Mechanism Research of Apatinib-Treated Breast Cancer Based on Network Pharmacology
ZHU Wan-ting1,2, FAN Xue-mei2*, WEI Hua3, WANG Yi-ming2 , LI Xiao-fang2, WANG Shu-mei1*, CHEN Wan-sheng3, LUO Guo-an2
1. Guangdong Pharmaceutical University, Guangzhou 510006, China; 2. Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Ministry of Education, Department of Chemistry, Tsinghua University, Beijing 100084, China; 3. Changzheng Hospital, The Second Military Medical University, Shanghai 200003, China
Abstract��OBJECTIVE To study the potential targets and action mechanism of apatinib-treated breast cancer. METHODS Combination with bioinformatic analysis, PharmMapper reverse docking technology was used to predict potential targets of apatinib and docking was performed using Autodock 4.0 to examine the interaction of aptinib wih predicted protein targets. RESULTS Cell division protein kinase 2,GTPase HRas, NONE and cytochrome P450 2C9 were found to be the potential targets of apatinib-treated breast cancer. Stable hydrogen bonds were formed between apatinib and the four predicted targets, and the binding free energy was low. CONCLUSION Apatinib maybe participate the functional regulation or biological action of cell division protein kinase 2, GTPase HRas, NONE and Cytochrome P4502C9 to treat breast cancer, which provides a theoretical basis and a clue for further exploration of the mechanism research of apatinib-treated breast cancer.
������, ��ѩ÷, λ��, ������, ��С��, ������, ������, ����. ��������ҩ��ѧ̽�ְ��������������ٰ������û���[J]. �й�ҩѧ��־, 2016, 51(18): 1569-1573.
ZHU Wan-ting, FAN Xue-mei, WEI Hua, WANG Yi-ming , LI Xiao-fang, WANG Shu-mei, CHEN Wan-sheng, LUO Guo-an. Mechanism Research of Apatinib-Treated Breast Cancer Based on Network Pharmacology. Chinese Pharmaceutical Journal, 2016, 51(18): 1569-1573.
ZHANG Y E, ZHANG T B, TONG D J. Apatinib-treated gastric cancer listing [N]. Science and Technology Daily(�Ƽ��ձ�), 2014-11-08.
[2]
GENG R, LI J. Apatinib for the treatment of gastric cancer [J]. Expert Opin Pharmacother, 2015, 16(1):117-122.
[3]
ZHANG H J. Apatinib for molecular targeted therapy in tumor[J]. Drug Des Devel Ther, 2015, 9:6075-6081.
[4]
YAN J M, YONG J L, HUANG H B, et al. Apatinib (YN968D1) reverses multidrug resistance by inhibiting the efflux function of multiple ATP-binding cassette transporters [J]. Cancer Res, 2010, 70(20):7981-7991.
[5]
FANG M H. Studies on predictive and prognostic factors for recurrent or metastatic breast cancer treated with small molecular anti-angiogenic agents [D]. Shanghai : Fudan University, 2013.
[6]
HU X C, ZHANG H, XU B, et al. Multicenter phase II study of apatinib, a novel VEGFR inhibitor in heavily pretreated patients with metastatic triple-negative breast cancer[J]. Int J Cancer, 2014, 135(8) :1961-1969.
[7]
GAO L, LIU A L, DU G H. Application and progress of computer aided drug design(CADD) in drug development [J]. Chin Pharm J(�й�ҩѧ��־), 2011,46(9):641-645.
[8]
SONG J L, XIANGY H, ZHAO L L, et al. Potential target prediction and molecular docking studies of SAHA [J]. Comput Chem(�������Ӧ�û�ѧ),2013, 30 (1) :97-101.
[9]
HOPKINS A L. Network pharmacology [J]. Nat Biotechnol, 2007,25(10):1110-1111.
[10]
HSIN K Y, GHOSH S, KITANO H. Combining machine learning systems and multiple docking simulation packages to improve docking prediction reliability for network pharmacology [J]. PLoS One, 2013, 8 (12):16-16.
[11]
TAO W, XU X, WANG X, et al. Network pharmacology-based prediction of the Radix Curcumae ingredients and potential targets of Chinese herbal Radix Curcumae formula for application to cardiovascular disease [J]. J Ethnopharmacol, 2013, 145(1):1-10.
[12]
LIU X, OUYANG S, YU B, et al. PharmMapper server:a web server for potential drug target identification using pharmacophore mapping approach [J]. Nucleic Acids Res, 2010, 38(2):609-614.
[13]
BAI Y,FAN X M, SUN H, et al. The mechanism of rosiglitazone compound based on network pharmacology [J]. Acta Pharm Sin(ҩѧѧ��), 2015, 50 (3):284-290.
[14]
LI J H, HU A, ZHENG W J, et al. Screening of target protein of triptolide on psoriasis by molecular docking[J]. Chin Pharm J(�й�ҩѧ��־), 2014,49 (13) :1133-1138.
[15]
BERMAN H M, BATTISTUZ T, BHAT T N, et al. The protein data bank [J]. Nucleic Acids Res, 2000, 28(1):235-242 .
[16]
WANG Y R, ZHANG X Z, LI N, et al. Action mechanism of Shuangyu granules on upper respiratorytract infections based on network pharmacology [J]. Chin New Drugs J (�й���ҩ��־), 2015, 24(11):1222-1241.
[17]
KIM S J, MASUDA N, TSUKAMOTO F, et al. The cell cycle profiling-risk score based on CDK1 and 2 predicts early recurrence in node-negative, hormone receptor-positive breast cancer treated with endocrine therapy [J]. Cancer Lett, 2014, 355(2):217-223.
[18]
KIM S J, NAKAYAMA S, SHIMAZU K, et al. Recurrence risk score based on the specific activity of CDK1 and CDK2 predicts response to neoadjuvant paclitaxel followed by 5-fluorouracil, epirubicin and cyclophosphamide in breast cancers[J]. Ann Oncol, 2012, 23(4):891-897.
[19]
JAUTELAT R, BRUMBY T, SCHAFER M, et al. From the insoluble dye indirubin towards highly active, soluble CDK2-inhibitors [J]. Chembiochem, 2005, 6(3):531-540.
[20]
SCHUBBERT S, SHANNON K, BOLLAG G. Hyperactive Ras in developmental disorders and cancer [J]. Nat Rev Cancer, 2007, 7(4):295-308.
[21]
DA SILVA L, SIMPSON P T, SMART C E, et al. HER3 and downstream pathways are involved in colonization of brain metastases from breast cancer [J]. Breast Cancer Res, 2010, 12(4):46.
[22]
CASTAGNINO N, TORTOLINA L, BALBI A, et al. Dynamic simulations of pathways downstream of ERBB-family, including mutations and treatments:concordance with experimental results [J]. Curr Cancer Drug Targets,2010, 10(7):737-757.
[23]
FINLAYSON C A, CHAPPELL J, LEITNER J W, et al. Enhanced insulin signaling via Shc in human breast cancer [J]. Metabolism, 2003, 52(12):1606-1611.
[24]
USHA T, MIDDHA S K, GOYAL A K, et al. Molecular docking studies of anti-cancerous candidates in Hippophae rhamnoides and Hippophae salicifolia [J]. J Biomed Mater Res, 2014, 28(5):406-415.
[25]
APOSTOLI A J, ROCHE J M, SCHNEIDER M M, et al. Opposing roles for mammary epithelial-specific PPAR�� signaling and activation during breast tumour progression [J]. Mol Cancer, 2015, 14(1):1-14.
[26]
KOPP T L, LUNDQVIST J, PETERSEN R K, et al. In vitro screening of inhibition of PPAR-�� activity as a first step in identification of potential breast carcinogens [J]. Hum Exp Toxicol, 2015, 34(11):1106-1118.
[27]
CASIMIRO-GARCIA A, BIGGE C F, DAVIS J A, et al. Synthesis and evaluation of novelalpha-heteroaryl-phenylpropanoicacidderivatives as PPAR alpha/gammadualagonists [J]. Bioorg Med Chem, 2009, 17(20):7113-7125.
[28]
MICHELIS U R, FISSLTHALER B, BARBOSA-SICARD E, et al. Cytochrome P450 epoxygenases 2C8 and 2C9 are implicated in hypoxia-induced endothelial cell migration and angiogenesis [J]. J Cell Sci, 2005,118(23):5489-5498.
[29]
BELTON O, FITZGERALD D J. Cyclooxygenase isoforms and atherosclerosis [J]. Expert Rev Mol Med, 2003, 5 (9) :1-18.
[30]
DING Y F. Metabolism and pharmacokinetics of anti-cancer drug, apatinib in human [D]. Beijing:University of Chinese Academy of Sciences,2013.
2016, Vol. 51 
