m6A-centered Drug Response Information

General Information of the Drug (ID: M6ADRUG0005)
Name
Fluorouracil
Synonyms
5-Fluorouracil; 51-21-8; fluorouracil; 5-FU; Fluoroplex; Adrucil; Efudex; Carac; Fluracil; Fluoroblastin; 5-fluoropyrimidine-2,4(1H,3H)-dione; Kecimeton; Timazin; Carzonal; Efudix; Arumel; Fluril; Queroplex; Fluracilum; Ulup; 5-Fluoracil; Phthoruracil; Fluro Uracil; 5-Fluoro-2,4(1H,3H)-pyrimidinedione; Ftoruracil; Fluorouracilum; Efurix; Fluri; 5 Fluorouracil; Effluderm (free base); 5-fluoro-1H-pyrimidine-2,4-dione; Fluorouracilo; Fluroblastin; Phtoruracil; 2,4-Dihydroxy-5-fluoropyrimidine; 2,4(1H,3H)-Pyrimidinedione, 5-fluoro-; Adrucil; Effluderm; Fluorouracile; Fluoruracil; Fluracedyl; Flurodex; Neofluor; Onkofluor; Ribofluor; Tetratogen; URF; Allergan Brand of Fluorouracil; Biosyn Brand of Fluorouracil; CSP Brand of Fluorouracil; Cinco FU; Dakota Brand of Fluorouracil; Dermatech Brand of Fluorouracil; Dermik Brandof Fluorouracil; Ferrer Brand of Fluorouracil; Fluoro Uracile ICN; Fluorouracil GRY; Fluorouracil Mononitrate; Fluorouracil Monopotassium Salt; Fluorouracil Monosodium Salt; Fluorouracil Potassium Salt; Fluorouracil Teva Brand; Fluorouracile Dakota; Fluorouracile [DCIT]; Fluorouracilo Ferrer Far; Gry Brand of Fluorouracil; Haemato Brand of Fluorouracil; Haemato fu; Hexal Brand of Fluorouracil; ICN Brand of Fluorouracil; Inhibits thymilidate synthetase; Medac Brand of Fluorouracil; Neocorp Brand of Fluorouracil; Onkoworks Brand of Fluorouracil; Ribosepharm Brand of Fluorouracil; Riemser Brand of Fluorouracil; Roche Brand of Fluorouracil; Teva Brand of Fluorouracil; F 6627; F0151; IN1335; U 8953; Adrucil (TN); Carac (TN); Dakota, Fluorouracile; Efudex (TN); Fluoro-Uracile ICN; Fluoro-uracile; Fluoro-uracilo; Fluoroplex (TN); Fluorouracil-GRY; Fluorouracilo [INN-Spanish]; Fluorouracilum [INN-Latin]; Haemato-fu; Ro 2-9757; U-8953; Ro-2-9757; Fluorouracil (JP15/USP/INN); Fluorouracil [USAN:INN:BAN:JAN]; 1-fluoro-1h-pyrimidine-2,4-dione; 2,4-Dioxo-5-fluoropryimidine; 2,4-Dioxo-5-fluoropyrimidine; 5 FU Lederle; 5 FU medac; 5 Fluorouracil biosyn; 5 HU Hexal; 5-FU (TN); 5-FU Lederle; 5-FU medac; 5-Faracil; 5-Fluor-2,4(1H,3H)-pyrimidindion; 5-Fluor-2,4(1H,3H)-pyrimidindion [Czech]; 5-Fluor-2,4-dihydroxypyrimidin; 5-Fluor-2,4-dihydroxypyrimidin [Czech]; 5-Fluor-2,4-pyrimidindiol; 5-Fluor-2,4-pyrimidindiol [Czech]; 5-Fluoracil [German]; 5-Fluoracyl; 5-Fluoro-2,4-pyrimidinedione; 5-Fluoropyrimidin-2,4-diol; 5-Fluoropyrimidine-2,4-dione; 5-Fluorouracil-biosyn; 5-Fluoruracil; 5-Fluoruracil [German]; 5-Ftouracyl; 5-HU Hexal; 5-fluoro uracil; 5FU
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Status Approved [1]
Structure
Formula
C4H3FN2O2
InChI
InChI=1S/C4H3FN2O2/c5-2-1-6-4(9)7-3(2)8/h1H,(H2,6,7,8,9)
InChIKey
GHASVSINZRGABV-UHFFFAOYSA-N
PubChem CID
3385
TTD Drug ID
D05LEO
DrugBank ID
DB00544
Full List of m6A Targets Related to This Drug
DNA damage-inducible transcript 3 protein (DDIT3/CHOP)
 Target Info 
In total 1 item(s) under this target gene
Experiment 1 Reporting the m6A-centered Drug Response by This Target Gene [2]
Response Summary Omeprazole pretreatment could enhance the inhibitory effect of 5-Fu, DDP and TAX on gastric cancer cells. FTO inhibition induced by omeprazole enhanced the activation of mTORC1 signal pathway that inhibited the prosurvival autophagy so as to improve the antitumor efficiency of chemotherapeutic drugs on GC cells. Meanwhile, transcript level of DNA damage-inducible transcript 3 protein (DDIT3), which is an apoptosis-related tumor suppressor gene downstream of mTORC1, was regulated by omeprazole-induced FTO silence through an m6A-dependent mechanism. m6A modification and its eraser FTO plays a role in the improvement of chemosensitivity mediated by proton pump inhibitor omeprazole.
Responsed Disease Gastric cancer ICD-11: 2B72
 Disease Info 
Target Regulator Fat mass and obesity-associated protein (FTO) ERASER
 Regulator Info 
Target Regulation Down regulation
Pathway Response mTOR signaling pathway hsa04150
Apoptosis hsa04210
Cell Process Cell apoptosis
In-vitro Model AGS Gastric adenocarcinoma Homo sapiens CVCL_0139
HGC-27 Gastric carcinoma Homo sapiens CVCL_1279
Mammalian target of rapamycin complex 1 (mTORC1)
 Target Info 
In total 1 item(s) under this target gene
Experiment 1 Reporting the m6A-centered Drug Response by This Target Gene [2]
Response Summary Omeprazole pretreatment could enhance the inhibitory effect of 5-Fu, DDP and TAX on gastric cancer cells. FTO inhibition induced by omeprazole enhanced the activation of Mammalian target of rapamycin complex 1 (mTORC1) signal pathway that inhibited the prosurvival autophagy so as to improve the antitumor efficiency of chemotherapeutic drugs on GC cells. Meanwhile, transcript level of DDIT3, which is an apoptosis-related tumor suppressor gene downstream of mTORC1, was regulated by omeprazole-induced FTO silence through an m6A-dependent mechanism. m6A modification and its eraser FTO plays a role in the improvement of chemosensitivity mediated by proton pump inhibitor omeprazole.
Responsed Disease Gastric cancer ICD-11: 2B72
 Disease Info 
Target Regulator Fat mass and obesity-associated protein (FTO) ERASER
 Regulator Info 
Target Regulation Down regulation
Pathway Response mTOR signaling pathway hsa04150
Cell Process Cell apoptosis
In-vitro Model AGS Gastric adenocarcinoma Homo sapiens CVCL_0139
HGC-27 Gastric carcinoma Homo sapiens CVCL_1279
Neurocalcin-delta (NCALD)
 Target Info 
In total 1 item(s) under this target gene
Experiment 1 Reporting the m6A-centered Drug Response by This Target Gene [3]
Response Summary METTL3?dependent m6A methylation was upregulated in CRC to promote the processing of miR?181d?5p by DGCR8. This led to increased miR?181d?5p expression, which inhibited the 5?FU sensitivity of CRC cells by targeting Neurocalcin-delta (NCALD).
Responsed Disease Colorectal cancer ICD-11: 2B91
 Disease Info 
Target Regulator Methyltransferase-like 3 (METTL3) WRITER
 Regulator Info 
Target Regulation Down regulation
In-vitro Model HT29 Colon cancer Mus musculus CVCL_A8EZ
HCT 116 Colon carcinoma Homo sapiens CVCL_0291
In-vivo Model A tumor-bearing model was established by subcutaneously injecting 100 ul HT29 cells (5×106) followed by an intravenous injection of CAFs-derived exosomes (50 ug/mouse every three days) into the tail vein of the mice. An intraperitoneal injection of 5-FU (50 mg/kg, every week) was administered on day 12.
RAD51-associated protein 1 (RAD51AP1)
 Target Info 
In total 1 item(s) under this target gene
Experiment 1 Reporting the m6A-centered Drug Response by This Target Gene [4]
Response Summary METTL3 augmented 5?FU?induced DNA damage and overcame 5?FU?resistance in HCT?8R cells, which could be mimicked by inhibition of RAD51-associated protein 1 (RAD51AP1). The present study revealed that the METTL3/RAD51AP1 axis plays an important role in the acquisition of 5?FU resistance in CRC.
Responsed Disease Colorectal cancer ICD-11: 2B91
 Disease Info 
Target Regulator Methyltransferase-like 3 (METTL3) WRITER
 Regulator Info 
Target Regulation Up regulation
In-vitro Model HCT 8 Colon adenocarcinoma Homo sapiens CVCL_2478
Rho GTPase activating protein 5 (ARHGAP5)
 Target Info 
In total 1 item(s) under this target gene
Experiment 1 Reporting the m6A-centered Drug Response by This Target Gene [5]
Response Summary ARHGAP5-AS1 also stabilized ARHGAP5 mRNA in the cytoplasm by recruiting METTL3 to stimulate m6A modification of Rho GTPase activating protein 5 (ARHGAP5) mRNA. As a result, ARHGAP5 was upregulated to promote chemoresistance and its upregulation was also associated with poor prognosis in gastric cancer. downregulation of ARHGAP5-AS1 in resistant cells evidently reversed the resistance to chemotherapeutic drugs including cisplatin (DDP), ADM, and 5-FU.
Responsed Disease Gastric cancer ICD-11: 2B72
 Disease Info 
Target Regulator Methyltransferase-like 3 (METTL3) WRITER
 Regulator Info 
Target Regulation Up regulation
Pathway Response Autophagy hsa04140
Cell Process Cellular processes
Cellular transport, Cellular catabolism
In-vitro Model BGC-823 Gastric carcinoma Homo sapiens CVCL_3360
SGC-7901 Gastric carcinoma Homo sapiens CVCL_0520
Translocation protein SEC62 (SEC62)
 Target Info 
In total 1 item(s) under this target gene
Experiment 1 Reporting the m6A-centered Drug Response by This Target Gene [6]
Response Summary Translocation protein SEC62 (SEC62) upregulated by the METTL3-mediated m6A modification promotes the stemness and chemoresistance of colorectal cancer by binding to beta-catenin and enhancing Wnt signalling. Depletion of Sec62 sensitized the CRC cells to 5-Fu or oxaliplatin treatment.
Responsed Disease Colorectal cancer ICD-11: 2B91
 Disease Info 
Target Regulator Methyltransferase-like 3 (METTL3) WRITER
 Regulator Info 
Target Regulation Up regulation
Pathway Response Wnt signaling pathway hsa04310
Cell Process Protein degradation
In-vitro Model DLD-1 Colon adenocarcinoma Homo sapiens CVCL_0248
HT29 Colon cancer Mus musculus CVCL_A8EZ
In-vivo Model DLD-1 cells were subcutaneously implanted into 4-6 weeks old female nude mice. When tumors reached a size of about 50 mm3, the nude mice were randomly divided into 6 groups.
LBX2 antisense RNA 1 (LBX2-AS1)
 Target Info 
In total 1 item(s) under this target gene
Experiment 1 Reporting the m6A-centered Drug Response by This Target Gene [7]
Response Summary The increased LBX2 antisense RNA 1 (LBX2-AS1) in CRC was mediated by METTL3-dependent m6A methylation. LBX2-AS1 serves as a therapeutic target and predictor of 5-FU benefit in colorectal cancer patients.
Responsed Disease Colorectal cancer ICD-11: 2B91
 Disease Info 
Target Regulator Methyltransferase-like 3 (METTL3) WRITER
 Regulator Info 
Target Regulation Up regulation
In-vitro Model HCT 116 Colon carcinoma Homo sapiens CVCL_0291
SW480 Colon adenocarcinoma Homo sapiens CVCL_0546
hsa-miR-181d-5p
 Target Info 
In total 1 item(s) under this target gene
Experiment 1 Reporting the m6A-centered Drug Response by This Target Gene [3]
Response Summary METTL3?dependent m6A methylation was upregulated in CRC to promote the processing of miR?181d?5p by DGCR8. This led to increased hsa-miR-181d-5p expression, which inhibited the 5?FU sensitivity of CRC cells by targeting NCALD.
Responsed Disease Colorectal cancer ICD-11: 2B91
 Disease Info 
Target Regulator Methyltransferase-like 3 (METTL3) WRITER
 Regulator Info 
Target Regulation Up regulation
In-vitro Model HT29 Colon cancer Mus musculus CVCL_A8EZ
HCT 116 Colon carcinoma Homo sapiens CVCL_0291
In-vivo Model A tumor-bearing model was established by subcutaneously injecting 100 ul HT29 cells (5×106) followed by an intravenous injection of CAFs-derived exosomes (50 ug/mouse every three days) into the tail vein of the mice. An intraperitoneal injection of 5-FU (50 mg/kg, every week) was administered on day 12.
References
Ref 1 Natural products as sources of new drugs over the last 25 years. J Nat Prod. 2007 Mar;70(3):461-77.
Ref 2 Omeprazole improves chemosensitivity of gastric cancer cells by m6A demethylase FTO-mediated activation of mTORC1 and DDIT3 up-regulation. Biosci Rep. 2021 Jan 29;41(1):BSR20200842. doi: 10.1042/BSR20200842.
Ref 3 N6?methyladenosine upregulates miR?181d?5p in exosomes derived from cancer?associated fibroblasts to inhibit 5?FU sensitivity by targeting NCALD in colorectal cancer. Int J Oncol. 2022 Feb;60(2):14. doi: 10.3892/ijo.2022.5304. Epub 2022 Jan 11.
Ref 4 METTL3 antagonizes 5?FU chemotherapy and confers drug resistance in colorectal carcinoma. Int J Oncol. 2022 Sep;61(3):106. doi: 10.3892/ijo.2022.5396. Epub 2022 Jul 20.
Ref 5 Impaired autophagic degradation of lncRNA ARHGAP5-AS1 promotes chemoresistance in gastric cancer. Cell Death Dis. 2019 May 16;10(6):383. doi: 10.1038/s41419-019-1585-2.
Ref 6 Sec62 promotes stemness and chemoresistance of human colorectal cancer through activating Wnt/Beta-catenin pathway. J Exp Clin Cancer Res. 2021 Apr 15;40(1):132. doi: 10.1186/s13046-021-01934-6.
Ref 7 LncRNA LBX2-AS1 promotes colorectal cancer progression and 5-fluorouracil resistance. Cancer Cell Int. 2021 Sep 17;21(1):501. doi: 10.1186/s12935-021-02209-y.