Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9B1CT3)

• DOT Name: L-lactate dehydrogenase B chain (LDHB)
• Synonyms: LDH-B; EC 1.1.1.27; LDH heart subunit; LDH-H; Renal carcinoma antigen NY-REN-46
• Gene Name: LDHB
• Related Disease:
  Esophageal squamous cell carcinoma
  Squamous cell carcinoma
  Triple negative breast cancer
  Adenocarcinoma
  Anal intraepithelial neoplasia
  Autism spectrum disorder
  Bladder cancer
  Breast neoplasm
  Carcinoma
  Chromosomal disorder
  Clear cell renal carcinoma
  Colon cancer
  Colon carcinoma
  Ductal breast carcinoma in situ
  Exanthem
  Hepatocellular carcinoma
  Inborn error of metabolism
  Lung cancer
  Lung carcinoma
  Lung neoplasm
  Matthew-Wood syndrome
  Medulloblastoma
  Metastatic malignant neoplasm
  Neoplasm
  Panic disorder
  Papillary renal cell carcinoma
  Primary myelofibrosis
  Prostate carcinoma
  Prostate neoplasm
  Renal cell carcinoma
  Type-1/2 diabetes
  Urinary bladder cancer
  Urinary bladder neoplasm
  Lung adenocarcinoma
  Glycogen storage disease due to lactate dehydrogenase H-subunit deficiency
  Acute coronary syndrome
  Breast cancer
  Breast carcinoma
  Colorectal carcinoma
  Invasive breast carcinoma
  Neuroblastoma
  Non-small-cell lung cancer
  Pancreatic cancer
  Prostate cancer
• UniProt ID: LDHB_HUMAN
• PDB ID: 1I0Z; 1T2F; 7DBJ; 7DBK
• EC Number: 1.1.1.27
• Pfam ID: PF02866 ; PF00056
• Sequence:
  MATLKEKLIAPVAEEEATVPNNKITVVGVGQVGMACAISILGKSLADELALVDVLEDKLK
  GEMMDLQHGSLFLQTPKIVADKDYSVTANSKIVVVTAGVRQQEGESRLNLVQRNVNVFKF
  IIPQIVKYSPDCIIIVVSNPVDILTYVTWKLSGLPKHRVIGSGCNLDSARFRYLMAEKLG
  IHPSSCHGWILGEHGDSSVAVWSGVNVAGVSLQELNPEMGTDNDSENWKEVHKMVVESAY
  EVIKLKGYTNWAIGLSVADLIESMLKNLSRIHPVSTMVKGMYGIENEVFLSLPCILNARG
  LTSVINQKLKDDEVAQLKKSADTLWDIQKDLKDL
• Function: Interconverts simultaneously and stereospecifically pyruvate and lactate with concomitant interconversion of NADH and NAD(+).
• Tissue Specificity: Predominantly expressed in aerobic tissues such as cardiac muscle.
• KEGG Pathway:
  Glycolysis / Gluconeogenesis (hsa00010)
  Cysteine and methionine metabolism (hsa00270)
  Pyruvate metabolism (hsa00620)
  Propanoate metabolism (hsa00640)
  Metabolic pathways (hsa01100)
  HIF-1 sig.ling pathway (hsa04066)
  Glucagon sig.ling pathway (hsa04922)
  Central carbon metabolism in cancer (hsa05230)
• Reactome Pathway: Pyruvate metabolism (R-HSA-70268)

Molecular Interaction Atlas (MIA) of This DOT

44 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Esophageal squamous cell carcinoma	DIS5N2GV	Definitive	Altered Expression	[1]
Squamous cell carcinoma	DISQVIFL	Definitive	Altered Expression	[2]
Triple negative breast cancer	DISAMG6N	Definitive	Biomarker	[3]
Adenocarcinoma	DIS3IHTY	Strong	Biomarker	[2]
Anal intraepithelial neoplasia	DISJ0JW3	Strong	Altered Expression	[4]
Autism spectrum disorder	DISXK8NV	Strong	Genetic Variation	[5]
Bladder cancer	DISUHNM0	Strong	Biomarker	[6]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[7]
Carcinoma	DISH9F1N	Strong	Altered Expression	[2]
Chromosomal disorder	DISM5BB5	Strong	Altered Expression	[8]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[9]
Colon cancer	DISVC52G	Strong	Altered Expression	[10]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[10]
Ductal breast carcinoma in situ	DISLCJY7	Strong	Biomarker	[7]
Exanthem	DISAFOQN	Strong	Biomarker	[11]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[12]
Inborn error of metabolism	DISO5FAY	Strong	Biomarker	[13]
Lung cancer	DISCM4YA	Strong	Altered Expression	[14]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[14]
Lung neoplasm	DISVARNB	Strong	Altered Expression	[14]
Matthew-Wood syndrome	DISA7HR7	Strong	Altered Expression	[4]
Medulloblastoma	DISZD2ZL	Strong	Biomarker	[15]
Metastatic malignant neoplasm	DIS86UK6	Strong	Altered Expression	[16]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[17]
Panic disorder	DISD3VNY	Strong	Biomarker	[18]
Papillary renal cell carcinoma	DIS25HBV	Strong	Biomarker	[9]
Primary myelofibrosis	DIS6L0CN	Strong	Biomarker	[19]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[20]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[21]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[9]
Type-1/2 diabetes	DISIUHAP	Strong	Biomarker	[22]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[6]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[6]
Lung adenocarcinoma	DISD51WR	moderate	Altered Expression	[23]
Glycogen storage disease due to lactate dehydrogenase H-subunit deficiency	DISLGH8W	Supportive	Autosomal dominant	[24]
Acute coronary syndrome	DIS7DYEW	Limited	Biomarker	[25]
Breast cancer	DIS7DPX1	Limited	Altered Expression	[26]
Breast carcinoma	DIS2UE88	Limited	Altered Expression	[26]
Colorectal carcinoma	DIS5PYL0	Limited	Biomarker	[27]
Invasive breast carcinoma	DISANYTW	Limited	Altered Expression	[28]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[29]
Non-small-cell lung cancer	DIS5Y6R9	Limited	Biomarker	[30]
Pancreatic cancer	DISJC981	Limited	Altered Expression	[31]
Prostate cancer	DISF190Y	Limited	Biomarker	[20]

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Fluorouracil	DMUM7HZ	Approved	L-lactate dehydrogenase B chain (LDHB) affects the response to substance of Fluorouracil.	[52]
Cyclophosphamide	DM4O2Z7	Approved	L-lactate dehydrogenase B chain (LDHB) affects the response to substance of Cyclophosphamide.	[52]
Cimetidine	DMH61ZB	Approved	L-lactate dehydrogenase B chain (LDHB) increases the Haemolytic anaemia ADR of Cimetidine.	[53]

This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
D-glucose	DMMG2TO	Investigative	L-lactate dehydrogenase B chain (LDHB) affects the metabolism of D-glucose.	[7]

18 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of L-lactate dehydrogenase B chain (LDHB).	[32]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of L-lactate dehydrogenase B chain (LDHB).	[33]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of L-lactate dehydrogenase B chain (LDHB).	[34]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of L-lactate dehydrogenase B chain (LDHB).	[35]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate affects the expression of L-lactate dehydrogenase B chain (LDHB).	[36]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of L-lactate dehydrogenase B chain (LDHB).	[37]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of L-lactate dehydrogenase B chain (LDHB).	[38]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of L-lactate dehydrogenase B chain (LDHB).	[39]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of L-lactate dehydrogenase B chain (LDHB).	[40]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of L-lactate dehydrogenase B chain (LDHB).	[41]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of L-lactate dehydrogenase B chain (LDHB).	[42]
Azacitidine	DMTA5OE	Approved	Azacitidine increases the expression of L-lactate dehydrogenase B chain (LDHB).	[7]
Fenofibrate	DMFKXDY	Approved	Fenofibrate increases the expression of L-lactate dehydrogenase B chain (LDHB).	[42]
Ibuprofen	DM8VCBE	Approved	Ibuprofen affects the expression of L-lactate dehydrogenase B chain (LDHB).	[44]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of L-lactate dehydrogenase B chain (LDHB).	[47]
Tanespimycin	DMNLQHK	Phase 2	Tanespimycin increases the expression of L-lactate dehydrogenase B chain (LDHB).	[48]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of L-lactate dehydrogenase B chain (LDHB).	[50]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of L-lactate dehydrogenase B chain (LDHB).	[51]

2 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Dihydroartemisinin	DMBXVMZ	Approved	Dihydroartemisinin affects the binding of L-lactate dehydrogenase B chain (LDHB).	[45]
Resveratrol	DM3RWXL	Phase 3	Resveratrol affects the secretion of L-lactate dehydrogenase B chain (LDHB).	[46]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of L-lactate dehydrogenase B chain (LDHB).	[49]

References

• [1] Usefulness of microRNA?75 as a prognostic and therapeutic tool in esophageal squamous cell carcinoma.Int J Oncol. 2015 Mar;46(3):1059-66. doi: 10.3892/ijo.2014.2789. Epub 2014 Dec 9.
• [2] Prognostic significance of lactate dehydrogenase B according to histologic type of non-small-cell lung cancer and its association with serum lactate dehydrogenase.Pathol Res Pract. 2017 Sep;213(9):1134-1138. doi: 10.1016/j.prp.2017.07.006. Epub 2017 Jul 6.
• [3] An integrated genomic screen identifies LDHB as an essential gene for triple-negative breast cancer.Cancer Res. 2012 Nov 15;72(22):5812-23. doi: 10.1158/0008-5472.CAN-12-1098. Epub 2012 Nov 8.
• [4] LDHB and FABP4 are Associated With Progression and Poor Prognosis of Pancreatic Ductal Adenocarcinomas.Appl Immunohistochem Mol Morphol. 2017 May/Jun;25(5):351-357. doi: 10.1097/PAI.0000000000000306.
• [5] Identification of the antigenic epitopes of maternal autoantibodies in autism spectrum disorders.Brain Behav Immun. 2018 Mar;69:399-407. doi: 10.1016/j.bbi.2017.12.014. Epub 2017 Dec 28.
• [6] A lentiviral sponge for miRNA-21 diminishes aerobic glycolysis in bladder cancer T24 cells via the PTEN/PI3K/AKT/mTOR axis.Tumour Biol. 2015 Jan;36(1):383-91. doi: 10.1007/s13277-014-2617-2. Epub 2014 Sep 30.
• [7] Lactate dehydrogenase-B is silenced by promoter methylation in a high frequency of human breast cancers. PLoS One. 2013;8(2):e57697. doi: 10.1371/journal.pone.0057697. Epub 2013 Feb 21.
• [8] Mapping by gene dosage, using aneuploid human lymphoid cell lines.Ann Hum Genet. 1981 May;45(2):169-79. doi: 10.1111/j.1469-1809.1981.tb00319.x.
• [9] Differential protein profiling in renal-cell carcinoma.Mol Carcinog. 2004 May;40(1):47-61. doi: 10.1002/mc.20015.
• [10] Colon cancer cells maintain low levels of pyruvate to avoid cell death caused by inhibition of HDAC1/HDAC3.Biochem J. 2009 Jan 1;417(1):379-89. doi: 10.1042/BJ20081132.
• [11] Comparative analysis of inflamed and non-inflamed colon biopsies reveals strong proteomic inflammation profile in patients with ulcerative colitis.BMC Gastroenterol. 2012 Jun 24;12:76. doi: 10.1186/1471-230X-12-76.
• [12] Decreased lactate dehydrogenase B expression enhances claudin 1-mediated hepatoma cell invasiveness via mitochondrial defects.Exp Cell Res. 2011 May 1;317(8):1108-18. doi: 10.1016/j.yexcr.2011.02.011. Epub 2011 Feb 26.
• [13] A missense mutation found in human lactate dehydrogenase-B (H) variant gene.Biochem Biophys Res Commun. 1990 Apr 30;168(2):672-6. doi: 10.1016/0006-291x(90)92373-8.
• [14] Lactate dehydrogenase B is required for the growth of KRAS-dependent lung adenocarcinomas.Clin Cancer Res. 2013 Feb 15;19(4):773-84. doi: 10.1158/1078-0432.CCR-12-2638. Epub 2012 Dec 6.
• [15] Molecular risk stratification of medulloblastoma patients based on immunohistochemical analysis of MYC, LDHB, and CCNB1 expression.Clin Cancer Res. 2008 Jul 1;14(13):4154-60. doi: 10.1158/1078-0432.CCR-07-4159.
• [16] Lactate dehydrogenase-B is silenced by promoter hypermethylation in human prostate cancer.Oncogene. 2006 May 11;25(20):2953-60. doi: 10.1038/sj.onc.1209262.
• [17] Aurora-A mediated phosphorylation of LDHB promotes glycolysis and tumor progression by relieving the substrate-inhibition effect.Nat Commun. 2019 Dec 5;10(1):5566. doi: 10.1038/s41467-019-13485-8.
• [18] Association of an exonic LDHA polymorphism with altered respiratory response in probands at high risk for panic disorder.Am J Med Genet B Neuropsychiatr Genet. 2003 Feb;117B(1):11-7. doi: 10.1002/ajmg.b.10015.
• [19] Increased serum lactate dehydrogenase isoenzymes in Ph-negative chronic myeloproliferative diseases: a metabolic adaptation?.Hematology. 2006 Aug;11(4):239-44. doi: 10.1080/10245330600774835.
• [20] Aberrant FGFR Tyrosine Kinase Signaling Enhances the Warburg Effect by Reprogramming LDH Isoform Expression and Activity in Prostate Cancer.Cancer Res. 2018 Aug 15;78(16):4459-4470. doi: 10.1158/0008-5472.CAN-17-3226. Epub 2018 Jun 11.
• [21] Proteome analysis of human androgen-independent prostate cancer cell lines: variable metastatic potentials correlated with vimentin expression.Proteomics. 2007 Jun;7(12):1973-83. doi: 10.1002/pmic.200600643.
• [22] Glycation profile of minor abundant erythrocyte proteome across varying glycemic index in diabetes mellitus.Anal Biochem. 2019 May 15;573:37-43. doi: 10.1016/j.ab.2019.02.026. Epub 2019 Mar 2.
• [23] The drs tumor suppressor regulates glucose metabolism via lactate dehydrogenase-B.Mol Carcinog. 2016 Jan;55(1):52-63. doi: 10.1002/mc.22258. Epub 2015 Jan 24.
• [24] Clinical Practice Guidelines for Rare Diseases: The Orphanet Database. PLoS One. 2017 Jan 18;12(1):e0170365. doi: 10.1371/journal.pone.0170365. eCollection 2017.
• [25] Proteomic changes related to "bewildered" circulating platelets in the acute coronary syndrome.Proteomics. 2011 Aug;11(16):3335-48. doi: 10.1002/pmic.201000708. Epub 2011 Jul 14.
• [26] HMGB2 is associated with malignancy and regulates Warburg effect by targeting LDHB and FBP1 in breast cancer.Cell Commun Signal. 2018 Feb 20;16(1):8. doi: 10.1186/s12964-018-0219-0.
• [27] The KLF14 Transcription Factor Regulates Glycolysis by Downregulating LDHB in Colorectal Cancer.Int J Biol Sci. 2019 Jan 1;15(3):628-635. doi: 10.7150/ijbs.30652. eCollection 2019.
• [28] Gene expression signatures and biomarkers of noninvasive and invasive breast cancer cells: comprehensive profiles by representational difference analysis, microarrays and proteomics.Oncogene. 2006 Apr 13;25(16):2328-38. doi: 10.1038/sj.onc.1209265.
• [29] LDHA in Neuroblastoma Is Associated with Poor Outcome and Its Depletion Decreases Neuroblastoma Growth Independent of Aerobic Glycolysis.Clin Cancer Res. 2018 Nov 15;24(22):5772-5783. doi: 10.1158/1078-0432.CCR-17-2578. Epub 2018 Jun 20.
• [30] High developmental pluripotencyassociated 4 expression promotes cell proliferation and glycolysis, and predicts poor prognosis in nonsmallcell lung cancer.Mol Med Rep. 2019 Jul;20(1):445-454. doi: 10.3892/mmr.2019.10272. Epub 2019 May 22.
• [31] LAT2 regulates glutamine-dependent mTOR activation to promote glycolysis and chemoresistance in pancreatic cancer.J Exp Clin Cancer Res. 2018 Nov 12;37(1):274. doi: 10.1186/s13046-018-0947-4.
• [32] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [33] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [34] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [35] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [36] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [37] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [38] Proteomic and functional analyses reveal a dual molecular mechanism underlying arsenic-induced apoptosis in human multiple myeloma cells. J Proteome Res. 2009 Jun;8(6):3006-19.
• [39] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [40] Proteomic analysis revealed association of aberrant ROS signaling with suberoylanilide hydroxamic acid-induced autophagy in Jurkat T-leukemia cells. Autophagy. 2010 Aug;6(6):711-24. doi: 10.4161/auto.6.6.12397. Epub 2010 Aug 17.
• [41] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [42] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [43] Lactate dehydrogenase-B is silenced by promoter methylation in a high frequency of human breast cancers. PLoS One. 2013;8(2):e57697. doi: 10.1371/journal.pone.0057697. Epub 2013 Feb 21.
• [44] Protein profile in neuroblastoma cells incubated with S- and R-enantiomers of ibuprofen by iTRAQ-coupled 2-D LC-MS/MS analysis: possible action of induced proteins on Alzheimer's disease. Proteomics. 2008 Apr;8(8):1595-607. doi: 10.1002/pmic.200700556.
• [45] Untargeted Proteomics and Systems-Based Mechanistic Investigation of Artesunate in Human Bronchial Epithelial Cells. Chem Res Toxicol. 2015 Oct 19;28(10):1903-13. doi: 10.1021/acs.chemrestox.5b00105. Epub 2015 Sep 21.
• [46] Calorie restriction-induced changes in the secretome of human adipocytes, comparison with resveratrol-induced secretome effects. Biochim Biophys Acta. 2014 Sep;1844(9):1511-22. doi: 10.1016/j.bbapap.2014.04.023. Epub 2014 May 5.
• [47] Quantitative proteomics and transcriptomics addressing the estrogen receptor subtype-mediated effects in T47D breast cancer cells exposed to the phytoestrogen genistein. Mol Cell Proteomics. 2011 Jan;10(1):M110.002170.
• [48] Impact of Heat Shock Protein 90 Inhibition on the Proteomic Profile of Lung Adenocarcinoma as Measured by Two-Dimensional Electrophoresis Coupled with Mass Spectrometry. Cells. 2019 Jul 31;8(8):806. doi: 10.3390/cells8080806.
• [49] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [50] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [51] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [52] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.
• [53] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.
• [54] Lactate dehydrogenase-B is silenced by promoter methylation in a high frequency of human breast cancers. PLoS One. 2013;8(2):e57697. doi: 10.1371/journal.pone.0057697. Epub 2013 Feb 21.