Drug Information

Drug (ID: DG00286) and It's Reported Resistant Information
Name
Vinblastine
Synonyms
Nincaluicolflastine; Rozevin; VLB; Vinblastin; Vinblastina; Vinblastinum; Vincaleucoblastin; Vincaleucoblastine; Vincaleukoblastine; Vincoblastine; Vinblastina [DCIT]; VR-8; Vinblastina (TN); Vinblastine (INN); Vinblastine [INN:BAN]; Vinblastinum [INN-Latin]; NDC 0002-1452-01; (2ALPHA,2'BETA,3BETA,4ALPHA,5BETA)-VINCALEUKOBLASTINE; (2xi,3beta,4'beta,19xi)-vincaleukoblastine; 1H-Indolizino(8,1-cd)carbazole-5-carboxylic acid
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Indication
In total 1 Indication(s)
Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Approved
[1]
Structure
Drug Resistance Disease(s)
Disease(s) with Clinically Reported Resistance for This Drug (1 diseases)
Ovarian cancer [ICD-11: 2C73]
[2]
Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (4 diseases)
Brain cancer [ICD-11: 2A00]
[3]
Cervical cancer [ICD-11: 2C77]
[3]
Colorectal cancer [ICD-11: 2B91]
[3]
Oral squamous cell carcinoma [ICD-11: 2B6E]
[3]
Target Tubulin beta-2 chain (TUBB2) TBB2A_HUMAN [1]
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Formula
C46H58N4O9
IsoSMILES
CC[C@@]1(C[C@H]2C[C@@](C3=C(CCN(C2)C1)C4=CC=CC=C4N3)(C5=C(C=C6C(=C5)[C@]78CCN9[C@H]7[C@@](C=CC9)([C@H]([C@@]([C@@H]8N6C)(C(=O)OC)O)OC(=O)C)CC)OC)C(=O)OC)O
InChI
1S/C46H58N4O9/c1-8-42(54)23-28-24-45(40(52)57-6,36-30(15-19-49(25-28)26-42)29-13-10-11-14-33(29)47-36)32-21-31-34(22-35(32)56-5)48(4)38-44(31)17-20-50-18-12-16-43(9-2,37(44)50)39(59-27(3)51)46(38,55)41(53)58-7/h10-14,16,21-22,28,37-39,47,54-55H,8-9,15,17-20,23-26H2,1-7H3/t28-,37-,38+,39+,42-,43+,44+,45-,46-/m0/s1
InChIKey
JXLYSJRDGCGARV-CFWMRBGOSA-N
PubChem CID
13342
TTD Drug ID
D0W9MM
VARIDT ID
DR00308
DrugBank ID
DB00570
Type(s) of Resistant Mechanism of This Drug
  EADR: Epigenetic Alteration of DNA, RNA or Protein
  IDUE: Irregularity in Drug Uptake and Drug Efflux
  UAPP: Unusual Activation of Pro-survival Pathway
Drug Resistance Data Categorized by Their Corresponding Diseases
ICD-02: Benign/in-situ/malignant neoplasm
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Brain cancer [ICD-11: 2A00]
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Irregularity in Drug Uptake and Drug Efflux (IDUE) Click to Show/Hide
Key Molecule: Multidrug resistance protein 1 (ABCB1) [3]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Glioma [ICD-11: 2A00.1]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model U87-MG cells Brain Homo sapiens (Human) CVCL_0022
In Vivo Model Athymic nu/nu female mice xenograft model Mus musculus
Experiment for
Drug Resistance		 MTS assay
Mechanism Description In a cell line expressing a high level of P-glycoprotein, the IC50 of TTI-237 increased 25-fold whereas those of paclitaxel and vincristine increased 806-fold and 925-fold.
Chronic myeloid leukemia [ICD-11: 2A20]
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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
       Irregularity in Drug Uptake and Drug Efflux (IDUE) Click to Show/Hide
Key Molecule: Multidrug resistance protein 1 (ABCB1) [4]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Chronic myeloid leukemia [ICD-11: 2A20.0]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model NCI-H460 cells Lung Homo sapiens (Human) CVCL_0459
K562 cells Blood Homo sapiens (Human) CVCL_0004
HEK293 cells Kidney Homo sapiens (Human) CVCL_0045
K562-R cells Pleural effusion Homo sapiens (Human) CVCL_5950
NCI-H460/VBL cells Bone marrow Homo sapiens (Human) CVCL_0459
In Vivo Model SCID beige mice Mus musculus
Experiment for
Molecule Alteration		 Western blotting analysis
Experiment for
Drug Resistance		 MTT assay
Mechanism Description In ABCB1-overexpressing cell lines, HG-829 significantly enhanced cytotoxicity to daunorubicin, paclitaxel, vinblastine, vincristine, and etoposide. Coadministration of HG-829 fully restored in vivo antitumor activity of daunorubicin in mice without added toxicity. Functional assays showed that HG-829 is not a Pgp substrate or competitive inhibitor of Pgp-mediated drug efflux but rather acts as a noncompetitive modulator of P-glycoprotein transport function.
Oral squamous cell carcinoma [ICD-11: 2B6E]
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Irregularity in Drug Uptake and Drug Efflux (IDUE) Click to Show/Hide
Key Molecule: Multidrug resistance protein 1 (ABCB1) [3]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Squamous cell carcinoma [ICD-11: 2B6E.3]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model KB-3-1 cells Lung Homo sapiens (Human) CVCL_2088
KB-8-5 cells Mouth Homo sapiens (Human) CVCL_5994
KB-V1 cells Mouth Homo sapiens (Human) CVCL_2089
In Vivo Model Athymic nu/nu female mice xenograft model Mus musculus
Experiment for
Drug Resistance		 MTS assay
Mechanism Description In a cell line expressing a high level of P-glycoprotein, the IC50 of TTI-237 increased 25-fold whereas those of paclitaxel and vincristine increased 806-fold and 925-fold.
Colorectal cancer [ICD-11: 2B91]
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Irregularity in Drug Uptake and Drug Efflux (IDUE) Click to Show/Hide
Key Molecule: Multidrug resistance protein 1 (ABCB1) [3]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Colorectal carcinoma [ICD-11: 2B91.3]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model LOVO cells Colon Homo sapiens (Human) CVCL_0399
In Vivo Model Athymic nu/nu female mice xenograft model Mus musculus
Experiment for
Drug Resistance		 MTS assay
Mechanism Description In a cell line expressing a high level of P-glycoprotein, the IC50 of TTI-237 increased 25-fold whereas those of paclitaxel and vincristine increased 806-fold and 925-fold.
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
       Irregularity in Drug Uptake and Drug Efflux (IDUE) Click to Show/Hide
Key Molecule: ATP-binding cassette sub-family B5 (ABCB5) [5]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Colorectal carcinoma [ICD-11: 2B91.3]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model CaCo2 cells Colon Homo sapiens (Human) CVCL_0025
HCT-8 cells Colon Homo sapiens (Human) CVCL_2478
NIH-G185 cells Ovary Homo sapiens (Human) CVCL_L991
NIH 3T3 cells Colon Homo sapiens (Human) CVCL_0594
Experiment for
Molecule Alteration		 Western blotting analysis
Experiment for
Drug Resistance		 MTT assay
Mechanism Description G185 cells were 27-135 fold more resistant to the cytotoxic drugs doxorubicin, vinblastine, colchicine and paclitaxel than the parental NIH 3T3 cells. Co-administration of TPGS enhanced the cytotoxicity of doxorubicin, vinblastine, paclitaxel, and colchicine in the G185 cells to levels comparable to the parental.
Liver cancer [ICD-11: 2C12]
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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
       Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: hsa-mir-335 [1]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Sensitive Disease Hepatocellular carcinoma [ICD-11: 2C12.2]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell invasion Inhibition hsa05200
Cell migration Inhibition hsa04670
Cell proliferation Inhibition hsa05200
miR335/SIAH2/HDAC3 signaling pathway Regulation hsa05206
In Vitro Model SNU387 cells Liver Homo sapiens (Human) CVCL_0250
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 Trypan blue exclusion assay; Transwell assay
Mechanism Description miR-335-mediated increased sensitivity to anti-cancer drugs was associated with its effect on HDAC3 and SIAH2 expression. miR-335 exerted apoptotic effects and inhibited ubiquitination of HDAC3 in anti-cancer drug-resistant cancer cell lines. miR-335 negatively regulated the invasion, migration, and growth rate of cancer cells. The mouse xenograft model showed that miR-335 negatively regulated the tumorigenic potential of cancer cells. The down-regulation of SIAH2 conferred sensitivity to anti-cancer drugs. The results of the study indicated that the miR-335/SIAH2/HDAC3 axis regulates the response to anti-cancer drugs.
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: E3 ubiquitin-protein ligase SIAH2 (SIAH2) [1]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Hepatocellular carcinoma [ICD-11: 2C12.2]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell invasion Inhibition hsa05200
Cell migration Inhibition hsa04670
Cell proliferation Inhibition hsa05200
miR335/SIAH2/HDAC3 signaling pathway Regulation hsa05206
In Vitro Model SNU387 cells Liver Homo sapiens (Human) CVCL_0250
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 Trypan blue exclusion assay; Transwell assay
Mechanism Description miR-335-mediated increased sensitivity to anti-cancer drugs was associated with its effect on HDAC3 and SIAH2 expression. miR-335 exerted apoptotic effects and inhibited ubiquitination of HDAC3 in anti-cancer drug-resistant cancer cell lines. miR-335 negatively regulated the invasion, migration, and growth rate of cancer cells. The mouse xenograft model showed that miR-335 negatively regulated the tumorigenic potential of cancer cells. The down-regulation of SIAH2 conferred sensitivity to anti-cancer drugs. The results of the study indicated that the miR-335/SIAH2/HDAC3 axis regulates the response to anti-cancer drugs.
Ovarian cancer [ICD-11: 2C73]
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: hsa-let-7g [2]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Resistant Disease Ovarian cancer [ICD-11: 2C73.0]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model T47D cells Breast Homo sapiens (Human) CVCL_0553
IGROV1 cells Ovary Homo sapiens (Human) CVCL_1304
OVCAR8 cells Ovary Homo sapiens (Human) CVCL_1629
LOX-IMVI cells Ovary Homo sapiens (Human) CVCL_1381
NCI/ADR-RES cells Ovary Homo sapiens (Human) CVCL_1452
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 SRB cytotoxicity assay
Mechanism Description IMP-1 is an RNA binding protein that acts by stabilizing the mRNA of a number of target genes. In addition, IMP-1 was shown to protect the mRNA of MDR1 from endonucleolytic attack in an in vitro RNA stability assay. Introducing let-7g into ADR-RES cells expressing both IMP-1 and MDR1 reduced expression of both proteins rendering the cells more sensitive to treatment with either Taxol or vinblastine without affecting the sensitivity of the cells to carboplatin.
       Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) [2]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Ovarian cancer [ICD-11: 2C73.0]
 Disease Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model T47D cells Breast Homo sapiens (Human) CVCL_0553
IGROV1 cells Ovary Homo sapiens (Human) CVCL_1304
OVCAR8 cells Ovary Homo sapiens (Human) CVCL_1629
LOX-IMVI cells Ovary Homo sapiens (Human) CVCL_1381
NCI/ADR-RES cells Ovary Homo sapiens (Human) CVCL_1452
Experiment for
Molecule Alteration		 Western blotting analysis
Experiment for
Drug Resistance		 SRB cytotoxicity assay
Mechanism Description IMP-1 is an RNA binding protein that acts by stabilizing the mRNA of a number of target genes. In addition, IMP-1 was shown to protect the mRNA of MDR1 from endonucleolytic attack in an in vitro RNA stability assay. Introducing let-7g into ADR-RES cells expressing both IMP-1 and MDR1 reduced expression of both proteins rendering the cells more sensitive to treatment with either Taxol or vinblastine without affecting the sensitivity of the cells to carboplatin.
Cervical cancer [ICD-11: 2C77]
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Drug Resistance Data Categorized by Their Corresponding Mechanisms
       Irregularity in Drug Uptake and Drug Efflux (IDUE) Click to Show/Hide
Key Molecule: Multidrug resistance protein 1 (ABCB1) [3]
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Resistant Disease Cervical carcinoma [ICD-11: 2C77.1]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Hela cells Cervix uteri Homo sapiens (Human) CVCL_0030
In Vivo Model Athymic nu/nu female mice xenograft model Mus musculus
Experiment for
Drug Resistance		 MTS assay
Mechanism Description In a cell line expressing a high level of P-glycoprotein, the IC50 of TTI-237 increased 25-fold whereas those of paclitaxel and vincristine increased 806-fold and 925-fold.
Kidney cancer [ICD-11: 2C90]
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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
       Irregularity in Drug Uptake and Drug Efflux (IDUE) Click to Show/Hide
Key Molecule: Multidrug resistance protein 1 (ABCB1) [6]
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Sensitive Disease Renal cell carcinoma [ICD-11: 2C90.0]
 Disease Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Flp-In-293/Mock cells Kidney Homo sapiens (Human) CVCL_U421
Flp-In-293/ABCB1 cells Kidney Homo sapiens (Human) CVCL_U421
Experiment for
Molecule Alteration		 ATPase assay
Experiment for
Drug Resistance		 MTT assay
Mechanism Description Through calcein assays, we found that epimagnolin A inhibited the ABCB1-mediated export of calcein. This result suggests that epimagnolin A behaved as inhibitor or substrate for ABCB1. In ATPase assays, epimagnolin A stimulated ABCB1-dependent ATPase activity. This result indicates that epimagnolin A was recognised as a substrate by ABCB1, since ABCB1 utilises energy derived from ATP hydrolysis for substrate transport. Furthermore, in MTT assays we found that the cytotoxicity of daunorubicin, doxorubicin, vinblastine, and vincristine was enhanced by epimagnolin A in a manner comparable to verapamil, a typical substrate for ABCB1.
References
Ref 1 miR-335 Targets SIAH2 and Confers Sensitivity to Anti-Cancer Drugs by Increasing the Expression of HDAC3. Mol Cells. 2015 Jun;38(6):562-72. doi: 10.14348/molcells.2015.0051. Epub 2015 May 22.
Ref 2 Let-7 modulates acquired resistance of ovarian cancer to Taxanes via IMP-1-mediated stabilization of multidrug resistance 1. Int J Cancer. 2012 Apr 15;130(8):1787-97. doi: 10.1002/ijc.26190. Epub 2011 Aug 16.
Ref 3 TTI-237: a novel microtubule-active compound with in vivo antitumor activity. Cancer Res. 2008 Apr 1;68(7):2292-300. doi: 10.1158/0008-5472.CAN-07-1420.
Ref 4 HG-829 is a potent noncompetitive inhibitor of the ATP-binding cassette multidrug resistance transporter ABCB1. Cancer Res. 2012 Aug 15;72(16):4204-13. doi: 10.1158/0008-5472.CAN-12-0743. Epub 2012 Jul 3.
Ref 5 Inhibition of P-glycoprotein by D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS). Pharm Res. 1999 Oct;16(10):1550-6. doi: 10.1023/a:1015000503629.
Ref 6 Epimagnolin A, a tetrahydrofurofuranoid lignan from Magnolia fargesii, reverses ABCB1-mediated drug resistance .Phytomedicine. 2018 Dec 1;51:112-119. doi: 10.1016/j.phymed.2018.06.030. Epub 2018 Jun 20. 10.1016/j.phymed.2018.06.030

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