m6A-centered Drug Response Information

General Information of the Drug (ID: M6ADRUG0024)
Name
Gemcitabine
Synonyms
Gemcitabine hydrochloride; DDFC; DFdC; DFdCyd; Folfugem; GEO; Gamcitabine; GemLip; Gemcel; Gemcin; Gemcitabina; Gemcitabinum; Gemtro; Gemzar; Zefei; Gemcitabine HCl; Gemcitabine stereoisomer; LY 188011; LY188011; Gemcitabina [INN-Spanish]; Gemcitabinum [INN-Latin]; Gemzar (TN); Gemzar (hydrochloride); Inno-D07001; LY-188011; Gemcitabine (USAN/INN)
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Status Approved [1]
Structure
Formula
C9H11F2N3O4
InChI
InChI=1S/C9H11F2N3O4/c10-9(11)6(16)4(3-15)18-7(9)14-2-1-5(12)13-8(14)17/h1-2,4,6-7,15-16H,3H2,(H2,12,13,17)/t4-,6-,7-/m1/s1
InChIKey
SDUQYLNIPVEERB-QPPQHZFASA-N
PubChem CID
60750
TTD Drug ID
D03UVS
DrugBank ID
DB00441
Full List of m6A Targets Related to This Drug
Focal adhesion kinase 1 (Fak)
 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 WTAP could promote migration/invasion and suppress chemo-sensitivity to gemcitabine in PC. Further mechanical investigation revealed that WTAP could bind to and stabilize Focal adhesion kinase 1 (Fak) mRNA which in turn activated the Fak-PI3K-AKT and Fak-Src-GRB2-Erk1/2 signaling pathways.
Responsed Disease Pancreatic cancer ICD-11: 2C10
 Disease Info 
Target Regulator Wilms tumor 1-associating protein (WTAP) WRITER
 Regulator Info 
Target Regulation Up regulation
Pathway Response PI3K-Akt signaling pathway hsa04151
Cell Process RNA stability
In-vitro Model T3M-4 Pancreatic ductal adenocarcinoma Homo sapiens CVCL_4056
PANC-1 Pancreatic ductal adenocarcinoma Homo sapiens CVCL_0480
MIA PaCa-2 Pancreatic ductal adenocarcinoma Homo sapiens CVCL_0428
hTERT-HPNE Normal Homo sapiens CVCL_C466
HPDE6c7 Normal Homo sapiens CVCL_0P38
BxPC-3 Pancreatic ductal adenocarcinoma Homo sapiens CVCL_0186
AsPC-1 Pancreatic ductal adenocarcinoma Homo sapiens CVCL_0152
In-vivo Model Twenty-four female BALB/c athymic nude mice, which were 4-6 weeks old and weighed 20.0-25.0 g, were obtained from the Animal Research Center of PUMCH. WTAP-OE, WTAP-NC, shWTAP and shNC-lentivirus infected MIA PaCa-2 cells (5 × 106) were suspended in 50 uL PBS and then injected subcapsularly into the pancreatic tissue by 1-mL syringes.
Nucleobindin-1 (NUCB1)
 Target Info 
In total 2 item(s) under this target gene
Experiment 1 Reporting the m6A-centered Drug Response by This Target Gene [5]
Response Summary METTL3-mediated m6A modification on Nucleobindin-1 (NUCB1) 5'UTR via the reader YTHDF2 as a mechanism for NUCB1 downregulation in PDAC. This study revealed crucial functions of NUCB1 in suppressing proliferation and enhancing the effects of gemcitabine in pancreatic cancer cells.
Responsed Disease Pancreatic ductal adenocarcinoma ICD-11: 2C10.0
 Disease Info 
Target Regulator Methyltransferase-like 3 (METTL3) WRITER
 Regulator Info 
Target Regulation Down regulation
Pathway Response Autophagy hsa04140
Cell Process Cell proliferation
Cell autophagy
In-vitro Model SW1990 Pancreatic adenocarcinoma Homo sapiens CVCL_1723
PANC-1 Pancreatic ductal adenocarcinoma Homo sapiens CVCL_0480
HEK293T Normal Homo sapiens CVCL_0063
CFPAC-1 Cystic fibrosis Homo sapiens CVCL_1119
BxPC-3 Pancreatic ductal adenocarcinoma Homo sapiens CVCL_0186
AsPC-1 Pancreatic ductal adenocarcinoma Homo sapiens CVCL_0152
In-vivo Model 5 × 106 SW1990 cells expressing NUCB1 (oeNUCB1) or control vector (oeNC) were injected subcutaneously.
Experiment 2 Reporting the m6A-centered Drug Response by This Target Gene [5]
Response Summary METTL3-mediated m6A modification on Nucleobindin-1 (NUCB1) 5'UTR via the reader YTHDF2 as a mechanism for NUCB1 downregulation in PDAC. This study revealed crucial functions of NUCB1 in suppressing proliferation and enhancing the effects of gemcitabine in pancreatic cancer cells.
Responsed Disease Pancreatic ductal adenocarcinoma ICD-11: 2C10.0
 Disease Info 
Target Regulator YTH domain-containing family protein 2 (YTHDF2) READER
 Regulator Info 
Target Regulation Down regulation
Pathway Response Autophagy hsa04140
Cell Process Cell proliferation
Cell autophagy
In-vitro Model SW1990 Pancreatic adenocarcinoma Homo sapiens CVCL_1723
PANC-1 Pancreatic ductal adenocarcinoma Homo sapiens CVCL_0480
HEK293T Normal Homo sapiens CVCL_0063
CFPAC-1 Cystic fibrosis Homo sapiens CVCL_1119
BxPC-3 Pancreatic ductal adenocarcinoma Homo sapiens CVCL_0186
AsPC-1 Pancreatic ductal adenocarcinoma Homo sapiens CVCL_0152
In-vivo Model 5 × 106 SW1990 cells expressing NUCB1 (oeNUCB1) or control vector (oeNC) were injected subcutaneously.
Serine/arginine-rich splicing factor 3 (SRSF3)
 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 Serine/arginine-rich splicing factor 3 (SRSF3) promotes gemcitabine resistance by regulating ANRIL's splicing and ANRIL-208 (one of the ANRIL spliceosomes) can enhance DNA homologous recombination repair (HR) capacity by forming a complex with Ring1b and EZH2. Demonstrates that abnormal alternative splicing and m6A modification are closely related to chemotherapy resistance in pancreatic cancer.
Responsed Disease Pancreatic cancer ICD-11: 2C10
 Disease Info 
Pathway Response mRNA surveillance pathway hsa03015
Cell Process mRNA alternative splicing
In-vitro Model PANC-1 Pancreatic ductal adenocarcinoma Homo sapiens CVCL_0480
BxPC-3 Pancreatic ductal adenocarcinoma Homo sapiens CVCL_0186
In-vivo Model Gemcitabine-resistant Panc1 cells (Panc1-GR) were prepared as stable luciferase clones after transduction with CTRL or shSRSF3 or sh-ANRIL-L vector or SRSF3 or ANRIL-L. For the PDX models, pieces of fresh human pancreatic cancer tissues were transplanted subcutaneously into the axilla of 4-6 week-old NOD/SCID mice.
Wnt inhibitory factor 1 (WIF1)
 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 ALKBH5 overexpression sensitizes Pancreatic cancer cells to gemcitabine treatment, and it represses PDAC tumorigenesis by reducing m6A levels of Wnt inhibitory factor 1 (WIF1) and hindering activation of Wnt signaling.
Responsed Disease Pancreatic cancer ICD-11: 2C10
 Disease Info 
Target Regulator RNA demethylase ALKBH5 (ALKBH5) ERASER
 Regulator Info 
Target Regulation Up regulation
Pathway Response Wnt signaling pathway hsa04310
In-vitro Model AsPC-1 Pancreatic ductal adenocarcinoma Homo sapiens CVCL_0152
BxPC-3 Pancreatic ductal adenocarcinoma Homo sapiens CVCL_0186
Capan-1 Pancreatic ductal adenocarcinoma Homo sapiens CVCL_0237
Capan-2 Pancreatic ductal adenocarcinoma Homo sapiens CVCL_0026
CFPAC-1 Cystic fibrosis Homo sapiens CVCL_1119
HPDE6c7 Normal Homo sapiens CVCL_0P38
MIA PaCa-2 Pancreatic ductal adenocarcinoma Homo sapiens CVCL_0428
PANC-1 Pancreatic ductal adenocarcinoma Homo sapiens CVCL_0480
DBH antisense RNA 1 (Lnc_DBH-AS1)
 Target Info 
In total 1 item(s) under this target gene
Experiment 1 Reporting the m6A-centered Drug Response by This Target Gene [8]
Response Summary DBH antisense RNA 1 (Lnc_DBH-AS1) expression in pancreatic cancer(PC) was found to be linked to the METTL3-dependent m6A methylation of the lncRNA. MechanisticallyDBH-AS1 was able to increase PC cell sensitivity to gemcitabine by sequestering miR-3163 and thus upregulating USP44 in these tumor cells.
Responsed Disease Pancreatic cancer ICD-11: 2C10
 Disease Info 
Target Regulator Methyltransferase-like 3 (METTL3) WRITER
 Regulator Info 
In-vitro Model MIA PaCa-2 Pancreatic ductal adenocarcinoma Homo sapiens CVCL_0428
HPDE Normal Homo sapiens CVCL_4376
CFPAC-1 Cystic fibrosis Homo sapiens CVCL_1119
Canpan-2 (Pancreatic cancer cell line)
BxPC-3 Pancreatic ductal adenocarcinoma Homo sapiens CVCL_0186
AsPC-1 Pancreatic ductal adenocarcinoma Homo sapiens CVCL_0152
Full List of Crosstalk(s) between m6A Modification and Epigenetic Regulation Related to This Drug
In total 5 item(s) under this drug
Crosstalk ID: M6ACROT02118
 Crosstalk Info 
m6A Regulator Methyltransferase-like 3 (METTL3)
 Regulator Info 
m6A Target DBH antisense RNA 1 (Lnc_DBH-AS1)
 Target Gene 
Epigenetic Regulator DNA (cytosine-5)-methyltransferase 1 (DNMT1)
Regulated Target Methyltransferase-like protein 3 (METTL3)
Crosstalk relationship DNA modification → m6A
Disease Pancreatic cancer
 Disease Info 
Crosstalk ID: M6ACROT02127
 Crosstalk Info 
m6A Regulator Methyltransferase-like 3 (METTL3)
 Regulator Info 
m6A Target DBH antisense RNA 1 (Lnc_DBH-AS1)
 Target Gene 
Epigenetic Regulator Cysteine methyltransferase DNMT3A (DNMT3A)
Regulated Target Methyltransferase-like protein 3 (METTL3)
Crosstalk relationship DNA modification → m6A
Disease Pancreatic cancer
 Disease Info 
Crosstalk ID: M6ACROT05625
 Crosstalk Info 
m6A Regulator Methyltransferase-like 3 (METTL3)
 Regulator Info 
m6A Target DBH antisense RNA 1 (Lnc_DBH-AS1)
 Target Gene 
Epigenetic Regulator DBH antisense RNA 1 (Lnc_DBH-AS1)
Regulated Target MicroRNA 3163 (MIR3163)
Crosstalk relationship m6A → ncRNA
Disease Pancreatic cancer
 Disease Info 
Crosstalk ID: M6ACROT06041
 Crosstalk Info 
m6A Regulator Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2)
 Regulator Info 
m6A Target Macrophage colony-stimulating factor 1 (CSF1)
 Target Gene 
Epigenetic Regulator Histone acetyltransferase p300 (P300)
Regulated Target Histone H3 lysine 18 lactylation (H3K18la)
Crosstalk relationship Histone modification → m6A
Disease Pancreatic cancer
 Disease Info 
Crosstalk ID: M6ACROT06042
 Crosstalk Info 
m6A Regulator Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2)
 Regulator Info 
m6A Target Myc proto-oncogene protein (MYC)
 Target Gene 
Epigenetic Regulator Histone acetyltransferase p300 (P300)
Regulated Target Histone H3 lysine 18 lactylation (H3K18la)
Crosstalk relationship Histone modification → m6A
Disease Pancreatic cancer
 Disease Info 
References
Ref 1 URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 4793).
Ref 2 Comprehensive analysis of kinase inhibitor selectivity. Nat Biotechnol. 2011 Oct 30;29(11):1046-51. doi: 10.1038/nbt.1990.
Ref 3 WT1 associated protein promotes metastasis and chemo-resistance to gemcitabine by stabilizing Fak mRNA in pancreatic cancer. Cancer Lett. 2019 Jun 1;451:48-57. doi: 10.1016/j.canlet.2019.02.043. Epub 2019 Mar 6.
Ref 4 A patent review on PD-1/PD-L1 antagonists: small molecules, peptides, and macrocycles (2015-2018). Expert Opin Ther Pat. 2018 Sep;28(9):665-678. doi: 10.1080/13543776.2018.1512706. Epub 2018 Sep 10.
Ref 5 NUCB1 Suppresses Growth and Shows Additive Effects With Gemcitabine in Pancreatic Ductal Adenocarcinoma via the Unfolded Protein Response. Front Cell Dev Biol. 2021 Mar 29;9:641836. doi: 10.3389/fcell.2021.641836. eCollection 2021.
Ref 6 SRSF3-mediated regulation of N6-methyladenosine modification-related lncRNA ANRIL splicing promotes resistance of pancreatic cancer to gemcitabine. Cell Rep. 2022 May 10;39(6):110813. doi: 10.1016/j.celrep.2022.110813.
Ref 7 m(6)A demethylase ALKBH5 inhibits pancreatic cancer tumorigenesis by decreasing WIF-1 RNA methylation and mediating Wnt signaling. Mol Cancer. 2020 Jan 6;19(1):3. doi: 10.1186/s12943-019-1128-6.
Ref 8 Increased m(6)A modification of lncRNA DBH-AS1 suppresses pancreatic cancer growth and gemcitabine resistance via the miR-3163/USP44 axis. Ann Transl Med. 2022 Mar;10(6):304. doi: 10.21037/atm-22-556.
Ref 9 Association of genetic variation in cystathionine-beta-synthase and arsenic metabolism. Environ Res. 2010 Aug;110(6):580-7. doi: 10.1016/j.envres.2010.05.001. Epub 2010 Jun 1.
Ref 10 Identification of the human cytochrome P450 isoforms mediating in vitro N-dealkylation of perphenazine. Br J Clin Pharmacol. 2000 Dec;50(6):563-71. doi: 10.1046/j.1365-2125.2000.00298.x.
Ref 11 Evaluation of in vitro drug interactions with karenitecin, a novel, highly lipophilic camptothecin derivative in phase II clinical development. J Clin Pharmacol. 2003 Sep;43(9):1008-14. doi: 10.1177/0091270003255921.