Drug Details

General Information of the Drug (ID: DR9742)
Name
Gefitinib
Synonyms
Iressa; ZD1839; Irressat; gefitinib (zd1839); N-(3-Chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine; ZD 1839; ZD-1839; N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(morpholin-4-yl)propoxy]quinazolin-4-amine; N-(3-Chloro-4-fluoro-phenyl)-7-methoxy-6-(3-morpholin-4-ylpropoxy)quinazolin-4-amine; UNII-S65743JHBS; CCRIS 9011; CHEMBL939; 4-(3'-Chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline; N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(4-morpholinyl)propoxy]-4; 184475-35-2
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Molecular Type
Small molecule
Disease Lung cancer [ICD-11: 2C25] Approved [1]
Structure
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2D MOL

3D MOL

ADMET Property
BDDCS Class
Biopharmaceutics Drug Disposition Classification System (BDDCS) Class 2: low solubility and high permeability
Bioavailability
60% of drug becomes completely available to its intended biological destination(s)
Clearance
The clearance of drug is 595 mL/min
Elimination
2% of drug is excreted from urine in the unchanged form
Half-life
The concentration or amount of drug in body reduced by one-half in 48 hours
Metabolism
The drug is metabolized via the hepatic
MRTD
The Maximum Recommended Therapeutic Dose (MRTD) of drug that ensured maximising efficacy and moderate side effect is 8 micromolar/kg/day
Unbound Fraction
The unbound fraction of drug in plasma is 0.089%
Vd
The volume of distribution (Vd) of drug is 1400 L
Water Solubility
The ability of drug to dissolve in water is measured as 0.0017 mg/mL
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Formula
C22H24ClFN4O3
PubChem CID
123631
Canonical SMILES
COC1=C(C=C2C(=C1)N=CN=C2NC3=CC(=C(C=C3)F)Cl)OCCCN4CCOCC4
InChI
1S/C22H24ClFN4O3/c1-29-20-13-19-16(12-21(20)31-8-2-5-28-6-9-30-10-7-28)22(26-14-25-19)27-15-3-4-18(24)17(23)11-15/h3-4,11-14H,2,5-10H2,1H3,(H,25,26,27)
InChIKey
XGALLCVXEZPNRQ-UHFFFAOYSA-N
CAS Number
CAS 184475-35-2
GDSC
Gefitinib
TTD Drug ID
D09XZB
DrugBank ID
DB00317
Combinatorial Therapeutic Effect(s) Validated Clinically or Experimentally
    α. A List of Natural Product(s) Able to Enhance the Efficacy of This Drug
          Apigenin      Psilotum nudum     Click to Show/Hide the Molecular Data of This NP
                 Augmenting Drug Sensitivity     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [2]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Molecule(s)
                    Regulation		 Down-regulation Expression BCL-2  Molecule Info 
Pathway MAP
Up-regulation Expression BCL2L11  Molecule Info 
Pathway MAP
Up-regulation Cleavage CASP3  Molecule Info 
Pathway MAP
Down-regulation Expression CYB5R2  Molecule Info 
Pathway MAP
Down-regulation Expression CYM  Molecule Info 
Pathway MAP
Down-regulation Expression HIF-1A  Molecule Info 
Pathway MAP
Down-regulation Expression MYC  Molecule Info 
Pathway MAP
Up-regulation Cleavage PARP1  Molecule Info 
Pathway MAP
Down-regulation Phosphorylation PRKAA1  Molecule Info 
Pathway MAP
Down-regulation Expression SLC2A1  Molecule Info 
Pathway MAP
Down-regulation Expression SLC2A3  Molecule Info 
Pathway MAP
Down-regulation Expression SLC2A4  Molecule Info 
Pathway MAP
                    Biological
                    Regulation		 Down-regulation Autophagy flux
Induction Cell cycle arrest in G0/G1 phase
                    In-vitro Model NCI-H1975 CVCL_1511 Lung adenocarcinoma Homo sapiens
                    Experimental
                    Result(s)		 Apigenin combined with gefitinib blocks autophagy flux and induces apoptotic cell death through inhibition of HIF-1alpha, c-Myc, p-EGFR, and glucose metabolism in EGFR L858R+T790M-mutated H1975 Cells.
          Arsenic trioxide      Realgar and orpiment     Click to Show/Hide the Molecular Data of This NP
                 Achieving Therapeutic Synergy     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [3]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Molecule(s)
                    Regulation		 Up-regulation Expression ITGAM  Molecule Info 
Pathway MAP
Up-regulation Expression NDUFA2  Molecule Info 
Pathway MAP
                    In-vitro Model NB4 CVCL_0005 Acute promyelocytic leukemia Homo sapiens
                    Experimental
                    Result(s)		 Gefitinib enhances arsenic trioxide (AS2O3)-induced differentiation of acute promyelocytic leukemia cell line.
          Betulinic Acid      Rubus alceifolius     Click to Show/Hide the Molecular Data of This NP
                 Augmenting Drug Sensitivity     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [4]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Molecule(s)
                    Regulation		 Down-regulation Expression CDK6  Molecule Info 
Pathway MAP
Up-regulation Cleavage PARP1  Molecule Info 
Pathway MAP
Down-regulation Phosphorylation RB1  Molecule Info 
Pathway MAP
Up-regulation Expression SQSTM1  Molecule Info 
Pathway MAP
Down-regulation Expression TYMS  Molecule Info 
Pathway MAP
                    Biological
                    Regulation		 Induction Loss of mitochondrial membrane potential
                    In-vitro Model HCC827 CVCL_2063 Lung adenocarcinoma Homo sapiens
NCI-H1975 CVCL_1511 Lung adenocarcinoma Homo sapiens
                    Experimental
                    Result(s)		 Combining betulinic acid with an EGFR TKI improves drug efficacy in EGFR TKI-resistant lung cancer cells.
          Bufalin      Bufo gargarizans     Click to Show/Hide the Molecular Data of This NP
                 Achieving Therapeutic Synergy     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [5]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Molecule(s)
                    Regulation		 Down-regulation Phosphorylation AKT1  Molecule Info 
Pathway MAP
Down-regulation Phosphorylation EGFR  Molecule Info 
Pathway MAP
Down-regulation Phosphorylation MET  Molecule Info 
Pathway MAP
Down-regulation Phosphorylation mTOR  Molecule Info 
Pathway MAP
                    In-vitro Model NCI-H1975 CVCL_1511 Lung adenocarcinoma Homo sapiens
                    Experimental
                    Result(s)		 Combination of bufalin and gefitinib potently inhibited the growth of H1975 cells, and induced cell apoptosis. The potential mechanism for anti-tumor might be involved in blocking EGFR-PI3k/Akt pathway.
          Cryptotanshinone      Salvia miltiorrhiza     Click to Show/Hide the Molecular Data of This NP
                 Achieving Therapeutic Synergy     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [6]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Molecule(s)
                    Regulation		 Up-regulation Cleavage CASP3  Molecule Info 
Pathway MAP
Down-regulation Expression GABPA  Molecule Info 
Pathway MAP
Down-regulation Expression TK  Molecule Info 
Pathway MAP
                    In-vitro Model NCI-H1299 CVCL_0060 Lung large cell carcinoma Homo sapiens
NCI-H1975 CVCL_1511 Lung adenocarcinoma Homo sapiens
A-549 CVCL_0023 Lung adenocarcinoma Homo sapiens
                    In-vivo Model H1975 human lung cancer cells (5 * 107 in 1 ml) or PC9/GR human lung cancer cells (3 * 107 in 1 ml) were injected subcutaneously into the right flank of athymic BALB/c nude mice (3-4 weeks old).
                    Experimental
                    Result(s)		 Cryptotanshinone strengthens the effect of gefitinib against non-small cell lung cancer through inhibiting transketolase.
          Cucurbitacin B      Cucurbitaceae     Click to Show/Hide the Molecular Data of This NP
                 Achieving Therapeutic Synergy     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [7]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    In-vitro Model HCT 116 CVCL_0291 Colon carcinoma Homo sapiens
HT-29 CVCL_0320 Colon adenocarcinoma Homo sapiens
                    Experimental
                    Result(s)		 CuB plus Gef treatment caused a significant growth and cell cycle inhibition and induced apoptosis in both cell lines.
          Curcumin      Hellenia speciosa     Click to Show/Hide the Molecular Data of This NP
                 Achieving Therapeutic Synergy     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [8]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Molecule(s)
                    Regulation		 Down-regulation Phosphorylation AKT1  Molecule Info 
Pathway MAP
Down-regulation Phosphorylation EGFR  Molecule Info 
Pathway MAP
Down-regulation Phosphorylation ERK1  Molecule Info 
Pathway MAP
Down-regulation Phosphorylation ERK2  Molecule Info 
Pathway MAP
Down-regulation Phosphorylation MEK1  Molecule Info 
Pathway MAP
Down-regulation Phosphorylation MEK2  Molecule Info 
Pathway MAP
Down-regulation Expression PSG1  Molecule Info 
Pathway MAP
Down-regulation Phosphorylation S6K1  Molecule Info 
Pathway MAP
                    In-vitro Model H157 CVCL_2458 Mucosa squamous cell carcinoma Homo sapiens
NCI-H1299 CVCL_0060 Lung large cell carcinoma Homo sapiens
PC-9 CVCL_B260 Lung adenocarcinoma Homo sapiens
                    In-vivo Model H157 and H1299 cells (6*106 cells per mouse) were subcutaneously grafted into the right flanks of six-week-old female athymic nude BALBL/c mice.
                    Experimental
                    Result(s)		 Combination treatment with curcumin and gefitinib markedly downregulated EGFR activity through suppressing Sp1 and blocking interaction of Sp1 and HADC1, and markedly suppressed receptor tyrosine kinases as well as ERK/MEK and AKT/S6K pathways in the resistant NSCLC cells.
          Cyclopamine      Veratrum californicum     Click to Show/Hide the Molecular Data of This NP
                 Achieving Therapeutic Synergy     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [9]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Molecule(s)
                    Regulation		 Down-regulation Expression EGFR  Molecule Info 
Pathway MAP
                    In-vitro Model PC-3 CVCL_0035 Prostate carcinoma Homo sapiens
                    Experimental
                    Result(s)		 The combined cyclopamine and gefitinib were more effective at suppressing the invasiveness of PC3 cells through matrigel in vitro as the drugs alone.
          Elemene      Pogostemon cablin     Click to Show/Hide the Molecular Data of This NP
                 Achieving Therapeutic Synergy     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [11]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Molecule(s)
                    Regulation		 Up-regulation Expression CDH1  Molecule Info 
Pathway MAP
Down-regulation Expression CDH2  Molecule Info 
Pathway MAP
Up-regulation Expression HES1  Molecule Info 
Pathway MAP
Up-regulation Expression MYC  Molecule Info 
Pathway MAP
Up-regulation Expression NOTCH1  Molecule Info 
Pathway MAP
Up-regulation Expression SHH  Molecule Info 
Pathway MAP
Down-regulation Expression SNAI1  Molecule Info 
Pathway MAP
Up-regulation Expression SOX2  Molecule Info 
Pathway MAP
Down-regulation Expression TWIST1  Molecule Info 
Pathway MAP
Down-regulation Expression VIM  Molecule Info 
Pathway MAP
Down-regulation Expression ZEB1  Molecule Info 
Pathway MAP
                    In-vitro Model A-549 CVCL_0023 Lung adenocarcinoma Homo sapiens
NCI-H1299 CVCL_0060 Lung large cell carcinoma Homo sapiens
                    Experimental
                    Result(s)		 Beta-Elemene synergizes with gefitinib to inhibit stem-like phenotypes and progression of lung cancer via down-regulating EZH2.
          Genistein      Glycine max     Click to Show/Hide the Molecular Data of This NP
                 Achieving Therapeutic Synergy     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [12]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Molecule(s)
                    Regulation		 Down-regulation Phosphorylation AKT1  Molecule Info 
Pathway MAP
Up-regulation Cleavage CASP3  Molecule Info 
Pathway MAP
Up-regulation Cleavage COL11A2  Molecule Info 
Pathway MAP
Down-regulation Phosphorylation EGFR  Molecule Info 
Pathway MAP
Down-regulation Phosphorylation ERK1  Molecule Info 
Pathway MAP
Down-regulation Phosphorylation ERK2  Molecule Info 
Pathway MAP
Down-regulation Phosphorylation mTOR  Molecule Info 
Pathway MAP
                    In-vitro Model NCI-H1975 CVCL_1511 Lung adenocarcinoma Homo sapiens
                    In-vivo Model Detached H1975 cells were diluted and emulsified with medium to a final concentration of 2*107 cells/ml. The emulsion (200 uL) was inoculated subcutaneously into 4-6-week-old female nude BALB/c mice.
                    Experimental
                    Result(s)		 Genistein enhanced the antitumor effects of gefitinib in a NSCLC cell line carrying the T790M mutation. This synergistic activity may be due to increased inhibition of the downstream molecular and pro-apoptotic effects of EGFR.
          Luteolin      Abrus precatorius     Click to Show/Hide the Molecular Data of This NP
                 Achieving Therapeutic Synergy     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [13]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Biological
                    Regulation		 Arrest Cell cycle arrest in G0/G1 phase
                    In-vitro Model PC-3 CVCL_0035 Prostate carcinoma Homo sapiens
                    Experimental
                    Result(s)		 Luteolin and gefitinib regulate CCP gene expression through a common mechanism involving EGFR-associated tyrosine kinase.
          Metformin      Galega officinalis     Click to Show/Hide the Molecular Data of This NP
                 Achieving Therapeutic Synergy     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [14]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Molecule(s)
                    Regulation		 Up-regulation Expression c-RAF  Molecule Info 
Pathway MAP
Up-regulation Expression PRKAA2  Molecule Info 
Pathway MAP
                    In-vitro Model Calu-3 CVCL_0609 Lung adenocarcinoma Homo sapiens
GLC-82 CVCL_3371 Non-small cell lung cancer Homo sapiens
NCI-H1975 CVCL_1511 Lung adenocarcinoma Homo sapiens
NCI-H460 CVCL_0459 Lung large cell carcinoma Homo sapiens
NCI-H1299 CVCL_0060 Lung large cell carcinoma Homo sapiens
A-549 CVCL_0023 Lung adenocarcinoma Homo sapiens
                    Experimental
                    Result(s)		 Metformin and gefitinib are synergistic in LKB1 wild-type NSCLC cells.
          Shikonin      Lithospermum erythrorhizon     Click to Show/Hide the Molecular Data of This NP
                 Augmenting Drug Sensitivity     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [15]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Molecule(s)
                    Regulation		 Down-regulation Expression CCND1  Molecule Info 
Pathway MAP
Down-regulation Expression PKM  Molecule Info 
Pathway MAP
Down-regulation Expression STAT3  Molecule Info 
Pathway MAP
                    In-vitro Model A-549 CVCL_0023 Lung adenocarcinoma Homo sapiens
NCI-H1299 CVCL_0060 Lung large cell carcinoma Homo sapiens
NCI-H1975 CVCL_1511 Lung adenocarcinoma Homo sapiens
HCC827 CVCL_2063 Lung adenocarcinoma Homo sapiens
                    In-vivo Model Animal models were constructed by injecting A549 cells (1*107) into nude mice (six-week) in the dorsal area.
                    Experimental
                    Result(s)		 Shikonin enhances sensitization of gefitinib against wild-type EGFR non-small cell lung cancer via inhibition PKM2/stat3/cyclinD1 signal pathway.
          Vitamin E      Salmo salar     Click to Show/Hide the Molecular Data of This NP
                 Achieving Therapeutic Synergy     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [16]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Molecule(s)
                    Regulation		 Down-regulation Phosphorylation ERK1  Molecule Info 
Pathway MAP
                    In-vitro Model NRK-49F CVCL_2144 Healthy Rattus norvegicus
                    Experimental
                    Result(s)		 A combined treatment with low-dose gefitinib and vitamin E has synergistic effects that reduce TGF Beta1 induced fibroblast proliferation, cell-cycle arrest and the ERK phosphorylation pathway.
    β. A List of Natural Product(s) Able to Decrease the Adverse Effect of This Drug
          Cucurbitacin D      Cucurbitaceae     Click to Show/Hide the Molecular Data of This NP
                 Decreasing Adverse Drug Reaction     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [17]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Molecule(s)
                    Regulation		 Down-regulation Phosphorylation EGFR  Molecule Info 
Pathway MAP
                    In-vitro Model HCC827 CVCL_2063 Lung adenocarcinoma Homo sapiens
                    Experimental
                    Result(s)		 Cucurbitacin D overcomes gefitinib resistance by blocking EGF binding to EGFR and inducing cell death in NSCLCs.
          Sulforaphane      Brassica oleracea     Click to Show/Hide the Molecular Data of This NP
                 Decreasing Adverse Drug Reaction     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [18]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Molecule(s)
                    Regulation		 Down-regulation Expression BCL-2  Molecule Info 
Pathway MAP
Down-regulation Expression COX-2  Molecule Info 
Pathway MAP
                    In-vitro Model MCF-7 CVCL_0031 Invasive breast carcinoma Homo sapiens
                    Experimental
                    Result(s)		 The combination of SFN and gemcitabine potentiates the efficacy of gemcitabine and minimize the toxicity to normal cells.
    γ. A List of Natural Product(s) Able to Reverse the Resistance of This Drug
          Celastrol      Celastrus strigillosus     Click to Show/Hide the Molecular Data of This NP
                 Reversing Drug Resistance     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [19]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Molecule(s)
                    Regulation		 Down-regulation Phosphorylation AKT1  Molecule Info 
Pathway MAP
Down-regulation Phosphorylation EGFR  Molecule Info 
Pathway MAP
Down-regulation Phosphorylation ERK1  Molecule Info 
Pathway MAP
Down-regulation Phosphorylation STAT3  Molecule Info 
Pathway MAP
                    In-vitro Model A-549 CVCL_0023 Lung adenocarcinoma Homo sapiens
NCI-H1975 CVCL_1511 Lung adenocarcinoma Homo sapiens
                    In-vivo Model Each mouse (five-week-old BALB/c nude mice) was subcutaneously injected with 2 * 106 H1975 lung carcinoma cells in logarithmic growth phase.
                    Experimental
                    Result(s)		 Celastrol improves the therapeutic efficacy of EGFR-TKIs for non-small-cell lung cancer by overcoming EGFR T790M drug resistance.
          Epigallocatechin gallate      Hamamelis virginiana     Click to Show/Hide the Molecular Data of This NP
                 Reversing Drug Resistance     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [20]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Molecule(s)
                    Regulation		 Down-regulation Phosphorylation ERK1  Molecule Info 
Pathway MAP
Up-regulation Expression SQSTM1  Molecule Info 
Pathway MAP
                    In-vitro Model A-549 CVCL_0023 Lung adenocarcinoma Homo sapiens
                    In-vivo Model A549 cells were injected subcutaneously (1*106, 100 uL of PBS) into the left flanks of the 7-8-week old BALB/C male nude mice.
                    Experimental
                    Result(s)		 EGCG overcomes gefitinib resistance by inhibiting autophagy and augmenting cell death through targeting ERK phosphorylation in NSCLC.
          Gambogic acid      Garcinia morella     Click to Show/Hide the Molecular Data of This NP
                 Reversing Drug Resistance     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [21]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Molecule(s)
                    Regulation		 Down-regulation Phosphorylation AKT1  Molecule Info 
Pathway MAP
Up-regulation Expression BAX  Molecule Info 
Pathway MAP
Down-regulation Expression BCL-2  Molecule Info 
Pathway MAP
Down-regulation Phosphorylation ERK1  Molecule Info 
Pathway MAP
Down-regulation Phosphorylation MEK1  Molecule Info 
Pathway MAP
                    In-vitro Model NCI-H1975 CVCL_1511 Lung adenocarcinoma Homo sapiens
                    In-vivo Model The mice were subcutaneously injected with 1*107 NCI-H1975 cells suspended in 100 uL of Matrigel.
                    Experimental
                    Result(s)		 Gefitinib in combination with GA resulted in antitumor growth in the EGFR-T790M secondary mutation NCI-H1975 tumor model due to an enhanced apoptotic effect.
          Silibinin      Carduus marianus     Click to Show/Hide the Molecular Data of This NP
                 Reversing Drug Resistance     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [22]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Molecule(s)
                    Regulation		 Down-regulation Phosphorylation AKT1  Molecule Info 
Pathway MAP
Down-regulation Expression EGFR  Molecule Info 
Pathway MAP
Down-regulation Phosphorylation ERK1  Molecule Info 
Pathway MAP
                    In-vitro Model A-549 CVCL_0023 Lung adenocarcinoma Homo sapiens
NCI-H460 CVCL_0459 Lung large cell carcinoma Homo sapiens
NCI-H1299 CVCL_0060 Lung large cell carcinoma Homo sapiens
NCI-H1975 CVCL_1511 Lung adenocarcinoma Homo sapiens
HCC827 CVCL_2063 Lung adenocarcinoma Homo sapiens
LK2 CVCL_W132 Ovarian carcinoma Homo sapiens
PC-9 CVCL_B260 Lung adenocarcinoma Homo sapiens
293T GNE CVCL_0V13 Healthy Homo sapiens
                    In-vivo Model Animal models were constructed by implanting 5*106 PC-9 cells in Matrigel into the flanks of female severe combined immunodeficiency (SCID) mice.
                    Experimental
                    Result(s)		 Combined treatment with silibinin and epidermal growth factor receptor tyrosine kinase inhibitors overcomes drug resistance caused by T790M mutation.
          Triptolide      Tripterygium hypoglaucum     Click to Show/Hide the Molecular Data of This NP
                 Reversing Drug Resistance     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [23]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Molecule(s)
                    Regulation		 Down-regulation Expression MMP-9  Molecule Info 
Pathway MAP
Down-regulation Expression SNAI1  Molecule Info 
Pathway MAP
Down-regulation Expression VIM  Molecule Info 
Pathway MAP
                    In-vitro Model A-549 CVCL_0023 Lung adenocarcinoma Homo sapiens
                    In-vivo Model The A549/siE-cad cells (2*106) were injected subcutaneously into the underarms of the right forelimbs of 6-week-old BCLB/c mice.
                    Experimental
                    Result(s)		 Triptolide inhibits epithelial mesenchymal transition and induces apoptosis in gefitinib resistant lung cancer cells.
Target and Pathway
Target(s) Epidermal growth factor receptor (EGFR)  Molecule Info  [24]
KEGG Pathway MAPK signaling pathway Click to Show/Hide
2 ErbB signaling pathway
3 Ras signaling pathway
4 Rap1 signaling pathway
5 Calcium signaling pathway
6 Cytokine-cytokine receptor interaction
7 HIF-1 signaling pathway
8 FoxO signaling pathway
9 Endocytosis
10 PI3K-Akt signaling pathway
11 Dorso-ventral axis formation
12 Focal adhesion
13 Adherens junction
14 Gap junction
15 Regulation of actin cytoskeleton
16 GnRH signaling pathway
17 Estrogen signaling pathway
18 Oxytocin signaling pathway
19 Epithelial cell signaling in Helicobacter pylori infection
20 Hepatitis C
21 Pathways in cancer
22 Proteoglycans in cancer
23 MicroRNAs in cancer
24 Pancreatic cancer
25 Endometrial cancer
26 Glioma
27 Prostate cancer
28 Melanoma
29 Bladder cancer
30 Non-small cell lung cancer
31 Central carbon metabolism in cancer
32 Choline metabolism in cancer
NetPath Pathway IL4 Signaling Pathway Click to Show/Hide
2 EGFR1 Signaling Pathway
Panther Pathway Cadherin signaling pathway Click to Show/Hide
2 EGF receptor signaling pathway
Pathway Interaction Database LPA receptor mediated events Click to Show/Hide
2 Signaling events mediated by PTP1B
3 Arf6 signaling events
4 Signaling events mediated by TCPTP
5 Thromboxane A2 receptor signaling
6 SHP2 signaling
7 Regulation of Telomerase
8 EGF receptor (ErbB1) signaling pathway
9 EGFR-dependent Endothelin signaling events
10 Posttranslational regulation of adherens junction stability and dissassembly
11 Direct p53 effectors
12 ErbB1 downstream signaling
13 Urokinase-type plasminogen activator (uPA) and uPAR-mediated signaling
14 E-cadherin signaling in keratinocytes
15 ErbB receptor signaling network
16 Internalization of ErbB1
17 Stabilization and expansion of the E-cadherin adherens junction
18 a6b1 and a6b4 Integrin signaling
19 Syndecan-3-mediated signaling events
Reactome Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants Click to Show/Hide
2 SHC1 events in ERBB2 signaling
3 PLCG1 events in ERBB2 signaling
4 PIP3 activates AKT signaling
5 GRB2 events in EGFR signaling
6 GAB1 signalosome
7 SHC1 events in EGFR signaling
8 EGFR downregulation
9 GRB2 events in ERBB2 signaling
10 PI3K events in ERBB2 signaling
11 EGFR Transactivation by Gastrin
12 Constitutive Signaling by Aberrant PI3K in Cancer
13 Constitutive Signaling by EGFRvIII
14 RAF/MAP kinase cascade
WikiPathways ErbB Signaling Pathway Click to Show/Hide
2 Regulation of Actin Cytoskeleton
3 EGF/EGFR Signaling Pathway
4 MAPK Signaling Pathway
5 Focal Adhesion
6 Aryl Hydrocarbon Receptor Pathway
7 Extracellular vesicle-mediated signaling in recipient cells
8 TCA Cycle Nutrient Utilization and Invasiveness of Ovarian Cancer
9 Hair Follicle Development: Cytodifferentiation (Part 3 of 3)
10 Bladder Cancer
11 Hair Follicle Development: Induction (Part 1 of 3)
12 Signaling by ERBB4
13 Signaling by ERBB2
14 Gastrin-CREB signalling pathway via PKC and MAPK
15 PIP3 activates AKT signaling
16 Nanoparticle-mediated activation of receptor signaling
17 Aryl Hydrocarbon Receptor
18 Spinal Cord Injury
19 Integrated Pancreatic Cancer Pathway
20 Gastric cancer network 2
21 AGE/RAGE pathway
22 Signaling Pathways in Glioblastoma
23 Arylhydrocarbon receptor (AhR) signaling pathway
24 miR-targeted genes in muscle cell - TarBase
25 miR-targeted genes in lymphocytes - TarBase
26 miR-targeted genes in epithelium - TarBase
27 Integrated Breast Cancer Pathway
28 Signaling by EGFR
29 L1CAM interactions
References
Reference 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: 4941).
Reference 2 Apigenin Combined With Gefitinib Blocks Autophagy Flux and Induces Apoptotic Cell Death Through Inhibition of HIF-1alpha, c-Myc, p-EGFR, and Glucose Metabolism in EGFR L858R+T790M-Mutated H1975 Cells. Front Pharmacol. 2019 Mar 22;10:260.
Reference 3 Gefitinib enhances arsenic trioxide (AS2O3)-induced differentiation of acute promyelocytic leukemia cell line. Leuk Res. 2010 Nov;34(11):1501-5.
Reference 4 Effects and mechanisms of betulinic acid on improving EGFR TKI-resistance of lung cancer cells. Environ Toxicol. 2018 Nov;33(11):1153-1159.
Reference 5 [Effect of bufalin combined gefitinib on lung cancer H1975 cells and its mechanisms research]. Zhongguo Zhong Xi Yi Jie He Za Zhi. 2013 Aug;33(8):1081-5.
Reference 6 Cryptotanshinone strengthens the effect of gefitinib against non-small cell lung cancer through inhibiting transketolase. Eur J Pharmacol. 2021 Jan 5;890:173647.
Reference 7 Treatment with cucurbitacin B alone and in combination with gefitinib induces cell cycle inhibition and apoptosis via EGFR and JAK/STAT pathway in human colorectal cancer cell lines. Hum Exp Toxicol. 2016 May;35(5):526-43.
Reference 8 Curcumin overcome primary gefitinib resistance in non-small-cell lung cancer cells through inducing autophagy-related cell death. J Exp Clin Cancer Res. 2019 Jun 13;38(1):254.
Reference 9 Cytotoxic effects induced by a combination of cyclopamine and gefitinib, the selective hedgehog and epidermal growth factor receptor signaling inhibitors, in prostate cancer cells. Int J Cancer. 2006 Feb 15;118(4):1022-31.
Reference 10 Combined targeting of epidermal growth factor receptor and hedgehog signaling by gefitinib and cyclopamine cooperatively improves the cytotoxic effects of docetaxel on metastatic prostate cancer cells. Mol Cancer Ther. 2007 Mar;6(3):967-78.
Reference 11 Beta-Elemene Synergizes With Gefitinib to Inhibit Stem-Like Phenotypes and Progression of Lung Cancer via Down-Regulating EZH2. Front Pharmacol. 2018 Nov 30;9:1413.
Reference 12 Synergistic inhibitory effects by the combination of gefitinib and genistein on NSCLC with acquired drug-resistance in vitro and in vivo. Mol Biol Rep. 2012 Apr;39(4):4971-9.
Reference 13 Luteolin and gefitinib regulation of EGF signaling pathway and cell cycle pathway genes in PC-3 human prostate cancer cells. J Steroid Biochem Mol Biol. 2010 Oct;122(4):219-31.
Reference 14 Synergistic effects of metformin treatment in combination with gefitinib, a selective EGFR tyrosine kinase inhibitor, in LKB1 wild-type NSCLC cell lines. Clin Cancer Res. 2013 Jul 1;19(13):3508-19.
Reference 15 Shikonin enhances sensitization of gefitinib against wild-type EGFR non-small cell lung cancer via inhibition PKM2/stat3/cyclinD1 signal pathway. Life Sci. 2018 Jul 1;204:71-77.
Reference 16 Combined treatment with vitamin E and gefitinib has synergistic effects to inhibit TGF-Beta1-induced renal fibroblast proliferation. Mol Med Rep. 2016 Jun;13(6):5372-8.
Reference 17 Cucurbitacin D Overcomes Gefitinib Resistance by Blocking EGF Binding to EGFR and Inducing Cell Death in NSCLCs. Front Oncol. 2020 Feb 18;10:62.
Reference 18 Sulforaphane inhibits growth of human breast cancer cells and augments the therapeutic index of the chemotherapeutic drug, gemcitabine. Asian Pac J Cancer Prev. 2013;14(10):5855-60.
Reference 19 Celastrol improves the therapeutic efficacy of EGFR-TKIs for non-small-cell lung cancer by overcoming EGFR T790M drug resistance. Anticancer Drugs. 2018 Sep;29(8):748-755.
Reference 20 EGCG overcomes gefitinib resistance by inhibiting autophagy and augmenting cell death through targeting ERK phosphorylation in NSCLC. Onco Targets Ther. 2019 Jul 26;12:6033-6043.
Reference 21 Combined therapy with EGFR TKI and gambogic acid for overcoming resistance in EGFR-T790M mutant lung cancer. Oncol Lett. 2015 Oct;10(4):2063-2066.
Reference 22 Combined treatment with silibinin and epidermal growth factor receptor tyrosine kinase inhibitors overcomes drug resistance caused by T790M mutation. Mol Cancer Ther. 2010 Dec;9(12):3233-43.
Reference 23 Triptolide inhibits epithelial?mesenchymal transition and induces apoptosis in gefitinib?resistant lung cancer cells. Oncol Rep. 2020 May;43(5):1569-1579.
Reference 24 Gefitinib ('Iressa', ZD1839) and new epidermal growth factor receptor inhibitors. Br J Cancer. 2004 Feb 9;90(3):566-72.
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