Drug Information

Drug (ID: DG00020) and It's Reported Resistant Information

• Name: Carmustine
• Synonyms: Carmustine; carmustine; 154-93-8; 1,3-Bis(2-chloroethyl)-1-nitrosourea; BCNU; Carmustin; Nitrumon; Carmubris; Gliadel; BiCNU; Bi CNU; Carmustinum; Bischlorethylnitrosurea; Bischlorethylnitrosourea; Carmustina; Becenun; Becenum; Bischloroethyl nitrosourea; N,N'-BIS(2-CHLOROETHYL)-N-NITROSOUREA; Bis(2-chloroethyl)nitrosourea; Urea, N,N'-bis(2-chloroethyl)-N-nitroso-; Gliadel Wafer; FDA 0345; Bischloroethylnitrosourea; SRI 1720; 1,3-Bis(2-chloroethyl)nitrosourea; BiCNU (TN); Carmustinum [INN-Latin]; Carmustina [INN-Spanish]; DTI 015; NCI-C04773; SK; BCNU; Injectable carmustine, Direct Therapeutics
• Indication:
  In total 2 Indication(s)
  Brain cancer [ICD-11: 2A00]; Approved; [1]
  Liver cancer [ICD-11: 2C12]; Approved; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (1 diseases)
  Brain cancer [ICD-11: 2A00]; [2]
  Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (1 diseases)
  Brain cancer [ICD-11: 2A00]; [3]
• Target: Human Deoxyribonucleic acid (hDNA); NOUNIPROTAC; [1]
• Formula: C5H9Cl2N3O2
• IsoSMILES: C(CCl)NC(=O)N(CCCl)N=O
• InChI: 1S/C5H9Cl2N3O2/c6-1-3-8-5(11)10(9-12)4-2-7/h1-4H2,(H,8,11)
• InChIKey: DLGOEMSEDOSKAD-UHFFFAOYSA-N
• PubChem CID: 2578
• ChEBI ID: CHEBI:3423
• TTD Drug ID: D01OXI
• INTEDE ID: DR0278
• DrugBank ID: DB00262

Type(s) of Resistant Mechanism of This Drug

  DISM: Drug Inactivation by Structure Modification

  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

Brain cancer [ICD-11: 2A00]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Glutathione S-transferase P (GSTP1) [2]

• Resistant Disease: Anaplastic astrocytoma [ICD-11: 2A00.04]
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Brain cancer [ICD-11: 2A00]
• The Specified Disease: Anaplastic astrocytoma
• The Studied Tissue: Blood
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 3.99E-02; Fold-change: 1.21E-01; Z-score: 2.07E+00
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Malignant gliomas tissue; N.A.
• Experiment for Molecule Alteration: Immunohistochemistry assay
• Experiment for Drug Resistance: Oncotech EDR assay
• Mechanism Description: GSTP1 is the first major mechanism of resistance alkylator agents encounter after entering the cancer cell cytoplasm. GSTP1 acts to enzymatically conjugate glutathione to the reactive metabolites of BCNU. The mechanisms by which GSTP1 may be up-regulated in gliomas are under investigation. Constitutive expression is thought to be influenced by the proximal promoter factor Sp1, whereas increased expression levels may result from stabilization of GSTP1 mRNA. GSTP1 expression has been reported to be induced by drug exposure, indicating that it may play a role in acquired drug resistance.

Key Molecule: Glutathione S-transferase P (GSTP1) [2]

• Resistant Disease: Malignant glioma [ICD-11: 2A00.2]
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Brain cancer [ICD-11: 2A00]
• The Specified Disease: Malignant glioma
• The Studied Tissue: Blood
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 3.99E-02; Fold-change: 1.21E-01; Z-score: 2.07E+00
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Malignant gliomas tissue; N.A.
• Experiment for Molecule Alteration: Immunohistochemistry assay
• Experiment for Drug Resistance: EDR assay
• Mechanism Description: In vitro drug resistance in malignant gliomas was independent of prior therapy. High-grade glioblastomas showed a lower level of extreme drug resistance than low-grade astrocytomas to cisplatin (11% versus 27%), temozolomide (14% versus 27%), irinotecan (33% versus 53%), and BCNU (29% versus 38%). A substantial percentage of brain tumors overexpressed biomarkers associated with drug resistance, including MGMT (67%), GSTP1 (49%), and mutant p53 (41%). MGMT and GSTP1 overexpression was independently associated with in vitro resistance to BCNU, whereas coexpression of these two markers was associated with the greatest degree of BCNU resistance.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Protein sprouty homolog 2 (SPRY2) [1]

• Resistant Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Brain cancer [ICD-11: 2A00]
• The Specified Disease: Glioma
• The Studied Tissue: Nervous tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 6.16E-06; Fold-change: -6.62E-01; Z-score: -5.92E+00
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SWOZ2 cells; Brain; Homo sapiens (Human); N.A.
• In Vitro Model: SWOZ2-BCNU cells; Brain; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR21 enhanced glioma cells resistance to carmustine via decreasing Spry2 expression.

Key Molecule: Phosphatase and tensin homolog (PTEN) [3]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PI3K/PTEN/AKT signaling axis; Activation; hsa04151
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-221 regulated cell proliferation and BCNU resistance in glioma cells. Overexpression of miR-221 led to cell survival and BCNU resistance and reduced cell apoptosis induced by BCNU, whereas knockdown of miR-221 inhibited cell proliferation and prompted BCNU sensitivity and cell apoptosis. Further investigation revealed that miR-221 down-regulated PTEN and activated Akt, which resulted in cell survival and BCNU resistance. Overexpression of PTEN lacking 3'UTR or PI3-k/Akt specific inhibitor wortmannin attenuated miR-221-mediated BCNU resistance and prompted cell apoptosis. We propose that miR-221 regulated cell proliferation and BCNU resistance in glioma cells by targeting PI3-k/PTEN/Akt signaling axis.

Key Molecule: Methylated-DNA--protein-cysteine methyltransferase (MGMT) [2]

• Resistant Disease: Malignant glioma [ICD-11: 2A00.2]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Malignant gliomas tissue; N.A.
• Experiment for Molecule Alteration: Immunohistochemistry assay
• Experiment for Drug Resistance: EDR assay
• Mechanism Description: In vitro drug resistance in malignant gliomas was independent of prior therapy. High-grade glioblastomas showed a lower level of extreme drug resistance than low-grade astrocytomas to cisplatin (11% versus 27%), temozolomide (14% versus 27%), irinotecan (33% versus 53%), and BCNU (29% versus 38%). A substantial percentage of brain tumors overexpressed biomarkers associated with drug resistance, including MGMT (67%), GSTP1 (49%), and mutant p53 (41%). MGMT and GSTP1 overexpression was independently associated with in vitro resistance to BCNU, whereas coexpression of these two markers was associated with the greatest degree of BCNU resistance.

Key Molecule: Methylated-DNA--protein-cysteine methyltransferase (MGMT) [2]

• Resistant Disease: Anaplastic astrocytoma [ICD-11: 2A00.04]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Malignant gliomas tissue; N.A.
• Experiment for Molecule Alteration: Immunohistochemistry assay
• Experiment for Drug Resistance: Oncotech EDR assay
• Mechanism Description: For drugs that have evaded cytosolic mechanisms of drug resistance, the nucleus is equipped with the capacity to remove BCNU or temozolomide alkyl groups from the O6-position of guanine via a reaction catalyzed by MGMT. Repair occurs before cross-link formation and involves an irreversible stoichiometric covalent transfer of the O6-alkyl DNA adduct to a cysteine within the active site of MGMT, resulting in the inactivation and subsequent depletion of enzyme activity. MGMT-mediated repair is rapid, with a half-life of 35 hours. MGMT enzyme recovery occurs via de novo synthesis. In malignant glioma patients, MGMT overexpression has been associated with resistance to BCNU and similar alkylating agents and was an independent predictor of poor survival. MGMT is also thought to contribute to temozolomide resistance, which we did not detect in our study. This may be related to the in vitro pharmacokinetic differences between BCNU and temozolomide.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-21 [1]

• Resistant Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SWOZ2 cells; Brain; Homo sapiens (Human); N.A.
• In Vitro Model: SWOZ2-BCNU cells; Brain; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR21 enhanced glioma cells resistance to carmustine via decreasing Spry2 expression.

Key Molecule: hsa-mir-221 [3]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PI3-k/PTEN/AKT signaling axis; Activation; hsa04151
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-221 regulated cell proliferation and BCNU resistance in glioma cells. Overexpression of miR-221 led to cell survival and BCNU resistance and reduced cell apoptosis induced by BCNU, whereas knockdown of miR-221 inhibited cell proliferation and prompted BCNU sensitivity and cell apoptosis. Further investigation revealed that miR-221 down-regulated PTEN and activated Akt, which resulted in cell survival and BCNU resistance. Overexpression of PTEN lacking 3'UTR or PI3-k/Akt specific inhibitor wortmannin attenuated miR-221-mediated BCNU resistance and prompted cell apoptosis. We propose that miR-221 regulated cell proliferation and BCNU resistance in glioma cells by targeting PI3-k/PTEN/Akt signaling axis.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [2]

• Resistant Disease: Malignant glioma [ICD-11: 2A00.2]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Malignant gliomas tissue; N.A.
• Experiment for Molecule Alteration: Immunohistochemistry assay
• Experiment for Drug Resistance: EDR assay
• Mechanism Description: In vitro drug resistance in malignant gliomas was independent of prior therapy. High-grade glioblastomas showed a lower level of extreme drug resistance than low-grade astrocytomas to cisplatin (11% versus 27%), temozolomide (14% versus 27%), irinotecan (33% versus 53%), and BCNU (29% versus 38%). A substantial percentage of brain tumors overexpressed biomarkers associated with drug resistance, including MGMT (67%), GSTP1 (49%), and mutant p53 (41%). MGMT and GSTP1 overexpression was independently associated with in vitro resistance to BCNU, whereas coexpression of these two markers was associated with the greatest degree of BCNU resistance.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: let-7a-3p [4]

• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell autophagy; Inhibition; hsa04140
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The objective of the present research was to explore the potential of let-7a-3p when used in combination with carmustine in human glioblastoma cancer cells. Based on previous studies, the expression of let-7a is downregulated in the U87MG cell line. Let-7a-3p transfected into U87MG glioblastoma cells. Cell viability of the cells was assessed by MTT assay. The apoptotic induction in U87MG cancerous cells was determined through the utilization of DAPI and Annexin V/PI staining techniques. Moreover, the induction of autophagy and cell cycle arrest was evaluated by flow cytometry. Furthermore, cell migration was evaluated by the wound healing assay while colony formation assay was conducted to evaluate colony formation. Also, the expression of the relevant genes was evaluated using qRT-PCR. Transfection of let-7a-3p mimic in U87MG cells increased the expression of the miRNA and also increased the sensitivity of U87MG cells to carmustine.

References

• Ref 1: MiR-21 enhanced glioma cells resistance to carmustine via decreasing Spry2 expression. Eur Rev Med Pharmacol Sci. 2017 Nov;21(22):5065-5071. doi: 10.26355/eurrev_201711_13819.
• Ref 2: In vitro drug response and molecular markers associated with drug resistance in malignant gliomas .Clin Cancer Res. 2006 Aug 1;12(15):4523-32. doi: 10.1158/1078-0432.CCR-05-1830. 10.1158/1078-0432.CCR-05-1830
• Ref 3: MicroRNA-221 targeting PI3-K/Akt signaling axis induces cell proliferation and BCNU resistance in human glioblastoma. Neuropathology. 2014 Oct;34(5):455-64. doi: 10.1111/neup.12129. Epub 2014 Apr 30.
• Ref 4: Let-7a-3p overexpression increases chemosensitivity to carmustine and synergistically promotes autophagy and suppresses cell survival in U87MG glioblastoma cancer cells. Naunyn Schmiedebergs Arch Pharmacol. 2024 Sep;397(9):6903-6918.