{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T05:09:12Z","timestamp":1775797752544,"version":"3.50.1"},"reference-count":26,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T00:00:00Z","timestamp":1775779200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:sec>\n                    <jats:title>Purpose<\/jats:title>\n                    <jats:p>Colorectal cancer is the most prevalent gastrointestinal malignancy. Treatment usually includes 5-fluorouracil (5-FU), oxaliplatin, and irinotecan, with 5-FU usually being the first choice. 5-FU treatment failure occurs when cancer cells acquire resistance. Therefore, it is crucial to identify compounds effective against 5-FU-resistant tumors. Herein, we determined the efficacy and mechanism of anlotinib in 5-FU-resistant colon cancer cells.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Materials and methods<\/jats:title>\n                    <jats:p>Human colon cancer cells (HCT-8\/5-FU and HCT-15\/5-FU) resistant to 5-FU were subjected to treatment with anlotinib, 5-FU, or both. Cell proliferation was assessed via MTS and clone formation assays. Cell cycle progression was studied using flow cytometry. Through immunoblotting, we evaluated changes in the protein levels of p-AKT and multidrug resistance 1.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>MTS assays indicated that HCT-8\/5-FU and HCT-15\/5-FU cells were sensitive to anlotinib and resistant to 5-FU. At 48\u00a0h, HCT-8\/5-FU had an IC50 of 2246.5 \u00b1 204.5 \u03bcM, while HCT-15\/5-FU had an IC50 of 18.49 \u00b1 3.23 mM for 5-FU. The IC50 of anlotinib for HCT-8\/5-FU cells was 53.69 \u00b1 8.10\u03bcM at 24\u00a0h and 17.39 \u00b1 1.98\u03bcM at 48\u00a0h. The IC50 values for HCT-15\/5-FU at 24 and 48\u00a0h were 55.03 \u00b1 3.44\u03bcM and 8.83 \u00b1 3.02\u03bcM, respectively. Anlotinib enhanced 5-FU sensitivity in resistant cells, with low concentrations (IC10) considerably enhancing the antiproliferative effects of 5-FU. Further, anlotinib significantly increased the number of cells in the G0-G1 phase dose-dependently, while the proportion of cells entering S phase decreased. MDR1 and AKT expression decreased with increasing anlotinib concentration.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Anlotinib suppressed the proliferation of 5-FU-resistant colon cancer cells by preventing entry into S phase, thus sensitizing cells to 5-FU. Moreover, anlotinib may reverse the effect of 5-FU on drug-resistant cells by down-regulating the expression of multidrug-resistant proteins, in which the AKT signaling pathway may play an important role.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fonc.2026.1792045","type":"journal-article","created":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T04:27:23Z","timestamp":1775795243000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Inhibitory effect of the multi-target TKI, anlotinib, in 5-FU resistant colorectal cancer HCT-8\/15 cells: down regulation of drug resistance-associated protein expression"],"prefix":"10.3389","volume":"16","author":[{"given":"Juan","family":"Liu","sequence":"first","affiliation":[{"name":"Cancer Center, Beijing Friendship Hospital, Capital Medical University","place":["Beijing, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haolin","family":"Sun","sequence":"additional","affiliation":[{"name":"Cancer Center, Beijing Friendship Hospital, Capital Medical University","place":["Beijing, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xixi","family":"Zheng","sequence":"additional","affiliation":[{"name":"Cancer Center, Beijing Friendship Hospital, Capital Medical University","place":["Beijing, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nina","family":"Ma","sequence":"additional","affiliation":[{"name":"Cancer Center, Beijing Friendship Hospital, Capital Medical University","place":["Beijing, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoling","family":"Liu","sequence":"additional","affiliation":[{"name":"Shanxi Cancer Hospital Affiliated to Shanxi Medical University","place":["Taiyuan, Shanxi, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruizhen","family":"Cao","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Ordos Central Hospital, National Clinical Research Center for Digestive Disease-Ordos sub-center Ordos","place":["Inner Mongolia, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bangwei","family":"Cao","sequence":"additional","affiliation":[{"name":"Cancer Center, Beijing Friendship Hospital, Capital Medical University","place":["Beijing, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bing","family":"Liu","sequence":"additional","affiliation":[{"name":"Emergency Department, Beijing Friendship Hospital, Capital Medical University","place":["Beijing, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,10]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"394","DOI":"10.3322\/caac.21492","article-title":"Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"68","author":"Bray","year":"2018","journal-title":"CA Cancer J Clin"},{"key":"B2","article-title":"Primary curative surgery and preemptive or adjuvant hyperthermic peritoneal chemotherapy in colorectal cancer patients at high risk to develop peritoneal carcinomatosis. 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