Login Register Cart 0
General Review Article

Progress on the Mechanism for Aspirin’s Anti-tumor Effects

Author(s): Lin Zheng, Weibiao Lv*, Yuanqing Zhou, Xu Lin and Jie Yao*

Volume 22, Issue 1, 2021

Published on: 13 October, 2020

Page: [105 - 111] Pages: 7

DOI: 10.2174/1389450121999201013152931

Price: $65

Abstract

Since its discovery more than 100 years ago, aspirin has been widely used for its antipyretic, analgesic, anti-inflammatory, and anti-rheumatic activities. In addition to these applications, it is increasingly becoming clear that the drug also has great potential in the field of cancer. Here, we briefly review the current insights on aspirin’s anti-tumor effects. These are multiple and vary from inhibiting the major cellular mTOR pathways, acting as a calorie-restricted mimetic by inhibition of energy production, suppressing platelet aggregation and granule release, inhibiting the immune escape of tumor cells, to decreasing inflammatory responses. We consider these five mechanisms of action the most significant for aspirin’s anti-tumor effects, whereby the anti-tumor effect may ultimately stem from its inhibition of energy metabolism, platelet function, and inflammatory response. As such, aspirin can play an important role to reduce the occurrence, proliferation, and metastasis of various types of tumors. However, most of the collected data are still based on epidemiological investigations. More direct and effective evidence is needed, and the side effects of aspirin intake need to be solved before this drug can be widely applied in cancer treatment.

Keywords: Aspirin, acetyl salicylic acid, anti-tumor activity, cancer, cellular mTOR pathways, inflammatory.

« Previous Next »
Graphical Abstract

[1]
Hua H, Zhang H, Kong Q, Wang J, Jiang Y. Complex roles of the old drug aspirin in cancer chemoprevention and therapy. Med Res Rev 2019; 39(1): 114-45.
[http://dx.doi.org/10.1002/med.21514] [PMID: 29855050]
[2]
Kune GA, Kune S, Watson LF. Colorectal cancer risk, chronic illnesses, operations, and medications: case control results from the Melbourne Colorectal Cancer Study. Cancer Res 1988; 48(15): 4399-404.
[PMID: 3390835]
[3]
Din FV, Theodoratou E, Farrington SM, et al. Effect of aspirin and NSAIDs on risk and survival from colorectal cancer. Gut 2010; 59(12): 1670-9.
[http://dx.doi.org/10.1136/gut.2009.203000] [PMID: 20844293]
[4]
Ye S, Lee M, Lee D, Ha EH, Chun EM. Association of Long-term Use of Low-Dose Aspirin as Chemoprevention With Risk of Lung Cancer. JAMA Netw Open 2019; 2(3): e190185.
[http://dx.doi.org/10.1001/jamanetworkopen.2019.0185] [PMID: 30821825]
[5]
Chen WY, Holmes MD. Role of aspirin in breast cancer survival. Curr Oncol Rep 2017; 19(7): 48.
[http://dx.doi.org/10.1007/s11912-017-0605-6] [PMID: 28597105]
[6]
Di Maso M, Bosetti C, La Vecchia C, et al. Regular aspirin use and nasopharyngeal cancer risk: A case-control study in Italy. Cancer Epidemiol 2015; 39(4): 545-7.
[http://dx.doi.org/10.1016/j.canep.2015.04.012] [PMID: 25960427]
[7]
Simon TG, Ma Y, Ludvigsson JF, et al. Association Between Aspirin Use and Risk of Hepatocellular Carcinoma. JAMA Oncol 2018; 4(12): 1683-90.
[http://dx.doi.org/10.1001/jamaoncol.2018.4154] [PMID: 30286235]
[8]
Gee JR, Jarrard DF, Bruskewitz RC, et al. Reduced bladder cancer recurrence rate with cardioprotective aspirin after intravesical bacille Calmette-Guérin. BJU Int 2009; 103(6): 736-9.
[http://dx.doi.org/10.1111/j.1464-410X.2008.08123.x] [PMID: 19007364]
[9]
Shen X, Han L, Ma Z, et al. Aspirin: a potential therapeutic approach in pancreatic cancer. Curr Med Chem 2013; 20(33): 4153-62.
[http://dx.doi.org/10.2174/09298673113209990196] [PMID: 23895681]
[10]
Mitrugno A, Sylman JL, Ngo AT, et al. Aspirin therapy reduces the ability of platelets to promote colon and pancreatic cancer cell proliferation: Implications for the oncoprotein c-MYC. Am J Physiol Cell Physiol 2017; 312(2): C176-89.
[http://dx.doi.org/10.1152/ajpcell.00196.2016] [PMID: 27903583]
[11]
Guillem-Llobat P, Dovizio M, Bruno A, et al. Aspirin prevents colorectal cancer metastasis in mice by splitting the crosstalk between platelets and tumor cells. Oncotarget 2016; 7(22): 32462-77.
[http://dx.doi.org/10.18632/oncotarget.8655] [PMID: 27074574]
[12]
Lucotti S, Cerutti C, Soyer M, et al. Aspirin blocks formation of metastatic intravascular niches by inhibiting platelet-derived COX-1/thromboxane A2. J Clin Invest 2019; 129(5): 1845-62.
[http://dx.doi.org/10.1172/JCI121985] [PMID: 30907747]
[13]
Din FV, Valanciute A, Houde VP, et al. Aspirin inhibits mTOR signaling, activates AMP-activated protein kinase, and induces autophagy in colorectal cancer cells. Gastroenterology 2012; 142(7): 1504-15.
[14]
Sciulli MG, Filabozzi P, Tacconelli S, et al. Platelet activation in patients with colorectal cancer. Prostaglandins Leukot Essent Fatty Acids 2005; 72(2): 79-83.
[http://dx.doi.org/10.1016/j.plefa.2004.10.006] [PMID: 15626589]
[15]
Bertoni E, Salvadori M. Antineoplastic effect of proliferation signal inhibitors: from biology to clinical application. J Nephrol 2009; 22(4): 457-62.
[PMID: 19662600]
[16]
Qian J, Su S, Liu P. Experimental Approaches in Delineating mTOR Signaling. Genes (Basel) 2020; 11(7): E738.
[http://dx.doi.org/10.3390/genes11070738] [PMID: 32630768]
[17]
Liu GY, Sabatini DM. mTOR at the nexus of nutrition, growth, ageing and disease. Nat Rev Mol Cell Biol 2020; 21(4): 183-203.
[http://dx.doi.org/10.1038/s41580-019-0199-y] [PMID: 31937935]
[18]
Strimpakos AS, Karapanagiotou EM, Saif MW, Syrigos KN. The role of mTOR in the management of solid tumors: an overview. Cancer Treat Rev 2009; 35(2): 148-59.
[http://dx.doi.org/10.1016/j.ctrv.2008.09.006] [PMID: 19013721]
[19]
Yecies JL, Manning BD. mTOR links oncogenic signaling to tumor cell metabolism. J Mol Med (Berl) 2011; 89(3): 221-8.
[http://dx.doi.org/10.1007/s00109-011-0726-6] [PMID: 21301797]
[20]
Hua H, Kong Q, Zhang H, Wang J, Luo T, Jiang Y. Targeting mTOR for cancer therapy. J Hematol Oncol 2019; 12(1): 71.
[http://dx.doi.org/10.1186/s13045-019-0754-1] [PMID: 31277692]
[21]
Henry WS, Laszewski T, Tsang T, et al. Aspirin Suppresses Growth in PI3K-Mutant Breast Cancer by Activating AMPK and Inhibiting mTORC1 Signaling. Cancer Res 2017; 77(3): 790-801.
[http://dx.doi.org/10.1158/0008-5472.CAN-16-2400] [PMID: 27940576]
[22]
Chen S, Zhu X, Lai X, Xiao T, Wen A, Zhang J. Combined cancer therapy with non-conventional drugs: all roads lead to AMPK. Mini Rev Med Chem 2014; 14(8): 642-54.
[http://dx.doi.org/10.2174/1389557514666140820104444] [PMID: 25138094]
[23]
Zhao Q, Wang Z, Wang Z, Wu L, Zhang W. Aspirin may inhibit angiogenesis and induce autophagy by inhibiting mTOR signaling pathway in murine hepatocarcinoma and sarcoma models. Oncol Lett 2016; 12(4): 2804-10.
[http://dx.doi.org/10.3892/ol.2016.5017] [PMID: 27698862]
[24]
Honn KV, Tang DG, Crissman JD. Platelets and cancer metastasis: a causal relationship? Cancer Metastasis Rev 1992; 11(3-4): 325-51.
[http://dx.doi.org/10.1007/BF01307186] [PMID: 1423821]
[25]
Mege D, Aubert M, Lacroix R, Dignat-George F, Panicot-Dubois L, Dubois C. Involvement of Platelets in Cancers. Semin Thromb Hemost 2019; 45(6): 569-75.
[http://dx.doi.org/10.1055/s-0039-1693475] [PMID: 31382305]
[26]
Kapahi P, Kaeberlein M, Hansen M. Dietary restriction and lifespan: Lessons from invertebrate models. Ageing Res Rev 2017; 39: 3-14.
[http://dx.doi.org/10.1016/j.arr.2016.12.005] [PMID: 28007498]
[27]
Vermeij WP, Dollé ME, Reiling E, et al. Restricted diet delays accelerated ageing and genomic stress in DNA-repair-deficient mice. Nature 2016; 537(7620): 427-31.
[http://dx.doi.org/10.1038/nature19329] [PMID: 27556946]
[28]
Abiri B, Vafa M. Dietary Restriction, Cardiovascular Aging and Age-Related Cardiovascular Diseases: A Review of the Evidence. Adv Exp Med Biol 2019; 1178: 113-27.
[http://dx.doi.org/10.1007/978-3-030-25650-0_7] [PMID: 31493225]
[29]
Taylor R. Calorie restriction for long-term remission of type 2 diabetes. Clin Med (Lond) 2019; 19(1): 37-42.
[http://dx.doi.org/10.7861/clinmedicine.19-1-37] [PMID: 30651243]
[30]
Gray A, Dang BN, Moore TB, Clemens R, Pressman P. A review of nutrition and dietary interventions in oncology. SAGE Open Med 2020; 8: 2050312120926877.
[http://dx.doi.org/10.1177/2050312120926877] [PMID: 32537159]
[31]
Madeo F, Carmona-Gutierrez D, Hofer SJ, Kroemer G. Caloric restriction mimetics against age-associated disease: Targets, mechanisms, and therapeutic potential. Cell Metab 2019; 29(3): 592-610.
[http://dx.doi.org/10.1016/j.cmet.2019.01.018] [PMID: 30840912]
[32]
Pietrocola F, Castoldi F, Maiuri MC, Kroemer G. Aspirin-another caloric-restriction mimetic. Autophagy 2018; 14(7): 1162-3.
[http://dx.doi.org/10.1080/15548627.2018.1454810] [PMID: 29929449]
[33]
Pietrocola F, Castoldi F, Markaki M, et al. Aspirin Recapitulates Features of Caloric Restriction. Cell Rep 2018; 22(9): 2395-407.
[http://dx.doi.org/10.1016/j.celrep.2018.02.024] [PMID: 29490275]
[34]
Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 2009; 324(5930): 1029-33.
[http://dx.doi.org/10.1126/science.1160809] [PMID: 19460998]
[35]
Jung YR, Kim EJ, Choi HJ, et al. Aspirin Targets SIRT1 and AMPK to Induce Senescence of Colorectal Carcinoma Cells. Mol Pharmacol 2015; 88(4): 708-19.
[http://dx.doi.org/10.1124/mol.115.098616] [PMID: 26219912]
[36]
Liu YX, Feng JY, Sun MM, et al. Aspirin inhibits the proliferation of hepatoma cells through controlling GLUT1-mediated glucose metabolism. Acta Pharmacol Sin 2019; 40(1): 122-32.
[http://dx.doi.org/10.1038/s41401-018-0014-x] [PMID: 29925918]
[37]
Angin Y, Beauloye C, Horman S, Bertrand L. Regulation of Carbohydrate Metabolism, Lipid Metabolism, and Protein Metabolism by AMPK. Exp Suppl 2016; 107(107): 23-43.
[http://dx.doi.org/10.1007/978-3-319-43589-3_2] [PMID: 27812975]
[38]
He Z, Peng Y, Duan W, et al. Aspirin regulates hepatocellular lipid metabolism by activating AMPK signaling pathway. J Toxicol Sci 2015; 40(1): 127-36.
[http://dx.doi.org/10.2131/jts.40.127] [PMID: 25743752]
[39]
O’Brien AJ, Villani LA, Broadfield LA, et al. Salicylate activates AMPK and synergizes with metformin to reduce the survival of prostate and lung cancer cells ex vivo through inhibition of de novo lipogenesis. Biochem J 2015; 469(2): 177-87.
[http://dx.doi.org/10.1042/BJ20150122] [PMID: 25940306]
[40]
Flaumenhaft R. Platelet Secretion. Platelets 2013; 343-66.
[41]
Goubran HA, Burnouf T, Radosevic M, El-Ekiaby M. The platelet-cancer loop. Eur J Intern Med 2013; 24(5): 393-400.
[http://dx.doi.org/10.1016/j.ejim.2013.01.017] [PMID: 23433737]
[42]
Mitrugno A, Williams D, Kerrigan SW, Moran N. A novel and essential role for FcγRIIa in cancer cell-induced platelet activation. Blood 2014; 123(2): 249-60.
[http://dx.doi.org/10.1182/blood-2013-03-492447] [PMID: 24258815]
[43]
Geddings JE, Hisada Y, Boulaftali Y, et al. Tissue factor-positive tumor microvesicles activate platelets and enhance thrombosis in mice. J Thromb Haemost 2016; 14(1): 153-66.
[http://dx.doi.org/10.1111/jth.13181] [PMID: 26516108]
[44]
Pignatelli P, De Biase L, Lenti L, et al. Tumor necrosis factor-alpha as trigger of platelet activation in patients with heart failure. Blood 2005; 106(6): 1992-4.
[http://dx.doi.org/10.1182/blood-2005-03-1247] [PMID: 15956282]
[45]
Ferroni P, Riondino S, Portarena I, et al. Association between increased tumor necrosis factor alpha levels and acquired activated protein C resistance in patients with metastatic colorectal cancer. Int J Colorectal Dis 2012; 27(12): 1561-7.
[http://dx.doi.org/10.1007/s00384-012-1493-8] [PMID: 22581210]
[46]
Labelle M, Begum S, Hynes RO. Direct signaling between platelets and cancer cells induces an epithelial-mesenchymal-like transition and promotes metastasis. Cancer Cell 2011; 20(5): 576-90.
[http://dx.doi.org/10.1016/j.ccr.2011.09.009] [PMID: 22094253]
[47]
Lichtenberger LM, Fang D, Bick RJ, et al. Unlocking aspirin’s chemopreventive activity: Role of irreversibly inhibiting platelet cyclooxygenase-1. Cancer Prev Res (Phila) 2017; 10(2): 142-52.
[http://dx.doi.org/10.1158/1940-6207.CAPR-16-0241] [PMID: 27998883]
[48]
Zimmermann N, Wenk A, Kim U, et al. Functional and biochemical evaluation of platelet aspirin resistance after coronary artery bypass surgery. Circulation 2003; 108(5): 542-7.
[http://dx.doi.org/10.1161/01.CIR.0000081770.51929.5A] [PMID: 12874188]
[49]
Kopp HG, Placke T, Salih HR. Platelet-derived transforming growth factor-beta down-regulates NKG2D thereby inhibiting natural killer cell antitumor reactivity. Cancer Res 2009; 69(19): 7775-83.
[http://dx.doi.org/10.1158/0008-5472.CAN-09-2123] [PMID: 19738039]
[50]
Rachidi S, Metelli A, Riesenberg B, et al. Platelets subvert T cell immunity against cancer via GARP-TGFβ axis. Sci Immunol 2017; 2(11): eaai7911.
[http://dx.doi.org/10.1126/sciimmunol.aai7911] [PMID: 28763790]
[51]
Krall JA, Reinhardt F, Mercury OA, et al. The systemic response to surgery triggers the outgrowth of distant immune-controlled tumors in mouse models of dormancy. Sci Transl Med 2018; 10(436): eaan3464.
[http://dx.doi.org/10.1126/scitranslmed.aan3464] [PMID: 29643230]
[52]
Wu KK. Aspirin and other cyclooxygenase inhibitors: new therapeutic insights. Semin Vasc Med 2003; 3(2): 107-12.
[http://dx.doi.org/10.1055/s-2003-40668] [PMID: 15199473]
[53]
Hawkey CJ. COX-1 and COX-2 inhibitors. Best Pract Res Clin Gastroenterol 2001; 15(5): 801-20.
[http://dx.doi.org/10.1053/bega.2001.0236] [PMID: 11566042]
[54]
Pan P, Huang YW, Oshima K, et al. Could Aspirin and Diets High in Fiber Act Synergistically to Reduce the Risk of Colon Cancer in Humans? Int J Mol Sci 2018; 19(1): E166.
[http://dx.doi.org/10.3390/ijms19010166] [PMID: 29316620]
[55]
Rohwer N, Kühl AA, Ostermann AI, et al. Effects of chronic low-dose aspirin treatment on tumor prevention in three mouse models of intestinal tumorigenesis. Cancer Med 2020; 9(7): 2535-50.
[http://dx.doi.org/10.1002/cam4.2881] [PMID: 31994315]
[56]
Gilligan MM, Gartung A, Sulciner ML, et al. Aspirin-triggered proresolving mediators stimulate resolution in cancer. Proc Natl Acad Sci USA 2019; 116(13): 6292-7.
[http://dx.doi.org/10.1073/pnas.1804000116] [PMID: 30862734]
[57]
Lanas A, Scheiman J. Low-dose aspirin and upper gastrointestinal damage: epidemiology, prevention and treatment. Curr Med Res Opin 2007; 23(1): 163-73.
[http://dx.doi.org/10.1185/030079907X162656] [PMID: 17257477]

Rights & Permissions Print Cite
Article Metrics
36
© 2024 Bentham Science Publishers | Privacy Policy