马雪百合,张在平
MA Xuebaihe,ZHANG Zaiping

• 1:桂林医学院药学院

摘要(Abstract)：

通过检索、整理、分析近年来国内外发表的阿司匹林抗癌作用及机制的文献，为其临床防治癌症提供依据和参考。我们利用中国知网和PubMed检索平台，检索相关文献95篇，从癌细胞增殖、周期、凋亡、迁移侵袭、自噬等方面归纳总结阿司匹林在不同癌症中的抗癌作用及机制。发现阿司匹林对结直肠癌、肝癌、肺癌、乳腺癌、鼻咽癌、卵巢癌、食管癌、胆管癌、胰腺癌、前列腺癌等癌症均具有抑制作用。阿司匹林可通过COX、Bcl-2/Bax、PI3K/AKT/mTOR、NF-κB、Wnt/β-catenin等通路抑制癌细胞增殖、迁移侵袭、糖酵解及异常代谢、阻滞癌细胞周期、诱导癌细胞自噬、促进癌细胞凋亡，发挥其抗炎抑癌作用。综上所述，阿司匹林可通过不同途径对多种癌症发挥预防或治疗作用，具有一定的临床应用价值。
Through searching, sorting and analyzing the literatures about the anticancer effect and mechanism of aspirin published at home and abroad in recent years, the basis and reference for its clinical prevention and treatment of cancer were provided.95 relevant literatures were retrieved from CNKI and PubMed, and the anticancer effects and mechanisms of aspirin in different cancers were summarized from the aspects of cancer cell proliferation, cycle, apoptosis, migration and invasion, and autophagy. Aspirin had inhibitory effect on colorectal cancer, liver cancer, lung cancer, breast cancer, nasopharyngeal cancer, ovarian cancer, esophageal cancer, bile duct cancer, pancreatic cancer, prostate cancer and other cancers.Aspirin can inhibit the proliferation, migration and invasion, glycolysis and abnormal metabolism of cancer cells, block the cancer cell cycle, induce autophagy and promote apoptosis of cancer cells through COX,Bcl-2/Bax, PI3K/AKT/mTOR,NF-κB,Wnt/β-catenin and other pathways.In conclusion, aspirin can prevent or treat various cancers through different ways and has certain clinical application value.

关键词(KeyWords)： 阿司匹林;抗肿瘤;防治;癌症
aspirin;anti-tumor;prevention and treatment;cancer

Abstract:

Keywords:

基金项目(Foundation): 桂林医学院博士科研启动项目(20501019035)

作者(Author): 马雪百合,张在平
MA Xuebaihe,ZHANG Zaiping

DOI: 10.14066/j.cnki.cn21-1349/r.2021.0967

参考文献(References)：

• [1] FERLAY J,ERVIK M,LAM F,et al.Global Cancer Observatory:Cancer Today[EB/OL].[2021-04-05].Lyon:International Agency for Research on Cancer,https://gco.iarc.fr/today,accessed February 2021.
• [2] BRAY F,FERLAY J,SOERJOMATARAM I,et al.Global cancer statistics 2018:GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries [J].CA Cancer J Clin,2018,68(6):394-424.
• [3] DING K,CHEN R J.Progress in the treatment for nasopharyngeal carcinoma [J].Journal of Nanjing Medical University(南京医科大学学报),2021,41(6):921-926+936.
• [4] YANG X H,ZHANG L J,LUO M J,et al.Research progress in mechanism of berberine’s antitumor action [J].China Journal of Chinese Materia Medica(中国中药杂志),2021,46(10):2449-2455.
• [5] ZHOU R,ZHU J,CHEN X,et al.The efficacy and safety of docetaxel,cisplatin and fluorouracil (TPF)-based induction chemotherapy followed by concurrent chemoradiotherapy for locoregionally advanced nasopharyngeal carcinoma:a meta-analysis[J].Clin Transl Oncol,2020,22(3):429-439.
• [6] NIKOLAOU M,PAVLOPOULOU A,GEORGAKILAS A G,et al.The challenge of drug resistance in cancer treatment:a current overview[J].Clin Exp Metastasis,2018,35(4):309-318.
• [7] HYBIAK J,BRONIAREK ■,et al.Aspirin and its pleiotropic application [J].Eur J Pharmacol,2020,866:172762.
• [8] WILLIAMS C D,CHAN A T,ELMAN M R,et al.Aspirin use among adults in the US:results of a national survey [J].Am J Prev Med,2015,48(5):501-508.
• [9] JOHARATNAM-HOGAN N,CAFFERTY F,HUBNER R,et al.Aspirin as an adjuvant treatment for cancer:feasibility results from the Add-Aspirin randomised trial [J].Lancet Gastroenterol Hepatol,2019,4(11):854-862.
• [10] MA B,DUAN X,ZHOU Q,et al.Use of aspirin in the prevention of colorectal cancer through TIGIT-CD155 pathway [J].J Cell Mol Med,2019,23(7):4514-4522.
• [11] HENRY W S,LASZEWSKI T,TSANG T,et al.Aspirin suppresses growth in PI3K-Mutant breast cancer by activating AMPK and inhibiting mTORC1 signaling [J].Cancer Res,2017,77(3):790-801.
• [12] PONNUSAMY L,NATARAJAN S R,THANGARAJ K,et al.Therapeutic aspects of AMPK in breast cancer:progress,challenges,and future directions[J].Biochim Biophys Acta Rev Cancer,2020,1874(1):188379.
• [13] ZHANG Y,LV C,DONG Y,et al.Aspirin-targeted PD-L1 in lung cancer growth inhibition [J].Thorac Cancer,2020,11(6):1587-1593.
• [14] MA Y,MA M,MA L.Research of the aspirin inhibitory effect on HepG2 proliferation in hepatoma cells and its mechanism[J].Northwest Pharmaceutical Journal (西北药学杂志),2020,35(6):860-863.
• [15] KAR S.Unraveling cell-cycle dynamics in cancer [J].Cell Syst,2016,2(1):8-10.
• [16] CHEN J,XU R,XIA J,et al.Aspirin inhibits hypoxia-mediated lung cancer cell stemness and exosome function [J].Pathol Res Pract,2019,215(6):152379.
• [17] SHI T,FYJITA K,GONG J,et al.Aspirin inhibits hepatocellular carcinoma cell proliferation in vitro and in vivo via inducing cell cycle arrest and apoptosis [J].Oncol Rep,2020,44(2):457-468.
• [18] CHEN Z,WANG C,DONG H,et al.Aspirin has a better effect on PIK3CA mutant colorectal cancer cells by PI3K/Akt/Raptor pathway [J].Mol Med,2020,26(1):14.
• [19] CHEN Z,LI W,QIU F,et al.Aspirin cooperates with p300 to activate the acetylation of H3K9 and promote FasL-mediated apoptosis of cancer stem-like cells in colorectal cancer [J].Theranostics,2018,8(16):4447-4461.
• [20] MA B,DUAN X,ZHOU Q,et al.Use of aspirin in the prevention of colorectal cancer through TIGIT-CD155 pathway [J].J Cell Mol Med,2019,23(7):4514-4522.
• [21] TIAN Y,YE Y,GAO W,et al.Aspirin promotes apoptosis in a murine model of colorectal cancer by mechanisms involving downregulation of IL-6-STAT3 signaling pathway [J].Int J Colorectal Dis,2011,26(1):13-22.
• [22] LI L,HU M,WANG T,et al.Repositioning aspirin to treat lung and breast cancers and overcome acquired resistance to targeted therapy [J].Front Oncol,2020,9:1503.
• [23] WANG X J,ZHANG J,GUO L L,et al.Effect of aspirin radiosensitivity on nasopharyngeal carcinoma cells [J].The Journal of Practical Medicine(实用医学杂志),2009,25(8):1186-1188.
• [24] LI A F,LUO H D,CHEN Y,et al.Effects of aspirin on apoptosis of homologous nasopharyngeal carcinoma cells with different radioresistance [J].Chinese Journal of Pathophysiology(中国病理生理杂志),2017,33(11):1980-1986.
• [25] SEYFRIED T N,HUYSENTRUYT L C.On the origin of cancer metastasis [J].Crit Rev Oncog,2013,18(1/2):43-73.
• [26] DUNBAR K,VALANCIUTE A,LIMA A C S,et al.Aspirin rescues Wnt-driven stem-like phenotype in human intestinal organoids and increases the Wnt antagonist Dickkopf-1 [J].Cell Mol Gastroenterol Hepatol,2021,11(2):465-489.
• [27] KHAN F U,OWUSU-TIEKU N Y G,DAI X,et al.Wnt/β-catenin pathway-regulated fibromodulin expression is crucial for breast cancer metastasis and inhibited by aspirin [J].Front Pharmacol,2019,10:1308.
• [28] HSIEH C C,CHIU H H,WANG C H,et al.Aspirin modifies inflammatory mediators and metabolomic profiles and contributes to the suppression of obesity-associated breast cancer cell growth [J].Int J Mol Sci,2020,21(13):4652.
• [29] KHAN P,MANNA A,SAHA S,et al.Aspirin inhibits epithelial-to-mesenchymal transition and migration of oncogenic K-ras-expressing non-small cell lung carcinoma cells by down-regulating E-cadherin repressor Slug [J].BMC Cancer,2016,16:39.
• [30] KHAN P,BHATTACHARYA A,SENGUPTA D,et al.Aspirin enhances cisplatin sensitivity of resistant non-small cell lung carcinoma stem-like cells by targeting mTOR-Akt axis to repress migration [J].Sci Rep,2019,9(1):16913.
• [31] TANG M K,SUN Y M,QIN L J,et al.Effect of aspirin on brain metastasis of lung cancer and its possible mechanism [J].Journal of Sichuan University (Medical Sciences) [(四川大学学报(医学版)],2017,48(6):857-861.
• [32] OGAWA F,AMANO H,ITO Y,et al.Aspirin reduces lung cancer metastasis to regional lymph nodes [J].Biomed Pharmacother,2014,68(1):79-86.
• [33] CHENG B Q,LIN W G,ZHU Q,et al.Aspirin prevents metastasis of hepatology cells by regulating Wnt/β-catenin signaling pathway [J].Electronic Journal of Clinical Medical Literature(临床医药文献电子杂志),2018,5(7):13-15.
• [34] YANG L Y,LUO Q,LU L,et al.Increased neutrophil extracellular traps promote metastasis potential of hepatocellular carcinoma via provoking tumorous inflammatory response [J].J Hematol Oncol,2020,13(1):3.
• [35] AMARAVADI R K,KIMMELMAN A C,DEBNATH J.Targeting autophagy in cancer:recent advances and future directions [J].Cancer Discov,2019,9(9):1167-1181.
• [36] DIN F V,VALANCIUTE A,HOUDE V P,et al.Aspirin inhibits mTOR signaling,activates AMP-activated protein kinase,and induces autophagy in colorectal cancer cells [J].Gastroenterology,2012,142(7):1504-1515.
• [37] HUANG Z,FANG W,LIU W,et al.Aspirin induces Beclin-1-dependent autophagy of human hepatocellular carcinoma cell [J].Eur J Pharmacol,2018,823:58-64.
• [38] ZHU S Y.The effect of aspirin on hepatocellular carcinoma based on autophagy pathway [D].Hefei:Anhui Medical University (安徽医科大学),2018.
• [39] SAHA S,MUKHERJEE S,KHAN P,et al.Aspirin suppresses the acquisition of chemoresistance in breast cancer by disrupting an NFκB-IL6 signaling axis responsible for the generation of cancer stem cells [J].Cancer Res,2016,76(7):2000-2012.
• [40] PENG F,WANG J H,FAN W J,et al.Glycolysis gatekeeper PDK1 reprograms breast cancer stem cells under hypoxia [J].Oncogene,2018,37(8):1062-1074.
• [41] WANG J D,CHEN W Y,LI J R,et al.Aspirin mitigated tumor growth in obese mice involving metabolic inhibition [J].Cells,2020,9(3):569.
• [42] LIU Y X,FENG J Y,SUN M M,et al.Aspirin inhibits the proliferation of hepatoma cells through controlling GLUT1-mediated glucose metabolism[J].Acta Pharmacol Sin,2019,40(1):122-132.
• [43] YANG G,WANG Y,FENG J,et al.Aspirin suppresses the abnormal lipid metabolism in liver cancer cells via disrupting an NFκB-ACSL1 signaling [J].Biochem Biophys Res Commun,2017,486(3):827-832.
• [44] TODORIC J,ANTONUCCI L,KARIN M.Targeting inflammation in cancer prevention and therapy [J].Cancer Prev Res (Phila),2016,9(12):895-905.
• [45] LANG J P,DAI Q Y,LV P,et al.Advance in research on aspirin for chemoprevention of colorectal cancer [J].Journal of Molecular Imaging(分子影像学杂志),2021,44(2):405-411.
• [46] JIANG W,YAN Y,CHEN M,et al.Aspirin enhances the sensitivity of colon cancer cells to cisplatin by abrogating the binding of NF-κB to the COX-2 promoter [J].Aging (Albany NY),2020,12(1):611-627.
• [47] SAHASRABUDDHE V V,GUNJA M Z,GRAUBARD B I,et al.Nonsteroidal anti-inflammatory drug use chronic liver disease,and hepatocellular carcinoma [J].J Natl Cancer Inst,2012,104(23):1808-1814.
• [48] XU J F,CAI M L.Mechanism study of aspirin in prevention and treatment of liver cancer [J].World Latest Medicine Information (世界最新医学信息文摘),2018,18(48):30-31.
• [49] HUANG Y,LICHTENBERGER L M,TAYLOR M,et al.Antitumor and antiangiogenic effects of aspirin-PC in ovarian cancer [J].Mol Cancer Ther,2016,15(12):2894-2904.
• [50] WU Y,WANG X,XU F,et al.The regulation of acetylation and stability of HMGA2 via the HBXIP-activated Akt-PCAF pathway in promotion of esophageal squamous cell carcinoma growth [J].Nucleic Acids Res,2020,48(9):4858-4876.
• [51] SHI T,GONG J,FUJITA K,et al.Aspirin inhibits cholangiocarcinoma cell proliferation via cell cycle arrest in vitro and in vivo[J].Int J Oncol,2021,58(2):199-210.
• [52] YANG L,ZHU H,LIU D,et al.Aspirin suppresses growth of human gastric carcinoma cell by inhibiting survivin expression [J].J Biomed Res,2011,25(4):246-253.
• [53] LIN S,PAN Y,XU C.Effects of aspirin on pancreatic cancer cells PANC-1 and its potential molecular mechanism [J].J BUON,2020,25(5):2449-2455.
• [54] ZHU Y P.Aspirin inhibits the growth and enhances chemosensitivity of epithelial ovarian cancer cells(阿司匹林抑制上皮性卵巢癌进展和增敏顺铂化疗的作用及机制研究)[D].Wuhan:Huazhong University of Science and Technology,2016.
• [55] SHI C,ZHANG N,FENG Y,et al.Aspirin inhibits IKK-β-mediated prostate cancer cell invasion by targeting matrix metalloproteinase-9 and urokinase-type plasminogen activator [J].Cell Physiol Biochem,2017,41(4):1313-1324.
• [56] WENG J J.Effect of aspirin on prognosis of nasopharyngeal carcinoma and its mechanism(阿司匹林对鼻咽癌预后的影响及其机制研究)[D].Nanning:Guangxi Medical University,2018.
• [57] PATRIGNANI P,SACCO A,SOSTRES C,et al.Low-dose aspirin acetylates cyclooxygenase-1 in human colorectal mucosa:implications for the chemoprevention of colorectal cancer [J].Clin Pharmacol Ther,2017,102(1):52-61.
• [58] WANG T,FU X,JIN T,et al.Aspirin targets P4HA2 through inhibiting NF-κB and LMCD1-AS1/let-7g to inhibit tumour growth and collagen deposition in hepatocellular carcinoma [J].EBioMedicine,2019,45:168-180.
• [59] LIN HD,VORA P,SORIANO-GABARRó M,et al.Association between low-dose aspirin use and colorectal cancer incidence in Taiwan [J].JAMA Netw Open,2020,3(11):e2026494.
• [60] LI H,ZHU F,BOARDMAN L A,et al.Aspirin prevents colorectal cancer by normalizing EGFR expression [J].EBioMedicine,2015,2(5):447-455.
• [61] CUI Y,DEMING-HALVERSON S L,SHRUBSOLE M J,et al.Use of nonsteroidal anti-inflammatory drugs and reduced breast cancer risk among overweight women[J].Breast Cancer Res Treat,2014,146(2):439-446.
• [62] SHIN S,LEE S H,LEE M,et al.Aspirin and the risk of hepatocellular carcinoma development in patients with alcoholic cirrhosis [J].Medicine(Baltimore),2020,99(9):e19008.
• [63] LEE M,CHUNG G E,LEE J H,et al.Antiplatelet therapy and the risk of hepatocellular carcinoma in chronic hepatitis B patients on antiviral treatment [J].Hepatology,2017,66(5):1556-1569.
• [64] DU Z Q,ZHAO J Z,DONG J,et al.Effect of low-dose aspirin administration on long-term survival of cirrhotic patients after splenectomy:a retrospective single-center study [J].World J Gastroenterol,2019,25(28):3798-3807.
• [65] TAO Y,LI Y,LIU X,et al.Nonsteroidal anti-inflammatory drugs,especially aspirin,are linked to lower risk and better survival of hepatocellular carcinoma:a meta-analysis [J].Cancer Manag Res,2018,10:2695-2709.
• [66] SIMON T G,MA Y,LUDVIGSSON J F,et al.Association between aspirin use and risk of hepatocellular carcinoma [J].JAMA Oncol,2018,4(12):1683-1690.
• [67] PENCE B C,BELASCO E J,LYFORD C P.Combination aspirin and/or calcium chemoprevention with colonoscopy in colorectal cancer prevention:cost-effectiveness analyses [J].Cancer Epidemiol Biomarkers Prev,2013,22(3):399-405.
• [68] HIGURASHI T,ARIMOTO J,ASHIKARI K,et al.The efficacy of aspirin and metformin combination therapy in patients with rectal aberrant crypt foci:a double-blinded randomized controlled trial [J].BMC Cancer,2020,20(1):1043.
• [69] RODRíGUEZ-MIGUEL A,GARCíA-RODRíGUEZ L A,GIL M,et al.Clopidogrel and low-dose aspirin,alone or together,reduce risk of colorectal cancer [J].Clin Gastroenterol Hepatol,2019,17(10):2024-2033.
• [70] SANKARANARAYANAN R,KUMAR D R,PATEL J,et al.Do aspirin and flavonoids prevent cancer through a common mechanism involving hydroxybenzoic acids-the metabolite hypothesis [J].Molecules,2020,25(9):2243.
• [71] FU J,XU Y,YANG Y,et al.Aspirin suppresses chemoresistance and enhances antitumor activity of 5-Fu in 5-Fu-resistant colorectal cancer by abolishing 5-Fu-induced NF-κB activation [J].Sci Rep,2019,9(1):16937.
• [72] ZHAO C J,LI J B,LU X R,et al.Discussion on the effect of aspirin combined with 5-fluorouracil on nasopharyngeal carcinoma cells [J].Contemporary Medical Symposium(当代医药论丛),2013,11(8):276-277.
• [73] XIE Z Y,LIU M S,ZHANG C,et al.Aspirin enhances the sensitivity of hepatocellular carcinoma side population cells to doxorubicin via miR-491/ABCG2 [J].Biosci Rep,2018,38(6):BSR20180854.
• [74] MA J,FAN Z,TANG Q,et al.Aspirin attenuates YAP and β-catenin expression by promoting β-TrCP to overcome docetaxel and vinorelbine resistance in triple-negative breast cancer [J].Cell Death Dis,2020,11(7):530.
• [75] YU J,DUAN J J,ZHANG Y.Study on the synergistic effects of aspirin and atorvastatin on cell proliferation [J].Journal of Pharmaceutical Practice(药学实践杂志),2021,39(1):38-43.
• [76] USMAN M W,GAO J,ZHENG T,et al.Macrophages confer resistance to PI3K inhibitor GDC-0941 in breast cancer through the activation of NF-κB signaling [J].Cell Death Dis,2018,9(8):809.
• [77] ZHANG H,YANG S,WANG J,et al.Blockade of AMPK-mediated cAMP-PKA-CREB/ATF1 signaling synergizes with aspirin to inhibit hepatocellular carcinoma [J].Cancers (Basel),2021,13(7):1738.
• [78] YANG J.Effect of aspirin combined with cisplatin on esophageal squamous cell carcinoma and its mechanism (阿司匹林联合顺铂对食管癌细胞的影响及机制的初步研究)[D].Xinxiang:Xinxiang Medical University,2017.
• [79] CHENG R,LIU Y J,CUI J W,et al.Aspirin regulation of c-myc and cyclinD1 proteins to overcome tamoxifen resistance in estrogen receptor-positive breast cancer cells [J].Oncotarget,2017,8(18):30252-30264.
• [80] KILARI R S,BASHIR A I J,DEVITT A,et al.The cytotoxicity and synergistic potential of aspirin and aspirin analogues towards oesophageal and colorectal cancer [J].Curr Clin Pharmacol,2019,14(2):141-151.
• [81] CORTELLINI G,CARUSO C,ROMANO A.Aspirin challenge and desensitization:how,when and why [J].Curr Opin Allergy Clin Immunol,2017,17(4):247-254.
• [82] GOTTSCHALL H,SCHM?CKER C,HARTMANN D,et al.Aspirin alone and combined with a statin suppresses eicosanoid formation in human colon tissue [J].J Lipid Res,2018,59(5):864-871.
• [83] BIAN J,ZAHNG P H,LI J J.Study on the mechanism of aspirin combined with vinorelbine on inhibition of human breast cancer cell line MCF-7 [J].Northwest Pharmaceutical Journal (西北药学杂志),2021,36(1):52-56.
• [84] WU Y,YAN B,XU W,et al.Compound C enhances the anticancer effect of aspirin in HER-2-positive breast cancer by regulating lipid metabolism in an AMPK-independent pathway [J].Int J Biol Sci,2020,16(4):583-597.
• [85] MIAO R,XU X,WANG Z,et al.Synergistic effect of nutlin-3 combined with aspirin in hepatocellular carcinoma HepG2 cells through activation of Bcl-2/Bax signaling pathway [J].Mol Med Rep,2018,17(3):3735-3743.
• [86] QI L,YE J W,XUE W H,et al.The mechanism of aspirin combined with metformin induced apoptosis of thyroid cancer TPC-1 cells [J].Chinese Journal of Oncology(中华肿瘤杂志),2019,41(4):276-281.
• [87] CHEN R H,TIAN Y J.Enhanced anti-tumor efficacy of aspirin combined with triptolide in cervical cancer cells [J].Asian Pac J Cancer Prev,2013,14(5):3041-3044.
• [88] OU Y C,LI J R,WANG J D,et al.Aspirin restores ABT-737-mediated apoptosis in human renal carcinoma cells [J].Biochem Biophys Res Commun,2018,502(2):187-193.
• [89] KUNE G A,KUNE S,WATSON L F.Colorectal cancer risk,chronic illnesses,operations,and medications:case control results from the Melbourne Colorectal Cancer Study [J].Cancer Res,1988,48(15):4399-4404.
• [90] YE Y,WANG X,JESCHKE U,et al.COX-2-PGE2-EPs in gynecological cancers [J].Arch Gynecol Obstet,2020,301(6):1365-1375.
• [91] ZHU Y,SHI C,ZENG L,et al.High COX-2 expression in cancer-associated fibiroblasts contributes to poor survival and promotes migration and invasiveness in nasopharyngeal carcinoma [J].Mol Carcinog,2020,59(3):265-280.
• [92] BATTINELLI E M,MARKENS B A,ITALIANO J E.Release of angiogenesis regulatory proteins from platelet alpha granules:modulation of physiologic and pathologic angiogenesis[J].Blood,2011,118(5):1359-1369.
• [93] SANTILLI F,BOCCATONDA A,DAVì G.Aspirin,platelets,and cancer:The point of view of the internist [J].Eur J Intern Med,2016,34:11-20.
• [94] NAJAFI M,FARHOOD B,MORTEZAEE K.Cancer stem cells (CSCs) in cancer progression and therapy [J].J Cell Physiol,2019,234(6):8381-8395.