Details of the Drug Combination

General Information of Drug Combination (ID: DCDQ2K1)

• Drug Combination Name: Plicamycin + Chlorambucil
• Indication: Papillary renal cell carcinoma; Status: Investigative [1]
• Component Drugs:
  Plicamycin (DM7C8YV): Small molecular drug
  Chlorambucil (DMRKE63): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: ACHN
  Zero Interaction Potency (ZIP) Score: 0.35
  Bliss Independence Score: 4.29
  Loewe Additivity Score: 1.43
  LHighest Single Agent (HSA) Score: 1.81

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Plicamycin

Disease Entry	ICD 11	Status	REF
Hypercalcaemia	5B91.0	Approved	[2]
Testicular cancer	2C80	Approved	[2]
Solid tumour/cancer	2A00-2F9Z	Withdrawn from market	[3]
Lung cancer	2C25.0	Investigative	[4]
Ovarian cancer	2C73	Investigative	[4]

Plicamycin Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
RNA synthesis (hRNA synth)	TTX2AYW	NOUNIPROTAC	Modulator	[8]

Plicamycin Interacts with 16 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
17-beta-hydroxysteroid dehydrogenase type 2 (HSD17B2)	OT3K7HY5	DHB2_HUMAN	Decreases Expression	[9]
Cytochrome P450 1A1 (CYP1A1)	OTE4EFH8	CP1A1_HUMAN	Decreases Expression	[10]
Aryl hydrocarbon receptor (AHR)	OTFE4EYE	AHR_HUMAN	Decreases Expression	[10]
Cytochrome P450 1B1 (CYP1B1)	OTYXFLSD	CP1B1_HUMAN	Decreases Expression	[10]
Baculoviral IAP repeat-containing protein 5 (BIRC5)	OTILXZYL	BIRC5_HUMAN	Decreases Expression	[11]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Increases Activity	[11]
Epoxide hydrolase 1 (EPHX1)	OTBKWQER	HYEP_HUMAN	Decreases Expression	[12]
Transcription factor Sp1 (SP1)	OTISPT4X	SP1_HUMAN	Decreases Expression	[7]
Proto-oncogene tyrosine-protein kinase Src (SRC)	OTETYX40	SRC_HUMAN	Decreases Expression	[13]
Tissue factor (F3)	OT3MSU3B	TF_HUMAN	Decreases Expression	[14]
Tyrosine-protein kinase receptor UFO (AXL)	OTKA2SUX	UFO_HUMAN	Decreases Expression	[15]
Transcription factor Sp3 (SP3)	OTYDQZ1T	SP3_HUMAN	Decreases Expression	[7]
Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1)	OT2YYI1A	MCL1_HUMAN	Decreases Expression	[16]
Epidermal growth factor receptor kinase substrate 8 (EPS8)	OTZ6ES6V	EPS8_HUMAN	Decreases Expression	[13]
TNFAIP3-interacting protein 1 (TNIP1)	OTRAOTEW	TNIP1_HUMAN	Decreases Expression	[17]
Sphingomyelin phosphodiesterase 3 (SMPD3)	OTHQBETH	NSMA2_HUMAN	Decreases Expression	[18]

Indication(s) of Chlorambucil

Disease Entry	ICD 11	Status	REF
Chronic lymphocytic leukaemia	2A82.0	Approved	[5]
Small lymphocytic lymphoma	2A82.0	Approved	[6]
Classic Hodgkin lymphoma	N.A.	Investigative	[6]
Follicular lymphoma	2A80	Investigative	[6]

Chlorambucil Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
DNA replication (DNA repli)	TTABD5E	NOUNIPROTAC	Intercalator	[19]

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	[20]
Organic anion transporting polypeptide 1A2 (SLCO1A2)	DTE2B1D	SO1A2_HUMAN	Substrate	[21]

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	[22]

Chlorambucil Interacts with 37 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Glutathione S-transferase P (GSTP1)	OTLP0A0Y	GSTP1_HUMAN	Decreases Response To Substance	[23]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Increases Expression	[24]
Glutathione S-transferase A1 (GSTA1)	OTA7K5XA	GSTA1_HUMAN	Decreases Activity	[25]
Aldo-keto reductase family 1 member B10 (AKR1B10)	OTOA4HTH	AK1BA_HUMAN	Decreases Expression	[26]
Leukemia inhibitory factor (LIF)	OTO46S5S	LIF_HUMAN	Increases Expression	[26]
Aldo-keto reductase family 1 member C2 (AKR1C2)	OTQ2XMO3	AK1C2_HUMAN	Decreases Expression	[26]
Bcl-2-interacting killer (BIK)	OTTH1T3D	BIK_HUMAN	Increases Expression	[26]
F-box only protein 30 (FBXO30)	OTD1P6LA	FBX30_HUMAN	Decreases Expression	[26]
Histone chaperone ASF1A (ASF1A)	OT4S44GP	ASF1A_HUMAN	Decreases Expression	[26]
Tumor necrosis factor receptor superfamily member 10A (TNFRSF10A)	OTBPCU2O	TR10A_HUMAN	Affects Expression	[27]
Tumor necrosis factor receptor superfamily member 10B (TNFRSF10B)	OTA1CPBV	TR10B_HUMAN	Increases Expression	[28]
Baculoviral IAP repeat-containing protein 5 (BIRC5)	OTILXZYL	BIRC5_HUMAN	Affects Expression	[29]
Myc proto-oncogene protein (MYC)	OTPV5LUK	MYC_HUMAN	Increases Expression	[30]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Increases Expression	[28]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[30]
Histone H2AX (H2AX)	OT18UX57	H2AX_HUMAN	Increases Phosphorylation	[31]
HLA class II histocompatibility antigen, DP alpha 1 chain (HLA-DPA1)	OT7OG7Y2	DPA1_HUMAN	Affects Expression	[32]
Tumor necrosis factor receptor superfamily member 6 (FAS)	OTP9XG86	TNR6_HUMAN	Increases Expression	[33]
14-3-3 protein sigma (SFN)	OTLJCZ1U	1433S_HUMAN	Increases Expression	[28]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Increases Expression	[34]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[33]
Histone H4 (H4C1)	OTB71W46	H4_HUMAN	Decreases Expression	[31]
E3 ubiquitin-protein ligase Mdm2 (MDM2)	OTOVXARF	MDM2_HUMAN	Increases Expression	[29]
DNA repair protein RAD51 homolog 1 (RAD51)	OTNVWGC1	RAD51_HUMAN	Increases Expression	[35]
Apoptosis regulator BAX (BAX)	OTAW0V4V	BAX_HUMAN	Increases Expression	[36]
Caspase-8 (CASP8)	OTA8TVI8	CASP8_HUMAN	Increases Activity	[33]
kinase isozyme 4, mitochondrial (PDK4)	OTCMHMBZ	PDK4_HUMAN	Affects Expression	[37]
Bcl-2-binding component 3, isoforms 3/4 (BBC3)	OTUAXDAY	BBC3B_HUMAN	Increases Expression	[29]
Nuclear factor erythroid 2-related factor 2 (NFE2L2)	OT0HENJ5	NF2L2_HUMAN	Increases Response To Substance	[38]
Dihydrofolate reductase (DHFR)	OT3DVIGM	DYR_HUMAN	Decreases Response To Substance	[39]
Cytidine deaminase (CDA)	OT3HXP6N	CDD_HUMAN	Decreases Response To Substance	[40]
Fanconi anemia group G protein (FANCG)	OT7MC8TZ	FANCG_HUMAN	Increases Response To Substance	[41]
Baculoviral IAP repeat-containing protein 2 (BIRC2)	OTFXFREP	BIRC2_HUMAN	Decreases Response To Substance	[42]
Multidrug resistance-associated protein 1 (ABCC1)	OTGUN89S	MRP1_HUMAN	Decreases Response To Substance	[23]
ATP-binding cassette sub-family C member 2 (ABCC2)	OTJSIGV5	MRP2_HUMAN	Affects Export	[43]
Glutathione S-transferase Mu 1 (GSTM1)	OTSBF2MO	GSTM1_HUMAN	Decreases Response To Substance	[44]
Fanconi anemia group C protein (FANCC)	OTTIDM3P	FANCC_HUMAN	Increases Response To Substance	[41]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Adult T acute lymphoblastic leukemia	DCFMYUH	MOLT-4	Investigative	[1]
Childhood T acute lymphoblastic leukemia	DCY9LX0	CCRF-CEM	Investigative	[1]
Chronic myelogenous leukemia	DCBPG8U	K-562	Investigative	[1]
Clear cell renal cell carcinoma	DC4T49Z	TK-10	Investigative	[1]
Breast adenocarcinoma	DCV0MWR	MDA-MB-468	Investigative	[45]
Invasive ductal carcinoma	DC8UGUM	T-47D	Investigative	[45]
Adenocarcinoma	DC0NGWR	HCT116	Investigative	[46]
High grade ovarian serous adenocarcinoma	DCZPIWH	OVCAR-5	Investigative	[46]
Ovarian serous cystadenocarcinoma	DCLVOU2	SK-OV-3	Investigative	[46]

References

• [1] Recurrent recessive mutation in deoxyguanosine kinase causes idiopathic noncirrhotic portal hypertension.Hepatology. 2016 Jun;63(6):1977-86. doi: 10.1002/hep.28499. Epub 2016 Mar 31.
• [2] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [3] 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: 8394).
• [4] The Pluripotency Factor Musashi-2 Is a Novel Target for Lung Cancer Therapy.Ann Am Thorac Soc. 2018 Apr;15(Supplement_2):S124.
• [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: 7143).
• [6] Chlorambucil FDA Label
• [7] The activity of a novel mithramycin analog is related to its binding to DNA, cellular accumulation, and inhibition of Sp1-driven gene transcription. Chem Biol Interact. 2014 Aug 5;219:123-32. doi: 10.1016/j.cbi.2014.05.019. Epub 2014 Jun 4.
• [8] Role of magnesium ion in mithramycin-DNA interaction: binding of mithramycin-Mg2+ complexes with DNA. Biochemistry. 1995 Jan 31;34(4):1376-85.
• [9] SP1 and SP3 mediate progesterone-dependent induction of the 17beta hydroxysteroid dehydrogenase type 2 gene in human endometrium. Biol Reprod. 2006 Oct;75(4):605-14.
• [10] Metformin suppresses CYP1A1 and CYP1B1 expression in breast cancer cells by down-regulating aryl hydrocarbon receptor expression. Toxicol Appl Pharmacol. 2014 Oct 1;280(1):138-48.
• [11] Molecular mechanisms of transactivation and doxorubicin-mediated repression of survivin gene in cancer cells. J Biol Chem. 2007 Jan 26;282(4):2615-25. doi: 10.1074/jbc.M606203200. Epub 2006 Nov 22.
• [12] Sp1 and Sp3 transcription factors regulate the basal expression of human microsomal epoxide hydrolase (EPHX1) through interaction with the E1b far upstream promoter. Gene. 2014 Feb 15;536(1):135-44. doi: 10.1016/j.gene.2013.11.053. Epub 2013 Dec 4.
• [13] Mithramycin inhibits human epithelial carcinoma cell proliferation and migration involving downregulation of Eps8 expression. Chem Biol Interact. 2010 Jan 5;183(1):181-6. doi: 10.1016/j.cbi.2009.09.018.
• [14] Asbestos induces tissue factor in Beas-2B human lung bronchial epithelial cells in vitro. Lung. 2004;182(4):251-64. doi: 10.1007/s00408-004-2507-2.
• [15] The human receptor tyrosine kinase Axl gene--promoter characterization and regulation of constitutive expression by Sp1, Sp3 and CpG methylation. Biosci Rep. 2008 Jun;28(3):161-76. doi: 10.1042/BSR20080046.
• [16] CREB/Sp1-mediated MCL1 expression and NFB-mediated ABCB1 expression modulate the cytotoxicity of daunorubicin in chronic myeloid leukemia cells. Toxicol Appl Pharmacol. 2022 Jan 15;435:115847. doi: 10.1016/j.taap.2021.115847. Epub 2021 Dec 25.
• [17] Sp sites contribute to basal and inducible expression of the human TNIP1 (TNF-inducible protein 3-interacting protein 1) promoter. Biochem J. 2013 Jun 15;452(3):519-29. doi: 10.1042/BJ20121666.
• [18] Transcriptional regulation of neutral sphingomyelinase 2 gene expression of a human breast cancer cell line, MCF-7, induced by the anti-cancer drug, daunorubicin. Biochim Biophys Acta. 2009 Nov-Dec;1789(11-12):681-90. doi: 10.1016/j.bbagrm.2009.08.006. Epub 2009 Aug 19.
• [19] 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.
• [20] 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.
• [21] Transporters and renal drug elimination. Annu Rev Pharmacol Toxicol. 2004;44:137-66.
• [22] 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.
• [23] The influence of coordinate overexpression of glutathione phase II detoxification gene products on drug resistance. J Pharmacol Exp Ther. 2000 Aug;294(2):480-7.
• [24] 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.
• [25] Role of multidrug resistance protein 1 (MRP1) and glutathione S-transferase A1-1 in alkylating agent resistanceKinetics of glutathione conjugate formation and efflux govern differential cellular sensitivity to chlorambucil versus melphalan toxicity. J Biol Chem. 2001 Mar 16;276(11):7952-6.
• [26] Oxidative stress mechanisms do not discriminate between genotoxic and nongenotoxic liver carcinogens. Chem Res Toxicol. 2015 Aug 17;28(8):1636-46.
• [27] 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.
• [28] 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.
• [29] 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.
• [30] Theophylline synergizes with chlorambucil in inducing apoptosis of B-chronic lymphocytic leukemia cells. Blood. 1996 Sep 15;88(6):2172-82.
• [31] 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.
• [32] 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.
• [33] 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.
• [34] 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.
• [35] Chlorambucil induction of HsRad51 in B-cell chronic lymphocytic leukemia. Clin Cancer Res. 1999 Aug;5(8):2178-84.
• [36] Bcl-2 antisense oligonucleotides enhance the cytotoxicity of chlorambucil in B-cell chronic lymphocytic leukaemia cells. Leuk Lymphoma. 2001 Jul;42(3):491-8. doi: 10.3109/10428190109064606.
• [37] 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.
• [38] Characterization of the cancer chemopreventive NRF2-dependent gene battery in human keratinocytes: demonstration that the KEAP1-NRF2 pathway, and not the BACH1-NRF2 pathway, controls cytoprotection against electrophiles as well as redox-cycling compounds. Carcinogenesis. 2009 Sep;30(9):1571-80. doi: 10.1093/carcin/bgp176. Epub 2009 Jul 16.
• [39] Increased resistance to nitrogen mustards and antifolates following in vitro selection of murine fibroblasts and primary hematopoietic cells transduced with a bicistronic retroviral vector expressing the rat glutathione S-transferase A3 and a mutant dihydrofolate reductase. Cancer Gene Ther. 2003 Aug;10(8):637-46. doi: 10.1038/sj.cgt.7700619.
• [40] Coexpression of rat glutathione S-transferase A3 and human cytidine deaminase by a bicistronic retroviral vector confers in vitro resistance to nitrogen mustards and cytosine arabinoside in murine fibroblasts. Cancer Gene Ther. 2000 May;7(5):757-65. doi: 10.1038/sj.cgt.7700169.
• [41] 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.
• [42] Expression and prognostic significance of IAP-family genes in human cancers and myeloid leukemias. Clin Cancer Res. 2000 May;6(5):1796-803.
• [43] Role of multidrug resistance protein 2 (MRP2, ABCC2) in alkylating agent detoxification: MRP2 potentiates glutathione S-transferase A1-1-mediated resistance to chlorambucil cytotoxicity. J Pharmacol Exp Ther. 2004 Jan;308(1):260-7. doi: 10.1124/jpet.103.057729. Epub 2003 Oct 20.
• [44] Glutathione S-transferase M1 and multidrug resistance protein 1 act in synergy to protect melanoma cells from vincristine effects. Mol Pharmacol. 2004 Apr;65(4):897-905. doi: 10.1124/mol.65.4.897.
• [45] Biologically active neutrophil chemokine pattern in tonsillitis.Clin Exp Immunol. 2004 Mar;135(3):511-8. doi: 10.1111/j.1365-2249.2003.02390.x.
• [46] Loss of function mutations in VARS encoding cytoplasmic valyl-tRNA synthetase cause microcephaly, seizures, and progressive cerebral atrophy.Hum Genet. 2018 Apr;137(4):293-303. doi: 10.1007/s00439-018-1882-3. Epub 2018 Apr 24.