms26031186","type":"journal-article","created":{"date-parts":[[2025,1,30]],"date-time":"2025-01-30T04:01:39Z","timestamp":1738209699000},"page":"1186","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Lipids Metabolism Inhibition Antiproliferative Synergy with 5-Fluorouracil in Human Colorectal Cancer Model"],"prefix":"10.3390","volume":"26","author":[{"given":"Judyta","family":"Zabielska","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Faculty of Medicine, Medical University of Gdansk, 80-211 Gdansk, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8222-8575","authenticated-orcid":false,"given":"Ewa","family":"Stelmanska","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Medicine, Medical University of Gdansk, 80-211 Gdansk, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2667-7242","authenticated-orcid":false,"given":"Sylwia","family":"Szrok-Jurga","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Medicine, Medical University of Gdansk, 80-211 Gdansk, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaros\u0142aw","family":"Kobiela","sequence":"additional","affiliation":[{"name":"Department of Surgical Oncology, Transplant Surgery and General Surgery, Faculty of Medicine, Medical University of Gdansk, 80-211 Gdansk, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3072-6334","authenticated-orcid":false,"given":"Aleksandra","family":"Czumaj","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Medical University of Gdansk, 80-211 Gdansk, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"209","DOI":"10.3322\/caac.21660","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1001\/jama.2021.0106","article-title":"Diagnosis and treatment of metastatic colorectal cancer: A review","volume":"325","author":"Biller","year":"2021","journal-title":"JAMA\u2014J. Am. Med. Assoc."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"769305","DOI":"10.3389\/fonc.2021.769305","article-title":"Personalized Immunotherapy in Colorectal Cancers: Where Do We Stand?","volume":"11","author":"Hu","year":"2021","journal-title":"Front. Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1002\/(SICI)1097-0142(19960201)77:3<441::AID-CNCR4>3.0.CO;2-N","article-title":"Relationship between 5-fluorouracil (5-FU) dose intensity and therapeutic response in patients with advanced colorectal cancer receiving infusional therapy containing 5-FU","volume":"77","author":"Gamelin","year":"1996","journal-title":"Cancer"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1532","DOI":"10.1001\/jamaoncol.2024.3891","article-title":"Chimeric Antigen Receptor T Cells, Targeting CD19 and GCC in Metastatic Colorectal Cancer: A Nonrandomized Clinical Trial","volume":"10","author":"Chen","year":"2024","journal-title":"JAMA Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"111285","DOI":"10.1016\/j.biopha.2021.111285","article-title":"5-Fluorouracil (5-FU) resistance and the new strategy to enhance the sensitivity against cancer: Implication of DNA repair inhibition","volume":"137","author":"Sethy","year":"2021","journal-title":"Biomed. Pharmacother."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"310","DOI":"10.3389\/fphar.2016.00310","article-title":"Adherence and Patients\u2019 Experiences with the Use of Capecitabine in Daily Practice","volume":"7","author":"Timmers","year":"2016","journal-title":"Front. Pharmacol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1501","DOI":"10.2174\/1381612828666220509150918","article-title":"An Updated Review on Properties, Nanodelivery Systems, and Analytical Methods for the Determination of 5-Fluorouracil in Pharmaceutical and Biological Samples","volume":"28","author":"Junior","year":"2022","journal-title":"Curr. Pharm. Des."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.1093\/annonc\/mdh264","article-title":"5-Fluorouracil incorporation into RNA and DNA in relation to thymidylate synthase inhibition of human colorectal cancers","volume":"15","author":"Noordhuis","year":"2004","journal-title":"Ann. Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1038\/s43018-023-00702-z","article-title":"Lipids as mediators of cancer progression and metastasis","volume":"5","author":"Vogel","year":"2024","journal-title":"Nat. Cancer"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1675","DOI":"10.1016\/j.cmet.2022.09.023","article-title":"The role of lipids in cancer progression and metastasis","volume":"34","author":"Bigas","year":"2022","journal-title":"Cell Metab."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Szrok-Jurga, S., Czumaj, A., Turyn, J., Hebanowska, A., Swierczynski, J., Sledzinski, T., and Stelmanska, E. (2023). The Physiological and Pathological Role of Acyl-CoA Oxidation. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241914857"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e2593","DOI":"10.1038\/cddis.2017.21","article-title":"Adipocytes activate mitochondrial fatty acid oxidation and autophagy to promote tumor growth in colon cancer","volume":"8","author":"Wen","year":"2017","journal-title":"Cell Death Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/j.canlet.2018.08.006","article-title":"Fatty acid oxidation: An emerging facet of metabolic transformation in cancer","volume":"435","author":"Ma","year":"2018","journal-title":"Cancer Lett."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1038\/nrc3379","article-title":"Phospholipase signalling networks in cancer","volume":"12","author":"Park","year":"2012","journal-title":"Nat. Rev. Cancer"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1283","DOI":"10.1016\/j.cmet.2023.07.006","article-title":"Emerging therapies in cancer metabolism","volume":"35","author":"Xiao","year":"2023","journal-title":"Cell Metab."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"14328","DOI":"10.1074\/jbc.RA118.004442","article-title":"Inhibition of cholesterol biosynthesis overcomes enzalutamide resistance in castration-resistant prostate cancer (CRPC) X","volume":"293","author":"Kong","year":"2018","journal-title":"J. Biol. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Gyoten, M., Luo, Y., Fujiwara-Tani, R., Mori, S., Ogata, R., Kishi, S., and Kuniyasu, H. (2023). Lovastatin Treatment Inducing Apoptosis in Human Pancreatic Cancer Cells by Inhibiting Cholesterol Rafts in Plasma Membrane and Mitochondria. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms242316814"},{"key":"ref_19","first-page":"1557","article-title":"Lovastatin inhibits the proliferation of human cervical cancer hela cells through the regulation of tp53 pathway by mir-92a-1-5p","volume":"35","author":"Hu","year":"2022","journal-title":"Pak. J. Pharm. Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"927118","DOI":"10.3389\/fcell.2022.927118","article-title":"Targeting of the Lipid Metabolism Impairs Resistance to BRAF Kinase Inhibitor in Melanoma","volume":"10","author":"Vergani","year":"2022","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3385","DOI":"10.21873\/anticanres.13482","article-title":"Acyl-coenzyme A: Cholesterol acyltransferase inhibition in cancer treatment","volume":"39","author":"Zabielska","year":"2019","journal-title":"Anticancer. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"E1","DOI":"10.1152\/ajpendo.90926.2008","article-title":"Acyl-coenzyme A: Cholesterol acyltransferases","volume":"297","author":"Chang","year":"2009","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3115","DOI":"10.7150\/ijbs.85285","article-title":"FABP5 suppresses colorectal cancer progression via mTOR-mediated autophagy by decreasing FASN expression","volume":"19","author":"Ye","year":"2023","journal-title":"Int. J. Biol. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3815","DOI":"10.21873\/anticanres.13531","article-title":"In vivo effectiveness of orlistat in the suppression of human colorectal cancer cell proliferation","volume":"39","author":"Czumaj","year":"2019","journal-title":"Anticancer Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"5355","DOI":"10.1158\/0008-5472.CAN-19-0369","article-title":"Stearoyl-CoA desaturase 1 protects ovarian cancer cells from ferroptotic cell death","volume":"79","author":"Tesfay","year":"2019","journal-title":"Cancer Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1865","DOI":"10.1016\/j.bbalip.2016.09.009","article-title":"Stearoyl CoA desaturase-1: New insights into a central regulator of cancer metabolism","volume":"1861","author":"Igal","year":"2016","journal-title":"Biochim. Biophys. Acta\u2014Mol. Cell Biol. Lipids"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12885-020-06904-3","article-title":"Evaluation of adverse effects of chemotherapy regimens of 5-fluoropyrimidines derivatives and their association with DPYD polymorphisms in colorectal cancer patients","volume":"20","author":"Negarandeh","year":"2020","journal-title":"BMC Cancer"},{"key":"ref_28","first-page":"e1266","article-title":"Adverse Effects of 5-fluorouracil: Focus on Rare Side Effects","volume":"3","author":"Thomas","year":"2016","journal-title":"Cancer Cell Microenviron."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1758835918780140","DOI":"10.1177\/1758835918780140","article-title":"5-fluorouracil and cardiotoxicity: A review","volume":"10","author":"Sara","year":"2018","journal-title":"Ther. Adv. Med. Oncol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"118","DOI":"10.4143\/crt.2010.42.2.118","article-title":"A Case of 5-Fluorouracil Induced Encephalopathy","volume":"42","author":"Kwon","year":"2010","journal-title":"Cancer Res. Treat."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e0228024","DOI":"10.1371\/journal.pone.0228024","article-title":"Assessment of acyl-CoA cholesterol acyltransferase (ACAT-1) role in ovarian cancer progression-An in vitro study","volume":"15","author":"Ayyagari","year":"2020","journal-title":"PLoS ONE"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"957","DOI":"10.3389\/fonc.2019.00957","article-title":"ACAT1 and Metabolism-Related Pathways Are Essential for the Progression of Clear Cell Renal Cell Carcinoma (ccRCC), as Determined by Co-expression Network Analysis","volume":"9","author":"Chen","year":"2019","journal-title":"Front. Oncol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12944-018-0773-x","article-title":"Insulin promotes progression of colon cancer by upregulation of ACAT1","volume":"17","author":"Chen","year":"2018","journal-title":"Lipids Health Dis."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/j.lfs.2016.05.012","article-title":"TLR4 siRNA inhibits proliferation and invasion in colorectal cancer cells by downregulating ACAT1 expression","volume":"155","author":"Ye","year":"2016","journal-title":"Life Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1395192","DOI":"10.3389\/fonc.2024.1395192","article-title":"Targeting ACAT1 in cancer: From threat to treatment","volume":"14","author":"Sun","year":"2024","journal-title":"Front. Oncol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"4814","DOI":"10.1002\/jcp.29358","article-title":"Combined effects of avasimibe immunotherapy, doxorubicin chemotherapy, and metal\u2013organic frameworks nanoparticles on breast cancer","volume":"235","author":"Lei","year":"2020","journal-title":"J. Cell. Physiol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1111\/j.1527-3466.2003.tb00104.x","article-title":"Pharmacology of the ACAT inhibitor avasimibe (CI-1011)","volume":"21","author":"Laguna","year":"2003","journal-title":"Cardiovasc. Drug Rev."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"\u0160kara, L., Hu\u0111ek Turkovi\u0107, A., Pezelj, I., Vrtari\u0107, A., Sin\u010di\u0107, N., Kru\u0161lin, B., and Ulamec, M. (2021). Prostate Cancer\u2014Focus on Cholesterol. Cancers, 13.","DOI":"10.3390\/cancers13184696"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"6378","DOI":"10.1038\/onc.2016.168","article-title":"Abrogating cholesterol esterification suppresses growth and metastasis of pancreatic cancer","volume":"35","author":"Li","year":"2016","journal-title":"Oncogene"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1544","DOI":"10.1136\/gut.2011.237495","article-title":"Statins augment the chemosensitivity of colorectal cancer cells inducing epigenetic reprogramming and reducing colorectal cancer cell \u201cstemness\u201d via the bone morphogenetic protein pathway","volume":"60","author":"Kodach","year":"2011","journal-title":"Gut"},{"key":"ref_41","first-page":"2223","article-title":"Lovastatin augments apoptosis induced by chemotherapeutic agents in colon cancer cells","volume":"5","author":"Agarwal","year":"1999","journal-title":"Clin. Cancer Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1023\/A:1006481423298","article-title":"Phase II study of high-dose lovastatin in patients with advanced gastric adenocarcinoma","volume":"19","author":"Kim","year":"2001","journal-title":"Investig. New. Drugs"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.canlet.2017.07.027","article-title":"Blockade of Stearoyl-CoA-desaturase 1 activity reverts resistance to cisplatin in lung cancer stem cells","volume":"406","author":"Pisanu","year":"2017","journal-title":"Cancer Lett."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2101769","DOI":"10.1080\/2162402X.2022.2101769","article-title":"Targeting stearoyl-coa desaturase enhances radiation induced ferroptosis and immunogenic cell death in esophageal squamous cell carcinoma","volume":"11","author":"Luo","year":"2022","journal-title":"Oncoimmunology"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1016\/j.gpb.2022.01.004","article-title":"SynergyFinder Plus: Toward Better Interpretation and Annotation of Drug Combination Screening Datasets","volume":"20","author":"Zheng","year":"2022","journal-title":"Genomics. Proteom. Bioinform."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/3\/1186\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T10:38:39Z","timestamp":1759919919000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/3\/1186"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,30]]},"references-count":45,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2025,2]]}},"alternative-id":["ijms26031186"],"URL":"https:\/\/doi.org\/10.3390\/ijms26031186","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,30]]}}}