Details of the Drug Combination

General Information of Drug Combination (ID: DCYPC7C)

• Drug Combination Name: Chlorambucil + Sertraline
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Chlorambucil (DMRKE63): Small molecular drug
  Sertraline (DM0FB1J): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 9.31
  Bliss Independence Score: 9.31
  Loewe Additivity Score: 23.29
  LHighest Single Agent (HSA) Score: 23.31

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Chlorambucil

Disease Entry	ICD 11	Status	REF
Chronic lymphocytic leukaemia	2A82.0	Approved	[2]
Small lymphocytic lymphoma	2A82.0	Approved	[3]
Classic Hodgkin lymphoma	N.A.	Investigative	[3]
Follicular lymphoma	2A80	Investigative	[3]

Chlorambucil Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
DNA replication (DNA repli)	TTABD5E	NOUNIPROTAC	Intercalator	[6]

Chlorambucil Interacts with 2 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[7]
Organic anion transporting polypeptide 1A2 (SLCO1A2)	DTE2B1D	SO1A2_HUMAN	Substrate	[8]

Chlorambucil Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Glutathione S-transferase pi (GSTP1)	DEK6079	GSTP1_HUMAN	Metabolism	[9]

Chlorambucil Interacts with 21 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Increases Expression	[10]
Aldo-keto reductase family 1 member B10 (AKR1B10)	OTOA4HTH	AK1BA_HUMAN	Decreases Expression	[11]
Aldo-keto reductase family 1 member C2 (AKR1C2)	OTQ2XMO3	AK1C2_HUMAN	Decreases Expression	[11]
Bcl-2-interacting killer (BIK)	OTTH1T3D	BIK_HUMAN	Increases Expression	[11]
F-box only protein 30 (FBXO30)	OTD1P6LA	FBX30_HUMAN	Decreases Expression	[11]
Histone chaperone ASF1A (ASF1A)	OT4S44GP	ASF1A_HUMAN	Decreases Expression	[11]
Tumor necrosis factor receptor superfamily member 10A (TNFRSF10A)	OTBPCU2O	TR10A_HUMAN	Affects Expression	[12]
Tumor necrosis factor receptor superfamily member 10B (TNFRSF10B)	OTA1CPBV	TR10B_HUMAN	Increases Expression	[13]
Baculoviral IAP repeat-containing protein 5 (BIRC5)	OTILXZYL	BIRC5_HUMAN	Affects Expression	[14]
Myc proto-oncogene protein (MYC)	OTPV5LUK	MYC_HUMAN	Increases Expression	[15]
Histone H2AX (H2AX)	OT18UX57	H2AX_HUMAN	Increases Phosphorylation	[16]
HLA class II histocompatibility antigen, DP alpha 1 chain (HLA-DPA1)	OT7OG7Y2	DPA1_HUMAN	Affects Expression	[17]
Tumor necrosis factor receptor superfamily member 6 (FAS)	OTP9XG86	TNR6_HUMAN	Increases Expression	[18]
14-3-3 protein sigma (SFN)	OTLJCZ1U	1433S_HUMAN	Increases Expression	[13]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Increases Expression	[19]
Histone H4 (H4C1)	OTB71W46	H4_HUMAN	Decreases Expression	[16]
kinase isozyme 4, mitochondrial (PDK4)	OTCMHMBZ	PDK4_HUMAN	Affects Expression	[20]
Bcl-2-binding component 3, isoforms 3/4 (BBC3)	OTUAXDAY	BBC3B_HUMAN	Increases Expression	[14]
Fanconi anemia group G protein (FANCG)	OT7MC8TZ	FANCG_HUMAN	Increases Response To Substance	[21]
Baculoviral IAP repeat-containing protein 2 (BIRC2)	OTFXFREP	BIRC2_HUMAN	Decreases Response To Substance	[22]
Fanconi anemia group C protein (FANCC)	OTTIDM3P	FANCC_HUMAN	Increases Response To Substance	[21]

Indication(s) of Sertraline

Disease Entry	ICD 11	Status	REF
Coronary heart disease	BA80.Z	Approved	[4]
Depression	6A70-6A7Z	Approved	[5]
Epilepsy	8A60-8A68	Approved	[4]
Obsessive compulsive disorder	6B20	Approved	[4]
Panic disorder	6B01	Approved	[4]
Post-traumatic stress disorder	6B40	Approved	[4]

Sertraline Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Serotonin transporter (SERT)	TT3ROYC	SC6A4_HUMAN	Inhibitor	[27]

Sertraline Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[28]

Sertraline Interacts with 7 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[29]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[30]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[31]
Cytochrome P450 2E1 (CYP2E1)	DEVDYN7	CP2E1_HUMAN	Metabolism	[32]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[33]
Cytochrome P450 2B6 (CYP2B6)	DEPKLMQ	CP2B6_HUMAN	Metabolism	[34]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[34]

Sertraline Interacts with 55 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2C19 (CYP2C19)	OTFMJYYE	CP2CJ_HUMAN	Decreases Methylation	[35]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Increases Activity	[36]
Phytanoyl-CoA dioxygenase, peroxisomal (PHYH)	OTUG4BWA	PAHX_HUMAN	Increases Expression	[23]
Nuclear protein 1 (NUPR1)	OT4FU8C0	NUPR1_HUMAN	Increases Expression	[23]
Alpha-1-antichymotrypsin (SERPINA3)	OT9BP2S0	AACT_HUMAN	Increases Expression	[23]
Solute carrier family 2, facilitated glucose transporter member 3 (SLC2A3)	OT2HZK5M	GTR3_HUMAN	Decreases Expression	[23]
Inhibin beta E chain (INHBE)	OTOI2NYG	INHBE_HUMAN	Increases Expression	[23]
Acid ceramidase (ASAH1)	OT1DNGXL	ASAH1_HUMAN	Increases Expression	[23]
Nuclear receptor subfamily 0 group B member 2 (NR0B2)	OT7UVICX	NR0B2_HUMAN	Increases Expression	[23]
Lysophospholipase D GDPD3 (GDPD3)	OTOHM9QM	GDPD3_HUMAN	Increases Expression	[23]
Fibronectin type III domain-containing protein 4 (FNDC4)	OTOQK0WK	FNDC4_HUMAN	Increases Expression	[23]
Protein DEPP1 (DEPP1)	OTB36PHJ	DEPP1_HUMAN	Increases Expression	[23]
Mitogen-activated protein kinase kinase kinase 13 (MAP3K13)	OTS93BTX	M3K13_HUMAN	Increases Expression	[24]
Growth arrest and DNA damage-inducible protein GADD45 beta (GADD45B)	OTL9I7LO	GA45B_HUMAN	Increases Expression	[24]
Serine/threonine-protein kinase/endoribonuclease IRE1 (ERN1)	OTY9R6FZ	ERN1_HUMAN	Increases Expression	[24]
Protein phosphatase 1 regulatory subunit 15A (PPP1R15A)	OTYG179K	PR15A_HUMAN	Increases Expression	[24]
Dual specificity protein phosphatase 14 (DUSP14)	OTGODFCR	DUS14_HUMAN	Increases Expression	[24]
Mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4)	OTBMJUOC	M4K4_HUMAN	Decreases Expression	[24]
Protein c-Fos (FOS)	OTJBUVWS	FOS_HUMAN	Increases Expression	[24]
Myc proto-oncogene protein (MYC)	OTPV5LUK	MYC_HUMAN	Increases Expression	[24]
Albumin (ALB)	OTVMM513	ALBU_HUMAN	Affects Binding	[37]
Platelet basic protein (PPBP)	OT1FHGQS	CXCL7_HUMAN	Decreases Expression	[38]
Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1)	OTM0GDTP	IF2A_HUMAN	Increases Phosphorylation	[24]
Transcription factor Jun (JUN)	OTCYBO6X	JUN_HUMAN	Increases Expression	[24]
Transcription factor AP-2-alpha (TFAP2A)	OTMYT3NK	AP2A_HUMAN	Increases Expression	[39]
Heat shock cognate 71 kDa protein (HSPA8)	OTJI2RCI	HSP7C_HUMAN	Decreases Expression	[24]
Cyclic AMP-dependent transcription factor ATF-2 (ATF2)	OTNIZPEA	ATF2_HUMAN	Increases Expression	[24]
Heat shock 70 kDa protein 6 (HSPA6)	OTH4S7WB	HSP76_HUMAN	Increases Expression	[24]
Transcription factor JunD (JUND)	OTNKACJD	JUND_HUMAN	Increases Expression	[24]
Cyclic AMP-dependent transcription factor ATF-4 (ATF4)	OTRFV19J	ATF4_HUMAN	Increases Expression	[24]
Nuclear factor NF-kappa-B p105 subunit (NFKB1)	OTNRRD8I	NFKB1_HUMAN	Increases Expression	[24]
Growth arrest and DNA damage-inducible protein GADD45 alpha (GADD45A)	OTDRV63V	GA45A_HUMAN	Increases Expression	[24]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Increases Phosphorylation	[40]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Increases Phosphorylation	[40]
DNA damage-inducible transcript 3 protein (DDIT3)	OTI8YKKE	DDIT3_HUMAN	Increases Expression	[24]
Mitogen-activated protein kinase kinase kinase 8 (MAP3K8)	OTOZTA1F	M3K8_HUMAN	Increases Expression	[24]
Translocon-associated protein subunit beta (SSR2)	OTQJSL7M	SSRB_HUMAN	Increases Expression	[24]
Protein transport protein Sec61 subunit gamma (SEC61G)	OT7MJRXY	SC61G_HUMAN	Decreases Expression	[24]
E3 ubiquitin-protein ligase RBX1 (RBX1)	OTYA1UIO	RBX1_HUMAN	Decreases Expression	[24]
S-phase kinase-associated protein 1 (SKP1)	OT5BPAZ4	SKP1_HUMAN	Decreases Expression	[24]
Nuclear factor NF-kappa-B p100 subunit (NFKB2)	OTS231V7	NFKB2_HUMAN	Increases Expression	[24]
Transcription factor RelB (RELB)	OTU3QYEF	RELB_HUMAN	Increases Expression	[24]
Acetyl-CoA carboxylase 1 (ACACA)	OT5CQPZY	ACACA_HUMAN	Increases Phosphorylation	[26]
Dual specificity protein phosphatase 8 (DUSP8)	OTPLMPG9	DUS8_HUMAN	Increases Expression	[24]
Cullin-1 (CUL1)	OTXPE1UZ	CUL1_HUMAN	Decreases Expression	[24]
Homocysteine-responsive endoplasmic reticulum-resident ubiquitin-like domain member 1 protein (HERPUD1)	OT9EROL6	HERP1_HUMAN	Increases Expression	[24]
Serine/threonine-protein kinase STK11 (STK11)	OT1YZSP3	STK11_HUMAN	Increases Phosphorylation	[26]
E3 ubiquitin-protein ligase synoviolin (SYVN1)	OTZ4ZJP5	SYVN1_HUMAN	Increases Expression	[24]
Dual specificity protein phosphatase 16 (DUSP16)	OTK7S078	DUS16_HUMAN	Increases Expression	[24]
Microtubule-associated proteins 1A/1B light chain 3B (MAP1LC3B)	OTUYHB84	MLP3B_HUMAN	Increases Lipidation	[26]
DnaJ homolog subfamily C member 5 (DNAJC5)	OTCZDXAL	DNJC5_HUMAN	Increases Expression	[41]
Eukaryotic translation initiation factor 2-alpha kinase 3 (EIF2AK3)	OT0DZGY4	E2AK3_HUMAN	Increases Expression	[24]
Serine/threonine-protein kinase TAO2 (TAOK2)	OTNUMOZ1	TAOK2_HUMAN	Increases Expression	[24]
C-Jun-amino-terminal kinase-interacting protein 3 (MAPK8IP3)	OT0X8ACY	JIP3_HUMAN	Increases Expression	[24]
Sodium-dependent serotonin transporter (SLC6A4)	OT6FGDLW	SC6A4_HUMAN	Increases Response To Substance	[42]

References

• [1] CheMBL Affinity Phenotypic Cellular Interaction Assay ID: CHEMBL1125966
• [2] 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: 7143).
• [3] Chlorambucil FDA Label
• [4] Sertraline FDA Label
• [5] 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: 4798).
• [6] Roles of DNA repair and reductase activity in the cytotoxicity of the hypoxia-activated dinitrobenzamide mustard PR-104A. Mol Cancer Ther. 2009 Jun;8(6):1714-23.
• [7] Mammalian drug efflux transporters of the ATP binding cassette (ABC) family in multidrug resistance: A review of the past decade. Cancer Lett. 2016 Jan 1;370(1):153-64.
• [8] Transporters and renal drug elimination. Annu Rev Pharmacol Toxicol. 2004;44:137-66.
• [9] The anti-cancer drug chlorambucil as a substrate for the human polymorphic enzyme glutathione transferase P1-1: kinetic properties and crystallographic characterisation of allelic variants. J Mol Biol. 2008 Jun 27;380(1):131-44.
• [10] Enhanced in vitro invasiveness and drug resistance with altered gene expression patterns in a human lung carcinoma cell line after pulse selection with anticancer drugs. Int J Cancer. 2004 Sep 10;111(4):484-93. doi: 10.1002/ijc.20230.
• [11] Oxidative stress mechanisms do not discriminate between genotoxic and nongenotoxic liver carcinogens. Chem Res Toxicol. 2015 Aug 17;28(8):1636-46.
• [12] Role of the TRAIL/APO2-L death receptors in chlorambucil- and fludarabine-induced apoptosis in chronic lymphocytic leukemia. Oncogene. 2003 Nov 13;22(51):8356-69. doi: 10.1038/sj.onc.1207004.
• [13] Differential effects of chemotherapeutic drugs versus the MDM-2 antagonist nutlin-3 on cell cycle progression and induction of apoptosis in SKW6.4 lymphoblastoid B-cells. J Cell Biochem. 2008 May 15;104(2):595-605. doi: 10.1002/jcb.21649.
• [14] Differential gene expression induction by TRAIL in B chronic lymphocytic leukemia (B-CLL) cells showing high versus low levels of Zap-70. J Cell Physiol. 2007 Oct;213(1):229-36. doi: 10.1002/jcp.21116.
• [15] Theophylline synergizes with chlorambucil in inducing apoptosis of B-chronic lymphocytic leukemia cells. Blood. 1996 Sep 15;88(6):2172-82.
• [16] A two-hit mechanism for pre-mitotic arrest of cancer cell proliferation by a polyamide-alkylator conjugate. Cell Cycle. 2006 Jul;5(14):1537-48. doi: 10.4161/cc.5.14.2913. Epub 2006 Jul 17.
• [17] Systems pharmacological analysis of drugs inducing stevens-johnson syndrome and toxic epidermal necrolysis. Chem Res Toxicol. 2015 May 18;28(5):927-34. doi: 10.1021/tx5005248. Epub 2015 Apr 3.
• [18] Caspase 8 activation independent of Fas (CD95/APO-1) signaling may mediate killing of B-chronic lymphocytic leukemia cells by cytotoxic drugs or gamma radiation. Blood. 2001 Nov 1;98(9):2800-7. doi: 10.1182/blood.v98.9.2800.
• [19] Disruption of gene expression and induction of apoptosis in prostate cancer cells by a DNA-damaging agent tethered to an androgen receptor ligand. Chem Biol. 2005 Jul;12(7):779-87. doi: 10.1016/j.chembiol.2005.05.009.
• [20] The MT1G Gene in LUHMES Neurons Is a Sensitive Biomarker of Neurotoxicity. Neurotox Res. 2020 Dec;38(4):967-978. doi: 10.1007/s12640-020-00272-3. Epub 2020 Sep 1.
• [21] In vivo therapeutic responses contingent on Fanconi anemia/BRCA2 status of the tumor. Clin Cancer Res. 2005 Oct 15;11(20):7508-15. doi: 10.1158/1078-0432.CCR-05-1048.
• [22] Expression and prognostic significance of IAP-family genes in human cancers and myeloid leukemias. Clin Cancer Res. 2000 May;6(5):1796-803.
• [23] A toxicogenomic approach to drug-induced phospholipidosis: analysis of its induction mechanism and establishment of a novel in vitro screening system. Toxicol Sci. 2005 Feb;83(2):282-92.
• [24] Sertraline induces endoplasmic reticulum stress in hepatic cells. Toxicology. 2014 Aug 1;322:78-88. doi: 10.1016/j.tox.2014.05.007. Epub 2014 May 24.
• [25] Relationship between release of platelet/endothelial biomarkers and plasma levels of sertraline and N-desmethylsertraline in acute coronary syndrome patients receiving SSRI treatment for depression. Am J Psychiatry. 2005 Jun;162(6):1165-70. doi: 10.1176/appi.ajp.162.6.1165.
• [26] Antidepressant drug sertraline modulates AMPK-MTOR signaling-mediated autophagy via targeting mitochondrial VDAC1 protein. Autophagy. 2021 Oct;17(10):2783-2799. doi: 10.1080/15548627.2020.1841953. Epub 2020 Nov 9.
• [27] Psychopharmacological treatment of dermatological patients--when simply talking does not help. J Dtsch Dermatol Ges. 2007 Dec;5(12):1101-6.
• [28] Improving the prediction of the brain disposition for orally administered drugs using BDDCS. Adv Drug Deliv Rev. 2012 Jan;64(1):95-109.
• [29] New orally active anticoagulant agents for the prevention and treatment of venous thromboembolism in cancer patients. Ther Clin Risk Manag. 2014 Jun 13;10:423-36.
• [30] The selective serotonin reuptake inhibitor sertraline: its profile and use in psychiatric disorders. CNS Drug Rev. 2001 Spring;7(1):1-24.
• [31] Some aspects of genetic polymorphism in the biotransformation of antidepressants. Therapie. 2004 Jan-Feb;59(1):5-12.
• [32] PharmGKB: A worldwide resource for pharmacogenomic information. Wiley Interdiscip Rev Syst Biol Med. 2018 Jul;10(4):e1417. (ID: PA166181117)
• [33] Sertraline is metabolized by multiple cytochrome P450 enzymes, monoamine oxidases, and glucuronyl transferases in human: an in vitro study. Drug Metab Dispos. 2005 Feb;33(2):262-70.
• [34] Influence of CYP2B6 and CYP2C19 polymorphisms on sertraline metabolism in major depression patients. Int J Clin Pharm. 2016 Apr;38(2):388-94.
• [35] Pharmacokinetics of sertraline in relation to genetic polymorphism of CYP2C19. Clin Pharmacol Ther. 2001 Jul;70(1):42-7.
• [36] Michaelis-Menten kinetic analysis of drugs of abuse to estimate their affinity to human P-glycoprotein. Toxicol Lett. 2013 Feb 27;217(2):137-42. doi: 10.1016/j.toxlet.2012.12.012. Epub 2012 Dec 27.
• [37] Exploring binding properties of sertraline with human serum albumin: Combination of spectroscopic and molecular modeling studies. Chem Biol Interact. 2015 Dec 5;242:235-46. doi: 10.1016/j.cbi.2015.10.006. Epub 2015 Oct 22.
• [38] Platelet/endothelial biomarkers in depressed patients treated with the selective serotonin reuptake inhibitor sertraline after acute coronary events: the Sertraline AntiDepressant Heart Attack Randomized Trial (SADHART) Platelet Substudy. Circulation. 2003 Aug 26;108(8):939-44. doi: 10.1161/01.CIR.0000085163.21752.0A. Epub 2003 Aug 11.
• [39] Impact of selective serotonin reuptake inhibitors on neural crest stem cell formation. Toxicol Lett. 2017 Nov 5;281:20-25. doi: 10.1016/j.toxlet.2017.08.012. Epub 2017 Aug 24.
• [40] Sertraline, an antidepressant, induces apoptosis in hepatic cells through the mitogen-activated protein kinase pathway. Toxicol Sci. 2014 Feb;137(2):404-15. doi: 10.1093/toxsci/kft254. Epub 2013 Nov 5.
• [41] Induction of cysteine string protein after chronic antidepressant treatment in rat frontal cortex. Neurosci Lett. 2001 Apr 6;301(3):183-6. doi: 10.1016/s0304-3940(01)01638-x.
• [42] The serotonin transporter polymorphism, 5HTTLPR, is associated with a faster response time to sertraline in an elderly population with major depressive disorder. Psychopharmacology (Berl). 2004 Aug;174(4):525-9. doi: 10.1007/s00213-003-1562-3. Epub 2003 Sep 4.