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Unfortunately, ~50\u201360% of patients eventually develop resistance to 5FU, leading to poor survival outcomes. Our previous work revealed that andrographis enhanced 5FU-induced anti-cancer activity, but the underlying mechanistic understanding largely remains unclear. In this study, we first established 5FU-resistant (5FUR) CRC cells and observed that combined treatment with andrographis-5FU in 5FUR cells exhibited superior effect on cell viability, proliferation, and colony formation capacity compared with individual treatments (P &amp;lt; 0.001). To identify key genes and pathways responsible for 5FU resistance, we analyzed genome-wide transcriptomic profiling data from CRC patients who either responded or did not respond to 5FU. Among a panel of differentially expressed genes, Dickkopf-1 (DKK1) overexpression was a critical event for 5FU resistance. Moreover, andrographis significantly downregulated 5FU-induced DKK1 overexpression, accompanied with enhanced anti-tumor effects by abrogating downstream Akt-phosphorylation. In line with in vitro findings, andrographis enhanced 5FU-induced anti-cancer activity in mice xenografts and patient-derived tumoroids (P &amp;lt; 0.01). In conclusion, our data provide novel evidence for andrographis-mediated reversal of 5FU resistance, highlighting its potential role as an adjunct to conventional chemotherapy in CRC.<\/jats:p>","DOI":"10.1093\/carcin\/bgab027","type":"journal-article","created":{"date-parts":[[2021,4,1]],"date-time":"2021-04-01T19:24:07Z","timestamp":1617305047000},"page":"814-825","source":"Crossref","is-referenced-by-count":29,"title":["Andrographis overcomes 5-fluorouracil-associated chemoresistance through inhibition of DKK1 in colorectal cancer"],"prefix":"10.1093","volume":"42","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1105-8980","authenticated-orcid":false,"given":"Yinghui","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope Comprehensive Cancer Center, Duarte, CA, USA"},{"name":"Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuanxin","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China"},{"name":"Shandong Engineering and Technology Research Center for Tumor Marker Detection, Jinan, China"},{"name":"Shandong Provincial Clinical Medicine Research Center for Clinical Laboratory, Jinan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1396-6341","authenticated-orcid":false,"given":"Ajay","family":"Goel","sequence":"additional","affiliation":[{"name":"Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope Comprehensive Cancer Center, Duarte, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,4,5]]},"reference":[{"key":"2021070818180446400_CIT0001","doi-asserted-by":"crossref","first-page":"7","DOI":"10.3322\/caac.21590","article-title":"Cancer statistics, 2020","volume":"70","author":"Siegel","year":"2020","journal-title":"CA. 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