Drug Information

Drug (ID: DG00002) and It's Reported Resistant Information

• Name: Melphalan
• Synonyms: Alkeran; Levofalan; Levofolan; Levopholan; Melfalan; Melfalano; Melphalanum; Alanine Nitrogen Mustard; Phenylalanine mustard; Phenylalanine nitrogen mu stard; Phenylalanine nitrogen mustard; AY3360000; CB 3025; ALKERAN (TN); Alkeran (TN); At-290; CB-3025; L-PAM; L-Phenylalanine mustard; L-Sarcolysin; L-Sarcolysine; L-Sarkolysin; Melfalano [INN-Spanish]; Melphalanum [INN-Latin]; SK-15673; TRANSGENIC MODEL EVALUATION (MELPHALAN); MELPHALAN (SEE ALSO TRANSGENIC MODEL EVALUATION (MELPHALAN)); P-L-Sarcolysin; P-L-sarcolysine; TRANSGENIC LEP (MELPHALAN) (SEE ALSO MELPHALAN); Melphalan (JP15/USP/INN); Melphalan [USAN:INN:BAN:JAN]; P-Bis(beta-chloroethyl)aminophenylalanine; P-N-Di(chloroethyl)aminophenylalanine; P-N-di(chloroethyl)aminophenylala nine; P-Di-(2-chloroethyl)amino-L-phenylalanine; P-N-Bis(2-chloroethyl)amino-L-phenylalanine; L-3-(p-(Bis(2-chloroethyl)amino)phenyl)alanine; L-3-(para-(Bis(2-chloroethyl)amino)phenyl)alanine; P-N,N-bis(2-chloroethyl)amino-L-phenylalanine; (2S)-2-amino-3-[4-[bis(2-chloroethyl)amino]phenyl]propanoic acid; (2s)-2-amino-3-(4-[bis(2-chloroethyl)amino]phenyl)propanoic acid; 3-(p-(Bis(2-chloroethyl)amino)phenyl)-L-alanine; 3-(p-(Bis(2-chloroethyl)amino)phenyl)alanine; 3-p-(Di(2-chloroethyl)amino)-phenyl-L-alanine; 4-(Bis(2-chloroethyl)amino)-L-phenylalanine; 4-[Bis(2-chloroethyl)amino]-L-phenylalanine; 4-[Bis-(2-chloroethyl)amino]-L-phenylalanine
• Indication:
  In total 2 Indication(s)
  Multiple myeloma [ICD-11: 2A83]; Approved; [1]
  Liver cancer [ICD-11: 2C12]; Phase 3; [1]
• Drug Resistance Disease(s):
  Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (2 diseases)
  Mature B-cell neoplasms/lymphoma [ICD-11: 2A85]; [2]
  Multiple myeloma [ICD-11: 2A83]; [3]
• Target: Human Deoxyribonucleic acid (hDNA); NOUNIPROTAC; [1]
• Formula: C13H18Cl2N2O2
• IsoSMILES: C1=CC(=CC=C1C[C@@H](C(=O)O)N)N(CCCl)CCCl
• InChI: 1S/C13H18Cl2N2O2/c14-5-7-17(8-6-15)11-3-1-10(2-4-11)9-12(16)13(18)19/h1-4,12H,5-9,16H2,(H,18,19)/t12-/m0/s1
• InChIKey: SGDBTWWWUNNDEQ-LBPRGKRZSA-N
• PubChem CID: 460612
• ChEBI ID: CHEBI:28876
• TTD Drug ID: D00FGO
• VARIDT ID: DR00379
• INTEDE ID: DR1021
• DrugBank ID: DB01042

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

Multiple myeloma [ICD-11: 2A83]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Long non-protein coding RNA (LINC00515) [1]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Multiple myeloma [ICD-11: 2A83.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: KMS11 cells; Peripheral blood; Homo sapiens (Human); CVCL_2989
• In Vitro Model: LP1 cells; Bone marrow; Homo sapiens (Human); CVCL_0012
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Linc00515 enhanced autophagy and chemoresistance of melphalan-resistant myeloma by directly inhibiting miR-140-5p, which elevated ATG14 level.

Key Molecule: hsa-miR-140-5p [1]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Multiple myeloma [ICD-11: 2A83.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell autophagy; Activation; hsa04140
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: KMS11 cells; Peripheral blood; Homo sapiens (Human); CVCL_2989
• In Vitro Model: LP1 cells; Bone marrow; Homo sapiens (Human); CVCL_0012
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Linc00515 enhanced autophagy and chemoresistance of melphalan-resistant myeloma by directly inhibiting miR-140-5p, which elevated ATG14 level.

Key Molecule: hsa-mir-221 [3]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Multiple myeloma [ICD-11: 2A83.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: NCI-H929 cells; Bone marrow; Homo sapiens (Human); CVCL_1600
• In Vitro Model: U266 cells; Bone marrow; Homo sapiens (Human); CVCL_0566
• In Vitro Model: RPMI-8226/BTZ cells; Pancreas; Homo sapiens (Human); CVCL_XK17
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: miR-221/222 expression inversely correlated with melphalan-sensitivity of MM cells. Inhibition of miR-221/222 overcame melphalan-resistance and triggered apoptosis of MM cells in vitro, in the presence or absence of human bone marrow stromal cells. Decreased MM cell growth induced by inhibition of miR-221/222 plus melphalan was associated with a marked upregulation of pro-apoptotic BBC3/PUMA protein, a miR-221/222 target, as well as with modulation of drug influx-efflux transporters SLC7A5/LAT1 and the ATP-binding cassette (ABC) transporter ABCC1/MRP1. Finally, in vivo treatment of SCID/NOD mice bearing human melphalan-refractory MM xenografts with systemic LNA-i-miR-221 plus melphalan overcame drug-resistance, evidenced by growth inhibition with significant antitumor effects together with modulation of PUMA and ABCC1 in tumors retrieved from treated mice.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Beclin 1-associated autophagy-related key regulator (ATG14) [1]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Multiple myeloma [ICD-11: 2A83.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell autophagy; Activation; hsa04140
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: KMS11 cells; Peripheral blood; Homo sapiens (Human); CVCL_2989
• In Vitro Model: LP1 cells; Bone marrow; Homo sapiens (Human); CVCL_0012
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Linc00515 enhanced autophagy and chemoresistance of melphalan-resistant myeloma by directly inhibiting miR-140-5p, which elevated ATG14 level.

Key Molecule: Bcl-2-binding component 3 (BBC3) [3]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Multiple myeloma [ICD-11: 2A83.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: NCI-H929 cells; Bone marrow; Homo sapiens (Human); CVCL_1600
• In Vitro Model: U266 cells; Bone marrow; Homo sapiens (Human); CVCL_0566
• In Vitro Model: RPMI-8226/BTZ cells; Pancreas; Homo sapiens (Human); CVCL_XK17
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: miR-221/222 expression inversely correlated with melphalan-sensitivity of MM cells. Inhibition of miR-221/222 overcame melphalan-resistance and triggered apoptosis of MM cells in vitro, in the presence or absence of human bone marrow stromal cells. Decreased MM cell growth induced by inhibition of miR-221/222 plus melphalan was associated with a marked upregulation of pro-apoptotic BBC3/PUMA protein, a miR-221/222 target, as well as with modulation of drug influx-efflux transporters SLC7A5/LAT1 and the ATP-binding cassette (ABC) transporter ABCC1/MRP1. Finally, in vivo treatment of SCID/NOD mice bearing human melphalan-refractory MM xenografts with systemic LNA-i-miR-221 plus melphalan overcame drug-resistance, evidenced by growth inhibition with significant antitumor effects together with modulation of PUMA and ABCC1 in tumors retrieved from treated mice.

Key Molecule: Bcl-2-binding component 3 (BBC3) [3]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Multiple myeloma [ICD-11: 2A83.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: NCI-H929 cells; Bone marrow; Homo sapiens (Human); CVCL_1600
• In Vitro Model: U266 cells; Bone marrow; Homo sapiens (Human); CVCL_0566
• In Vitro Model: RPMI-8226/BTZ cells; Pancreas; Homo sapiens (Human); CVCL_XK17
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: miR-221/222 expression inversely correlated with melphalan-sensitivity of MM cells. Inhibition of miR-221/222 overcame melphalan-resistance and triggered apoptosis of MM cells in vitro, in the presence or absence of human bone marrow stromal cells. Decreased MM cell growth induced by inhibition of miR-221/222 plus melphalan was associated with a marked upregulation of pro-apoptotic BBC3/PUMA protein, a miR-221/222 target, as well as with modulation of drug influx-efflux transporters SLC7A5/LAT1 and the ATP-binding cassette (ABC) transporter ABCC1/MRP1. Finally, in vivo treatment of SCID/NOD mice bearing human melphalan-refractory MM xenografts with systemic LNA-i-miR-221 plus melphalan overcame drug-resistance, evidenced by growth inhibition with significant antitumor effects together with modulation of PUMA and ABCC1 in tumors retrieved from treated mice.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-140-5p [1]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Multiple myeloma [ICD-11: 2A83.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell autophagy; Activation; hsa04140
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: KMS11 cells; Peripheral blood; Homo sapiens (Human); CVCL_2989
• In Vitro Model: LP1 cells; Bone marrow; Homo sapiens (Human); CVCL_0012
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Linc00515 enhanced autophagy and chemoresistance of melphalan-resistant myeloma by directly inhibiting miR-140-5p, which elevated ATG14 level.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Beclin 1-associated autophagy-related key regulator (ATG14) [1]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Multiple myeloma [ICD-11: 2A83.0]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell autophagy; Activation; hsa04140
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: KMS11 cells; Peripheral blood; Homo sapiens (Human); CVCL_2989
• In Vitro Model: LP1 cells; Bone marrow; Homo sapiens (Human); CVCL_0012
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Linc00515 enhanced autophagy and chemoresistance of melphalan-resistant myeloma by directly inhibiting miR-140-5p, which elevated ATG14 level.

Mature B-cell neoplasms/lymphoma [ICD-11: 2A85]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

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

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Burkitt lymphoma [ICD-11: 2A85.6]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HS-Sultan cells; Ascites; Homo sapiens (Human); CVCL_2516
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Trypan blue dye exclusion assay
• Mechanism Description: MDR1 and Survivin upregulation are responsible for resistance to conventional drugs and dasatinib can restore drug sensitivity by reducing MDR1 and Survivin expression in drug-resistant BL cells. Src inhibitors could therefore be a novel treatment strategy for patients with drug resistant BL.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Baculoviral IAP repeat-containing protein 5 (BIRC5) [2]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Burkitt lymphoma [ICD-11: 2A85.6]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HS-Sultan cells; Ascites; Homo sapiens (Human); CVCL_2516
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Trypan blue dye exclusion assay
• Mechanism Description: MDR1 and Survivin upregulation are responsible for resistance to conventional drugs and dasatinib can restore drug sensitivity by reducing MDR1 and Survivin expression in drug-resistant BL cells. Src inhibitors could therefore be a novel treatment strategy for patients with drug resistant BL.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

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

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Burkitt lymphoma [ICD-11: 2A85.6]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HS-Sultan cells; Ascites; Homo sapiens (Human); CVCL_2516
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Trypan blue dye exclusion assay
• Mechanism Description: MDR1 and Survivin upregulation are responsible for resistance to conventional drugs and dasatinib can restore drug sensitivity by reducing MDR1 and Survivin expression in drug-resistant BL cells. Src inhibitors could therefore be a novel treatment strategy for patients with drug resistant BL.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Baculoviral IAP repeat-containing protein 5 (BIRC5) [2]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Burkitt lymphoma [ICD-11: 2A85.6]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HS-Sultan cells; Ascites; Homo sapiens (Human); CVCL_2516
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Trypan blue dye exclusion assay
• Mechanism Description: MDR1 and Survivin upregulation are responsible for resistance to conventional drugs and dasatinib can restore drug sensitivity by reducing MDR1 and Survivin expression in drug-resistant BL cells. Src inhibitors could therefore be a novel treatment strategy for patients with drug resistant BL.

References

• Ref 1: Knockdown of Linc00515 Inhibits Multiple Myeloma Autophagy and Chemoresistance by Upregulating miR-140-5p and Downregulating ATG14. Cell Physiol Biochem. 2018;48(6):2517-2527. doi: 10.1159/000492690. Epub 2018 Aug 17.
• Ref 2: Dasatinib reverses drug resistance by downregulating MDR1 and Survivin in Burkitt lymphoma cells .BMC Complement Med Ther. 2020 Mar 14;20(1):84. doi: 10.1186/s12906-020-2879-8. 10.1186/s12906-020-2879-8
• Ref 3: A 13 mer LNA-i-miR-221 Inhibitor Restores Drug Sensitivity in Melphalan-Refractory Multiple Myeloma Cells. Clin Cancer Res. 2016 Mar 1;22(5):1222-33. doi: 10.1158/1078-0432.CCR-15-0489. Epub 2015 Nov 2.