title: Modeling of non-steroidal anti-inflammatory drug effect within signaling pathways and miRNA-regulation pathways.
abstract: To date, it is widely recognized that Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) can exert considerable anti-tumor effects regarding many types of cancers. The prolonged use of NSAIDs is highly associated with diverse side effects. Therefore, tailoring down the NSAID application onto individual patients has become a necessary and relevant step towards personalized medicine. This study conducts the systemsbiological approach to construct a molecular model (NSAID model) containing a cyclooxygenase (COX)-pathway and its related signaling pathways. Four cancer hallmarks are integrated into the model to reflect different developmental aspects of tumorigenesis. In addition, a Flux-Comparative-Analysis (FCA) based on Petri net is developed to transfer the dynamic properties (including drug responsiveness) of individual cellular system into the model. The gene expression profiles of different tumor-types with available drug-response information are applied to validate the predictive ability of the NSAID model. Moreover, two therapeutic developmental strategies, synthetic lethality and microRNA (miRNA) biomarker discovery, are investigated based on the COX-pathway. In conclusion, the result of this study demonstrates that the NSAID model involving gene expression, gene regulation, signal transduction, protein interaction and other cellular processes, is able to predict the individual cellular responses for different therapeutic interventions (such as NS-398 and COX-2 specific siRNA inhibition). This strongly indicates that this type of model is able to reflect the physiological, developmental and pathological processes of an individual. The approach of miRNA biomarker discovery is demonstrated for identifying miRNAs with oncogenic and tumor suppressive functions for individual cell lines of breast-, colon- and lung-tumor. The achieved results are in line with different independent studies that investigated miRNA biomarker related to diagnostics of cancer treatments, therefore it might shed light on the development of biomarker discovery at individual level. Particular results of this study might contribute to step further towards personalized medicine with the systemsbiological approach.
authors: Institute for Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-University Munich, Munich, Germany. lijian@ibe.med.uni-muenchen.de
authors: Jian
authors: J
authors: Li
authors: Ulrich R
authors: UR
authors: Mansmann
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology* / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007700:Kinetics; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D014408:Biomarkers, Tumor; D035683:MicroRNAs; D011451:Prostaglandin-Endoperoxide Synthases
references: Biochem Pharmacol. 2001 Mar 15;61(6):631-7
references: 11266647
references: Haematologica. 2002 Dec;87(12):1324-41
references: 12495905
references: Breast Cancer Res. 2010;12(5):210
references: 21067538
references: N Engl J Med. 1999 Jun 17;340(24):1888-99
references: 10369853
references: Nat New Biol. 1971 Jun 23;231(25):232-5
references: 5284360
references: Nat Rev Genet. 2002 Jun;3(6):415-28
references: 12042769
references: J Biol Chem. 2001 Oct 19;276(42):38658-64
references: 11509575
references: Pharmacogenomics J. 2007 Oct;7(5):297-304
references: 17189960
references: Biochem Biophys Res Commun. 2011 Jan 7;404(1):273-8
references: 21130073
references: Ann Clin Lab Sci. 2000 Jan;30(1):3-21
references: 10678579
references: PLoS One. 2011;6(8):e23802
references: 21901137
references: Cancer Res. 2005 Oct 15;65(20):9473-8
references: 16230411
references: Int J Oncol. 2006 Feb;28(2):543-9
references: 16391811
references: Cell. 2011 Mar 4;144(5):646-74
references: 21376230
references: Clin Cancer Res. 2003 Apr;9(4):1566-72
references: 12684433
references: Clin Cancer Res. 2005 Feb 1;11(3):1268-76
references: 15709198
references: Cell. 1998 Sep 18;94(6):695-8
references: 9753316
references: Clin Cancer Res. 2000 Jan;6(1):135-8
references: 10656441
references: Cell. 1998 May 29;93(5):705-16
references: 9630216
references: Br J Cancer. 2006 May 8;94(9):1300-10
references: 16622456
references: Proc Natl Acad Sci U S A. 2007 Sep 18;104(38):15144-9
references: 17848513
references: Cell. 1996 Aug 9;86(3):353-64
references: 8756718
references: Cancer Res. 2000 Feb 1;60(3):702-6
references: 10676656
references: Chin J Cancer. 2011 Jun;30(6):407-14
references: 21627863
references: Cancer Cell. 2004 Sep;6(3):285-95
references: 15380519
references: Carcinogenesis. 2012 Jan;33(1):68-76
references: 22072622
references: Ann Surg. 2012 Sep;256(3):544-51
references: 22868372
references: Cell Res. 2009 Apr;19(4):439-48
references: 19238171
references: Proc Natl Acad Sci U S A. 2006 Feb 14;103(7):2257-61
references: 16461460
references: World J Gastroenterol. 2011 Nov 14;17(42):4711-7
references: 22180714
references: N Engl J Med. 2005 Oct 27;353(17):1793-801
references: 16251535
references: Nat Med. 2000 Sep;6(9):1024-8
references: 10973323
references: J Steroid Biochem Mol Biol. 2002 Feb;80(2):203-12
references: 11897504
references: Nat Rev Cancer. 2003 Apr;3(4):253-66
references: 12671664
references: N Engl J Med. 2003 Mar 6;348(10):883-90
references: 12621132
references: Cancer Res. 2009 Mar 15;69(6):2623-9
references: 19258506
references: Int J Biol Sci. 2007 Jun 13;3(5):328-34
references: 17589567
references: Adv Pharmacol. 1997;39:1-20
references: 9160111
references: Proc Natl Acad Sci U S A. 2005 May 24;102(21):7695-700
references: 15897462
references: Cell Mol Life Sci. 2008 May;65(9):1295-301
references: 18292966
references: Gastroenterology. 2005 May;128(5):1445-61
references: 15887126
references: J Immunol. 1998 Apr 15;160(8):3783-9
references: 9558081
references: Trends Mol Med. 2003 Feb;9(2):73-8
references: 12615041
references: Nature. 2005 Jun 9;435(7043):834-8
references: 15944708
references: Cancer Res. 2006 Feb 15;66(4):2067-73
references: 16489006
references: Oncogene. 2003 Nov 27;22(54):8653-61
references: 14647459
references: Arch Otolaryngol Head Neck Surg. 2006 Nov;132(11):1231-6
references: 17116820
references: Proc Natl Acad Sci U S A. 2002 Nov 12;99(23):15112-7
references: 12415116
references: Annu Rev Biochem. 1986;55:69-102
references: 3017195
references: JAMA. 2008 Jan 30;299(4):425-36
references: 18230780
references: Mol Cancer Res. 2010 Dec;8(12):1656-64
references: 21097678
references: Nat Rev Cancer. 2005 Sep;5(9):689-98
references: 16110319
references: PLoS One. 2012;7(1):e30140
references: 22253908
references: Clin Cancer Res. 2011 Sep 1;17(17):5812-21
references: 21652542
references: Crit Rev Oncol Hematol. 2008 Mar;65(3):200-11
references: 18389522
references: Cell. 2000 Jan 7;100(1):57-70
references: 10647931
references: Life Sci. 2001 Nov 9;69(25-26):3045-54
references: 11758830
references: Cytogenet Cell Genet. 2000;89(1-2):121-8
references: 10894953
references: Adv Exp Med Biol. 2002;507:403-7
references: 12664617
references: Carcinogenesis. 2008 Jun;29(6):1092-5
references: 18453542
references: EMBO J. 2011 Sep 13;30(22):4628-41
references: 21915098
references: Science. 2010 Jul 9;329(5988):229-32
references: 20522742
references: Nat Rev Cancer. 2005 Nov;5(11):845-56
references: 16239904
references: Semin Oncol. 1999 Oct;26(5):499-504
references: 10528897
references: Nat Rev Mol Cell Biol. 2005 Feb;6(2):99-111
references: 15654321
references: Cancer Res. 2008 Jul 15;68(14):5619-27
references: 18632614
references: Neoplasia. 2008 Nov;10(11):1163-9
references: 18953425
references: Gastroenterology. 2001 Jun;120(7):1713-9
references: 11375952
references: Genes Dev. 2003 Oct 15;17(20):2481-95
references: 14561771
references: Mol Cell Biochem. 2008 Oct;317(1-2):179-88
references: 18592138
references: Gastroenterology. 2004 Jan;126(1):136-47
references: 14699495
references: J Thorac Oncol. 2011 Apr;6(4):671-8
references: 21270667
references: FEMS Microbiol Rev. 2009 Jan;33(1):164-90
references: 19067749