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Med."],"published-print":{"date-parts":[[2022,1]]},"abstract":"<jats:p> Combining innocuous natural products with cytotoxic agents may enhance the effectiveness of chemotherapy. Tangeretin is a citrus flavonoid that has antineoplastic properties, but its mechanism of action is still unknown. Here, we used a high throughput-screening (HTS) platform to screen for drugs that may synergize with tangeretin and confirmed the top hits against colorectal cancer (CRC) cells in vitro and in vivo. 5-Fluorouracil (5-FU) and PI3K\/Akt inhibitors have come out as top hits that show a strong synergy effect with tangeretin by HTS. We further confirmed the synergistic effect of tangeretin with 5-FU against CRC cells in vitro and in vivo. Since 5-FU can increase microRNA-21 (miR-21) expression and activate PI3K\/Akt signaling, we addressed if tangeretin acted at this level. In 5-FU treated cells, tangeretin inhibited miR-21 induction, rescued the expression of the target PTEN, reduced Akt activation, and induced autophagy. Together, our data indicated that a natural product, such as tangeretin, can modulate miR-21 expression and that this pathway might be a potential therapeutic target for CRC. Combining tangeretin with 5-FU may be useful in the clinic, since 5-FU is the current first line drug for treating CRC. <\/jats:p>","DOI":"10.1142\/s0192415x22500719","type":"journal-article","created":{"date-parts":[[2022,7,18]],"date-time":"2022-07-18T04:08:05Z","timestamp":1658117285000},"page":"1681-1701","source":"Crossref","is-referenced-by-count":23,"title":["Tangeretin Synergizes with 5-Fluorouracil to Induce Autophagy through MicroRNA-21 in Colorectal Cancer Cells"],"prefix":"10.1142","volume":"50","author":[{"given":"Yang","family":"Bai","sequence":"first","affiliation":[{"name":"Department of Pharmacology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, Sichuan 610041, P. R. China"},{"name":"Department of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, P. R. China"},{"name":"Department of Pharmacy, Chengdu Shangjinnanfu Hospital, Chengdu, Sichuan 611730, P. R. 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