Drug Information

Drug (ID: DG00165) and It's Reported Resistant Information

• Name: Metformin
• Synonyms: 657-24-9; 1,1-Dimethylbiguanide; N,N-dimethylimidodicarbonimidic diamide; Metiguanide; Dimethylbiguanide; Glucophage; Haurymelin; Gliguanid; Fluamine; Glumetza; Flumamine; Melbin; Diabex; N,N-Dimethylbiguanide; Metformina; Metforminum; Metformine; Islotin; Glifage; Siofor; N1,N1-Dimethylbiguanide; DMGG; NNDG; Dimethyldiguanide; N,N-Dimethyldiguanide; Metformina [DCIT]; Imidodicarbonimidic diamide, N,N-dimethyl-; Metformina [Spanish]; Metforminum [INN-Latin]; Metformine [INN-French]; Metformin [USAN:INN:BAN]; 1,1-Dimethyl; Diabetosan; Dimethylbiguanidine; Dimethylguanylguanidine; Glycon; Diabex (TN); Diaformin (TN); Dianben (TN); Fortamet (TN); Gen-Metformin; Glucophage (TN); Glumetza (TN); LA-6023; Nu-Metformin; Obimet (TN); Riomet (TN); Metformin (USAN/INN); 1,1-Dimethyl biguanide; 3-(diaminomethylidene)-1,1-dimethylguanidine; [14C]metformin
• Indication:
  In total 1 Indication(s)
  Type 2 diabetes mellitus [ICD-11: 5A11]; Approved; [1]
• Target: Acetyl-CoA carboxylase 2 (ACACB); ACACB_HUMAN; [1]
• Target: Solute carrier family 47 member 1 (SLC47A1); S47A1_HUMAN; [1]
• Formula: C4H11N5
• IsoSMILES: CN(C)C(=N)N=C(N)N
• InChI: 1S/C4H11N5/c1-9(2)4(7)8-3(5)6/h1-2H3,(H5,5,6,7,8)
• InChIKey: XZWYZXLIPXDOLR-UHFFFAOYSA-N
• PubChem CID: 4091
• ChEBI ID: CHEBI:6801
• TTD Drug ID: D0D7LA
• VARIDT ID: DR00133
• DrugBank ID: DB00331

Type(s) of Resistant Mechanism of This Drug

  EADR: Epigenetic Alteration of DNA, RNA or Protein

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-02: Benign/in-situ/malignant neoplasm

Acute lymphocytic leukemia [ICD-11: 2B33]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Cyclin-dependent kinase 1 (CDK1) [2]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: LKB1/AMPk signaling pathway; Activation; hsa04152
• Cell Pathway Regulation: mTOR signaling pathway; Inhibition; hsa04150
• In Vitro Model: ALL CEM cells; Lymph; Homo sapiens (Human); CVCL_0207
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: XTT assay
• Mechanism Description: In metformin-sensitive cells, autophagy was not induced but rather it blocked proliferation by means of arresting cells in the S and G2/M phases which was associated with the downregulation of cyclin A, cyclin B1, and cdc2, but not that of cyclin E. In 10E1-CEM cells that overexpress Bcl-2 and are drug-resistant, the effect of metformin on proliferation was more pronounced, also inducing the activation of the caspases 3/7 and hence apoptosis.

Key Molecule: Cyclin-A2 (CCNA2) [2]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: LKB1/AMPk signaling pathway; Activation; hsa04152
• Cell Pathway Regulation: mTOR signaling pathway; Inhibition; hsa04150
• In Vitro Model: ALL CEM cells; Lymph; Homo sapiens (Human); CVCL_0207
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: XTT assay
• Mechanism Description: In metformin-sensitive cells, autophagy was not induced but rather it blocked proliferation by means of arresting cells in the S and G2/M phases which was associated with the downregulation of cyclin A, cyclin B1, and cdc2, but not that of cyclin E. In 10E1-CEM cells that overexpress Bcl-2 and are drug-resistant, the effect of metformin on proliferation was more pronounced, also inducing the activation of the caspases 3/7 and hence apoptosis.

Key Molecule: G2/mitotic-specific cyclin-B1 (CCNB1) [2]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Acute lymphocytic leukemia [ICD-11: 2B33.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: LKB1/AMPk signaling pathway; Activation; hsa04152
• Cell Pathway Regulation: mTOR signaling pathway; Inhibition; hsa04150
• In Vitro Model: ALL CEM cells; Lymph; Homo sapiens (Human); CVCL_0207
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: XTT assay
• Mechanism Description: In metformin-sensitive cells, autophagy was not induced but rather it blocked proliferation by means of arresting cells in the S and G2/M phases which was associated with the downregulation of cyclin A, cyclin B1, and cdc2, but not that of cyclin E. In 10E1-CEM cells that overexpress Bcl-2 and are drug-resistant, the effect of metformin on proliferation was more pronounced, also inducing the activation of the caspases 3/7 and hence apoptosis.

Cervical cancer [ICD-11: 2C77]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-142-3p [1]

• Molecule Alteration: Demethylation; Up-regulation
• Sensitive Disease: Cervical cancer [ICD-11: 2C77.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• In Vitro Model: Siha cells; Cervix uteri; Homo sapiens (Human); CVCL_0032
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: Wound-healing assay; Transwell assay
• Mechanism Description: Metformin inhibits the expression of MALAT1 and upregulates miR-142-3p in cervical cancer cells.

Key Molecule: Metastasis associated lung adenocarcinoma transcript 1 (MALAT1) [1]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Cervical cancer [ICD-11: 2C77.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• In Vitro Model: Siha cells; Cervix uteri; Homo sapiens (Human); CVCL_0032
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Wound-healing assay; Transwell assay
• Mechanism Description: Metformin inhibits the expression of MALAT1 and upregulates miR-142-3p in cervical cancer cells.

ICD-05: Endocrine/nutritional/metabolic diseases

Type 2 diabetes mellitus [ICD-11: 5A11]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Solute carrier family 2 member 4 (SLC2A4) [3]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Type 2 diabetes mellitus [ICD-11: 5A11.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: OGTT assay
• Mechanism Description: The administration of chebulagic acid significantly reduced blood glucose by increasing insulin secretion. Further,chebulagic acid treatment increased the protein expression PPAR-Gamma and GLUT4 on insulin target tissues which indicates that chebulagic acid improved insulin sensitivity. PPAR-Gamma is a type of ligand-activated nuclear transcription factor that is associated with fat differentiation, obesity, and insulin resistance. The ability of insulin to reduce blood glucose levels results from the suppression of hepatic glucose production and increased glucose uptake in muscle and adipose tissue via GLUT4.

Key Molecule: Peroxisome proliferator-activated receptor gamma (PPARG) [3]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Type 2 diabetes mellitus [ICD-11: 5A11.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: OGTT assay
• Mechanism Description: The administration of chebulagic acid significantly reduced blood glucose by increasing insulin secretion. Further,chebulagic acid treatment increased the protein expression PPAR-Gamma and GLUT4 on insulin target tissues which indicates that chebulagic acid improved insulin sensitivity. PPAR-Gamma is a type of ligand-activated nuclear transcription factor that is associated with fat differentiation, obesity, and insulin resistance. The ability of insulin to reduce blood glucose levels results from the suppression of hepatic glucose production and increased glucose uptake in muscle and adipose tissue via GLUT4.

ICD-09: Visual system diseases

Retinopathy [ICD-11: 9B71]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Parkinson disease protein 7 homolog (PARK7) [4]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Diabetic retinopathy [ICD-11: 9B71.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Nrf2 signaling pathway; Inhibition; hsa05208
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: TUNEL staining assay
• Mechanism Description: After DJ-1 overexpression, apoptosis of rat retinal pericytes (RRPs) decreased, the ratio of B-cell lymphoma-2 (Bcl-2) to BCL2-Associated X Protein (BAX) increased, the production of ROS decreased, and the protein expression and activity of manganese superoxide dismutase (MnSOD, also called SOD2) and catalase (CAT) increased. DJ-1 overexpression activated Nrf2 expression, however, after Nrf2 silencing, apoptosis of RRPs increased, the ratio of Bcl-2 to BAX decreased, the production of ROS increased, the protein expression of MnSOD and CAT decreased, and the expression of heme oxygenase-1 (HO-1), NADP(H) quinone oxidoreductase (NQO1), glutamate-cysteine ligase catalytic subunit (GCLC) and modifier subunit (GCLM) decreased.

References

• Ref 1: Metformin, a first-line drug for type 2 diabetes mellitus, disrupts the MALAT1/miR-142-3p sponge to decrease invasion and migration in cervical cancer cells. Eur J Pharmacol. 2018 Jul 5;830:59-67. doi: 10.1016/j.ejphar.2018.04.027. Epub 2018 Apr 25.
• Ref 2: Metformin Induces Cell Cycle Arrest and Apoptosis in Drug-Resistant Leukemia Cells. Leuk Res Treatment. 2015;2015:516460. doi: 10.1155/2015/516460. Epub 2015 Nov 25.
• Ref 3: Chebulagic acid attenuates HFD/streptozotocin induced impaired glucose metabolism and insulin resistance via up regulations of PPAR Gamma and GLUT 4 in type 2 diabetic rats. Toxicol Mech Methods. 2022 Mar;32(3):159-170. doi: 10.1080/15376516.2021.1976333. Epub 2021 Sep 22.
• Ref 4: DJ-1 protects retinal pericytes against high glucose-induced oxidative stress through the Nrf2 signaling pathway. Sci Rep. 2020 Feb 12;10(1):2477. doi: 10.1038/s41598-020-59408-2.