SCIENCE CHINA Life Sciences, Volume 60, Issue 6: 601-616(2017) https://doi.org/10.1007/s11427-017-9047-4

Prevention and treatment of cancer targeting chronicinflammation: research progress, potential agents,clinical studies and mechanisms

More info
  • ReceivedJan 17, 2017
  • AcceptedApr 6, 2017
  • PublishedMay 29, 2017


Numerous experimental and clinical studies indicate that chronic inflammation is closely related to the initiation, progression, and spread of cancer, in which proinflammatory cytokines, such as interleukin (IL)-6, IL-1β, and tumor necrosis factor-α (TNF-α), and transcription factors, such as nuclear factor-κB (NF-κB), and signal transducer and activator of transcription 3 (STAT3), play pivotal roles. Stimulated by proinflammatory cytokines, NF-κB and STAT3 can modulate the expression of target genes, most of which are oncogenic ones, and promote the survival, proliferation, invasion, and metastasis of cancer cells. Now it is generally accepted that inflammation-related molecules and pathways are useful targets for the prevention and treatment of cancer. In this review, we summarize the relationship between chronic inflammation and cancer and describe some potentially useful agents including aspirin, meformin, statins, and some natural products (green tea catechins, andrographolide, curcumin) for their cancer prevention and treatment activities targeting chronic inflammation. The results of typical clinical studies are included, and the influences of these agents on the proinflammatory cytokines and inflammation-related pathways are discussed. Data from the present review support that agents targeting chronic inflammation may have a broad application prospect for the prevention and treatment of cancer in the future.

Funded by

National Natural Science Foundation of China(91329000 ,&, 91129000)


Acknowledgements This work was supported by the National Natural Science Foundation of China (91329000 & 91129000).

Interest statement

Compliance and ethics The author(s) declare that they have no conflict of interest.


[1] Alfonso L., Ai G., Spitale R.C., Bhat G.J.. Molecular targets of aspirin and cancer prevention. Br J Cancer, 2014, 111: 61-67 CrossRef PubMed Google Scholar

[2] Afzal M., Safer A.M., Menon M.. Green tea polyphenols and their potential role in health and disease. Inflammopharmacol, 2015, 23: 151-161 CrossRef PubMed Google Scholar

[3] Algra A.M., Rothwell P.M.. Effects of regular aspirin on long-term cancer incidence and metastasis: a systematic comparison of evidence from observational studies versus randomised trials. Lancet Oncology, 2012, 13: 518-527 CrossRef Google Scholar

[4] Altwairgi, A.K. (2015). Statins are potential anticancerous agents (review). Oncol Rep 33, 1019–1039. Google Scholar

[5] Balkwill F.R., Mantovani A.. Cancer-related inflammation: Common themes and therapeutic opportunities. Seminars Cancer Biol, 2012, 22: 33-40 CrossRef PubMed Google Scholar

[6] Bastiaannet E., Sampieri K., Dekkers O.M., de Craen A.J.M., van Herk-Sukel M.P.P., Lemmens V., van den Broek C.B.M., Coebergh J.W., Herings R.M.C., van de Velde C.J.H., Fodde R., Liefers G.J.. Use of Aspirin postdiagnosis improves survival for colon cancer patients. Br J Cancer, 2012, 106: 1564-1570 CrossRef PubMed Google Scholar

[7] Beales, I.L., Hensley, A., and Loke, Y. (2013). Reduced esophageal cancer incidence in statin users, particularly with cyclo-oxygenase inhibition. World J Gastrointest Pharmacol Ther 4, 69–79. Google Scholar

[8] Bettuzzi S., Brausi M., Rizzi F., Castagnetti G., Peracchia G., Corti A.. Chemoprevention of Human Prostate Cancer by Oral Administration of Green Tea Catechins in Volunteers with High-Grade Prostate Intraepithelial Neoplasia: A Preliminary Report from a One-Year Proof-of-Principle Study. Cancer Res, 2006, 66: 1234-1240 CrossRef PubMed Google Scholar

[9] Bibbins-Domingo, K., and U.S. Preventive Services Task Force. (2016). Aspirin use for the primary prevention of cardiovascular disease and colorectal cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 164, 836–845. Google Scholar

[10] Bimonte S., Barbieri A., Leongito M., Piccirillo M., Giudice A., Pivonello C., de Angelis C., Granata V., Palaia R., Izzo F.. Curcumin AntiCancer Studies in Pancreatic Cancer. Nutrients, 2016, 8: 433 CrossRef PubMed Google Scholar

[11] Bjarnadottir O., Romero Q., Bendahl P.O., Jirström K., Rydén L., Loman N., Uhlén M., Johannesson H., Rose C., Grabau D., Borgquist S.. Targeting HMG-CoA reductase with statins in a window-of-opportunity breast cancer trial. Breast Cancer Res Treat, 2013, 138: 499-508 CrossRef PubMed Google Scholar

[12] Blum A.. HMG-CoA reductase inhibitors (statins), inflammation, and endothelial progenitor cells-New mechanistic insights of atherosclerosis. BioFactors, 2014, 40: 295-302 CrossRef Google Scholar

[13] Bo, Q.F., Sun, X.M., Liu, J., Sui, X.M., and Li, G.X. (2015). Antitumor action of the peroxisome proliferator-activated receptor-γ agonist rosiglitazone in hepatocellular carcinoma. Oncol Lett 10, 1979–1984. Google Scholar

[14] Brennan C.A., Garrett W.S.. Gut Microbiota, Inflammation, and Colorectal Cancer. Annu Rev Microbiol, 2016, 70: 395-411 CrossRef PubMed Google Scholar

[15] Brewer T.M., Masuda H., Liu D.D., Shen Y., Liu P., Iwamoto T., Kai K., Barnett C.M., Woodward W.A., Reuben J.M., Yang P., Hortobagyi G.N., Ueno N.T.. Statin use in primary inflammatory breast cancer: a cohort study. Br J Cancer, 2013, 109: 318-324 CrossRef PubMed Google Scholar

[16] Brighenti E., Antonino Giannone F., Fornari F., Onofrillo C., Govoni M., Montanaro L., Treré D., Derenzini M.. Therapeutic dosages of aspirin counteract the IL-6 induced pro-tumorigenic effects by slowing down the ribosome biogenesis rate. Oncotarget, 2016, CrossRef PubMed Google Scholar

[17] Cai H., Zhang G., Wang Z., Luo Z., Zhou X.. Relationship Between the Use of Statins and Patient Survival in Colorectal Cancer: A Systematic Review and Meta-Analysis. PLoS ONE, 2015, 10: e0126944 CrossRef PubMed Google Scholar

[18] Carroll R.E., Benya R.V., Turgeon D.K., Vareed S., Neuman M., Rodriguez L., Kakarala M., Carpenter P.M., McLaren C., Meyskens F.L., Brenner D.E.. Phase IIa Clinical Trial of Curcumin for the Prevention of Colorectal Neoplasia. Cancer Prevention Res, 2011, 4: 354-364 CrossRef PubMed Google Scholar

[19] Cea Soriano L., Soriano-Gabarró M., García Rodríguez L.A.. The Protective Effect of Low-Dose Aspirin against Colorectal Cancer Is Unlikely Explained by Selection Bias: Results from Three Different Study Designs in Clinical Practice. PLoS ONE, 2016, 11: e0159179 CrossRef PubMed ADS Google Scholar

[20] Chae, Y.K., Arya, A., Malecek, M.K., Shin, D.S., Carneiro, B., Chandra, S., Kaplan, J., Kalyan, A., Altman, J.K., Platanias, L., and Giles, F. (2016). Repurposing metformin for cancer treatment: current clinical studies. Oncotarget 7, 40767–40780. Google Scholar

[21] Chainani-Wu N., Madden E., Lozada-Nur F., Silverman Jr. S.. High-dose curcuminoids are efficacious in the reduction in symptoms and signs of oral lichen planus. J Am Acad Dermatology, 2012, 66: 752-760 CrossRef PubMed Google Scholar

[22] Chao C.Y., Lii C.K., Hsu Y.T., Lu C.Y., Liu K.L., Li C.C., Chen H.W.. Induction of heme oxygenase-1 and inhibition of TPA-induced matrix metalloproteinase-9 expression by andrographolide in MCF-7 human breast cancer cells. Carcinogenesis, 2013, 34: 1843-1851 CrossRef PubMed Google Scholar

[23] Chen, J., Xu, T., and Chen, C. (2015). The critical roles of miR-21 in anticancer effects of curcumin. Ann Transl Med 3, 330. Google Scholar

[24] Cheng, A.L., Hsu, C.H., Lin, J.K., Hsu, M.M., Ho, Y.F., Shen, T.S., Ko, J.Y., Lin, J.T., Lin, B.R., Ming-Shiang, W., Yu, H.S., Jee, S.H., Chen, G.S., Chen, T.M., Chen, C.A., Lai, M.K., Pu, Y.S., Pan, M.H., Wang, Y.J., Tsai, C.C., and Hsieh, C.Y. (2001). Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions. Anticancer Res 21, 2895–2900. Google Scholar

[25] Coimbra M., Banciu M., Fens M.H.A.M., de Smet L., Cabaj M., Metselaar J.M., Storm G., Schiffelers R.M.. Liposomal pravastatin inhibits tumor growth by targeting cancer-related inflammation. J Control Release, 2010, 148: 303-310 CrossRef PubMed Google Scholar

[26] Colotta F., Allavena P., Sica A., Garlanda C., Mantovani A.. Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability. Carcinogenesis, 2009, 30: 1073-1081 CrossRef PubMed Google Scholar

[27] Costinean S., Zanesi N., Pekarsky Y., Tili E., Volinia S., Heerema N., Croce C.M.. Pre-B cell proliferation and lymphoblastic leukemia/high-grade lymphoma in E -miR155 transgenic mice. Proc Natl Acad Sci USA, 2006, 103: 7024-7029 CrossRef PubMed ADS Google Scholar

[28] Coyle C., Cafferty F.H., Rowley S., MacKenzie M., Berkman L., Gupta S., Pramesh C.S., Gilbert D., Kynaston H., Cameron D., Wilson R.H., Ring A., Langley R.E., Langley R.E.. ADD-ASPIRIN: A phase III, double-blind, placebo controlled, randomised trial assessing the effects of aspirin on disease recurrence and survival after primary therapy in common non-metastatic solid tumours. Contemporary Clinical Trials, 2016a, 51: 56-64 CrossRef PubMed Google Scholar

[29] Coyle C., Cafferty F.H., Vale C., Langley R.E.. Metformin as an adjuvant treatment for cancer: a systematic review and meta-analysis. Ann Oncol, 2016, 27: 2184-2195 CrossRef PubMed Google Scholar

[30] Crusz S.M., Balkwill F.R.. Inflammation and cancer: advances and new agents. Nat Rev Clin Oncol, 2015, 12: 584-596 CrossRef PubMed Google Scholar

[31] Cui, X., Kong, C., Zhu, Y., Zeng, Y., Zhang, Z., Liu, X., Zhan, B., Piao, C., and Jiang, Z. (2016). miR-130b, an onco-miRNA in bladder cancer, is directly regulated by NF-κB and sustains NF-κB activation by decreasing Cylindromatosis expression. Oncotarget 7, 48547–48561. Google Scholar

[32] Currie C.J., Poole C.D., Gale E.A.M.. The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia, 2009, 52: 1766-1777 CrossRef PubMed Google Scholar

[33] Drew D.A., Cao Y., Chan A.T.. Aspirin and colorectal cancer: the promise of precision chemoprevention. Nat Rev Cancer, 2016, 16: 173-186 CrossRef PubMed Google Scholar

[34] Ellis L.Z., Liu W., Luo Y., Okamoto M., Qu D., Dunn J.H., Fujita M.. Green tea polyphenol epigallocatechin-3-gallate suppresses melanoma growth by inhibiting inflammasome and IL-1β secretion. Biochem Biophysical Res Commun, 2011, 414: 551-556 CrossRef PubMed Google Scholar

[35] Elwood P.C., Morgan G., Pickering J.E., Galante J., Weightman A.L., Morris D., Kelson M., Dolwani S.. Aspirin in the Treatment of Cancer: Reductions in Metastatic Spread and in Mortality: A Systematic Review and Meta-Analyses of Published Studies. PLoS ONE, 2016, 11: e0152402 CrossRef PubMed Google Scholar

[36] Epstein J., Docena G., MacDonald T.T., Sanderson I.R.. Curcumin suppresses p38 mitogen-activated protein kinase activation, reduces IL-1β and matrix metalloproteinase-3 and enhances IL-10 in the mucosa of children and adults with inflammatory bowel disease. Br J Nutr, 2010, 103: 824-832 CrossRef PubMed Google Scholar

[37] Erreni M., Mantovani A., Allavena P.. Tumor-associated Macrophages (TAM) and Inflammation in Colorectal Cancer. Cancer Microenvironment, 2011, 4: 141-154 CrossRef PubMed Google Scholar

[38] Faillie J.L., Hillaire-Buys D.. Examples of how the pharmaceutical industries distort the evidence of drug safety: the case of pioglitazone and the bladder cancer issue. Pharmacoepidemiol Drug Saf, 2016, 25: 212-214 CrossRef PubMed Google Scholar

[39] Feng Y., Ke C., Tang Q., Dong H., Zheng X., Lin W., Ke J., Huang J., Yeung S.C.J., Zhang H.. Metformin promotes autophagy and apoptosis in esophageal squamous cell carcinoma by downregulating Stat3 signaling. Cell Death Dis, 2014, 5: e1088 CrossRef PubMed Google Scholar

[40] Fichtner-Feigl S., Kesselring R., Strober W.. Chronic inflammation and the development of malignancy in the GI tract. Trends Immunol, 2015, 36: 451-459 CrossRef PubMed Google Scholar

[41] Friis S., Riis A.H., Erichsen R., Baron J.A., Sørensen H.T.. Low-Dose Aspirin or Nonsteroidal Anti-inflammatory Drug Use and Colorectal Cancer Risk. Ann Intern Med, 2015, 163: 347-355 CrossRef PubMed Google Scholar

[42] Gala M.K., Chan A.T.. Molecular Pathways: Aspirin and Wnt Signaling--A Molecularly Targeted Approach to Cancer Prevention and Treatment. Clinical Cancer Res, 2015, 21: 1543-1548 CrossRef PubMed Google Scholar

[43] Gao, H., and Wang, J. (2016). Andrographolide inhibits multiple myeloma cells by inhibiting the TLR4/NF-κB signaling pathway. Mol Med Rep 13, 1827–1832. Google Scholar

[44] Gao, Z.Y., Liu, Z., Bi, M.H., Zhang, J.J., Han, Z.Q., Han, X., Wang, H.Y., Sun, G.P., and Liu, H. (2016). Metformin induces apoptosis via a mitochondria-mediated pathway in human breast cancer cells in vitro. Exp Ther Med 11, 1700–1706. Google Scholar

[45] García Rodríguez L.A., Martín-Pérez M., Hennekens C.H., Rothwell P.M., Lanas A.. Bleeding Risk with Long-Term Low-Dose Aspirin: A Systematic Review of Observational Studies. PLoS ONE, 2016, 11: e0160046 CrossRef PubMed ADS Google Scholar

[46] Ghasemzadeh M., Hosseini E.. Platelet-leukocyte crosstalk: Linking proinflammatory responses to procoagulant state. Thrombosis Res, 2013, 131: 191-197 CrossRef PubMed Google Scholar

[47] Gold-Smith F., Fernandez A., Bishop K.. Mangiferin and Cancer: Mechanisms of Action. Nutrients, 2016, 8: 396 CrossRef PubMed Google Scholar

[48] Goh, C.H., Leong, W.Q., Chew, M.H., Pan, Y.S., Tony, L.K., Chew, L., Tan, I.B., Toh, H.C., Tang, C.L., Fu, W.P., and Chia, W.K. (2014). Post-operative aspirin use and colorectal cancer-specific survival in patients with stage I–III colorectal cancer. Anticancer Res 34, 7407–7414. Google Scholar

[49] Gray R.T., Coleman H.G., Hughes C., Murray L.J., Cardwell C.R.. Statin use and survival in colorectal cancer: Results from a population-based cohort study and an updated systematic review and meta-analysis. Cancer Epidemiology, 2016, 45: 71-81 CrossRef PubMed Google Scholar

[50] Grivennikov S.I., Karin M.. Dangerous liaisons: STAT3 and NF-κB collaboration and crosstalk in cancer. Cytokine Growth Factor Rev, 2010, 21: 11-19 CrossRef PubMed Google Scholar

[51] Gu Q., Wang J.D., Xia H.H.X., Lin M.C.M., He H., Zou B., Tu S.P., Yang Y., Liu X.G., Lam S.K., Wong W.M., Chan A.O.O., Yuen M.F., Kung H.F., Wong B.C.Y.. Activation of the caspase-8/Bid and Bax pathways in aspirin-induced apoptosis in gastric cancer. Carcinogenesis, 2005, 26: 541-546 CrossRef PubMed Google Scholar

[52] Guo W., Sun Y., Liu W., Wu X., Guo L., Cai P., Wu X., Wu X., Shen Y., Shu Y., Gu Y., Xu Q.. Small molecule-driven mitophagy-mediated NLRP3 inflammasome inhibition is responsible for the prevention of colitis-associated cancer. Autophagy, 2014, 10: 972-985 CrossRef PubMed Google Scholar

[53] Guo Y., Liu Y., Zhang C., Su Z.Y., Li W., Huang M.T., Kong A.N.. The epigenetic effects of aspirin: the modification of histone H3 lysine 27 acetylation in the prevention of colon carcinogenesis in azoxymethane- and dextran sulfate sodium-treated CF-1 mice. CARCIN, 2016, 37: 616-624 CrossRef PubMed Google Scholar

[54] Gupta S.C., Patchva S., Aggarwal B.B.. Therapeutic Roles of Curcumin: Lessons Learned from Clinical Trials. AAPS J, 2013, 15: 195-218 CrossRef PubMed Google Scholar

[55] Han E., Jang S.Y., Kim G., Lee Y.H., Choe E.Y., Nam C.M., Kang E.S.. Rosiglitazone Use and the Risk of Bladder Cancer in Patients With Type 2 Diabetes. Med, 2016, 95: e2786 CrossRef PubMed Google Scholar

[56] Han J.Y., Lee S.H., Yoo N.J., Hyung L.S., Moon Y.J., Yun T., Kim H.T., Lee J.S.. A Randomized Phase II Study of Gefitinib Plus Simvastatin Versus Gefitinib Alone in Previously Treated Patients with Advanced Non-Small Cell Lung Cancer. Clinical Cancer Res, 2011, 17: 1553-1560 CrossRef PubMed Google Scholar

[57] Hanai H., Iida T., Takeuchi K., Watanabe F., Maruyama Y., Andoh A., Tsujikawa T., Fujiyama Y., Mitsuyama K., Sata M., Yamada M., Iwaoka Y., Kanke K., Hiraishi H., Hirayama K., Arai H., Yoshii S., Uchijima M., Nagata T., Koide Y.. Curcumin Maintenance Therapy for Ulcerative Colitis: Randomized, Multicenter, Double-Blind, Placebo-Controlled Trial. Clinical Gastroenterology Hepatology, 2006, 4: 1502-1506 CrossRef PubMed Google Scholar

[58] Harris, R.E., Beebe-Donk, J., Doss, H., and Burr Doss, D. (2005). Aspirin, ibuprofen, and other non-steroidal anti-inflammatory drugs in cancer prevention: a critical review of non-selective COX-2 blockade (review). Oncol Rep 13, 559–583. Google Scholar

[59] He, X.D., Gong, P., Qi, C.L., He, W., Wang, L.J., and Li, W.D. (2011a). The anti-tumor effects of andrographolide drop pills on murine B16 melanoma. J Guangdong Pharm Coll 27, 163–165. Google Scholar

[60] He Z.Y., Shi C.B., Wen H., Li F.L., Wang B.L., Wang J.. Upregulation of p53 Expression in Patients with Colorectal Cancer by Administration of Curcumin. Cancer Investigation, 2011b, 29: 208-213 CrossRef PubMed Google Scholar

[61] Heidland, A., Klassen, A., Rutkowski, P., and Bahner, U. (2006). The contribution of Rudolf Virchow to the concept of inflammation: what is still of importance? J Nephrol 19, S102–S109. Google Scholar

[62] Henning S.M., Wang P., Said J.W., Huang M., Grogan T., Elashoff D., Carpenter C.L., Heber D., Aronson W.J.. Randomized clinical trial of brewed green and black tea in men with prostate cancer prior to prostatectomy. Prostate, 2015, 75: 550-559 CrossRef PubMed Google Scholar

[63] Hirsch H.A., Iliopoulos D., Struhl K.. Metformin inhibits the inflammatory response associated with cellular transformation and cancer stem cell growth. Proc Natl Acad Sci USA, 2013, 110: 972-977 CrossRef PubMed ADS Google Scholar

[64] Hochmuth F., Jochem M., Schlattmann P.. Meta-analysis of aspirin use and risk of lung cancer shows notable results. Eur J Cancer Prevention, 2016, 25: 259-268 CrossRef PubMed Google Scholar

[65] Hosseini, A., and Ghorbani, A. (2015). Cancer therapy with phytochemicals: evidence from clinical studies. Avicenna J Phytomed 5, 84–97. Google Scholar

[66] Hsieh, M.C., Lee, T.C., Cheng, S.M., Tu, S.T., Yen, M.H., and Tseng, C.H. (2012). The influence of type 2 diabetes and glucose-lowering therapies on cancer risk in the Taiwanese. Exp Diabetes Res 2012, 413782. Google Scholar

[67] Hsu A., Bray T.M., Ho E.. Anti-inflammatory activity of soy and tea in prostate cancer prevention. Exp Biol Med, 2010, 235: 659-667 CrossRef PubMed Google Scholar

[68] Hsu A., Bruno R.S., Löhr C.V., Taylor A.W., Dashwood R.H., Bray T.M., Ho E.. Dietary soy and tea mitigate chronic inflammation and prostate cancer via NFκB pathway in the Noble rat model. J Nutritional Biochem, 2011, 22: 502-510 CrossRef PubMed Google Scholar

[69] Huang X.Z., Chen Y., Wu J., Zhang X., Wu C.C., Zhang C.Y., Sun S.S., Chen W.J.. Aspirin and non-steroidal anti-inflammatory drugs use reduce gastric cancer risk: A dose-response meta-analysis. Oncotarget, 2017, CrossRef PubMed Google Scholar

[70] Hur K.Y., Lee M.S.. Gut Microbiota and Metabolic Disorders. Diabetes Metab J, 2015, 39: 198-203 CrossRef PubMed Google Scholar

[71] Ide H., Tokiwa S., Sakamaki K., Nishio K., Isotani S., Muto S., Hama T., Masuda H., Horie S.. Combined inhibitory effects of soy isoflavones and curcumin on the production of prostate-specific antigen. Prostate, 2010, 70: 1127-1133 CrossRef PubMed Google Scholar

[72] Ishikawa H., Mutoh M., Suzuki S., Tokudome S., Saida Y., Abe T., Okamura S., Tajika M., Joh T., Tanaka S., Kudo S.E., Matsuda T., Iimuro M., Yukawa T., Takayama T., Sato Y., Lee K., Kitamura S., Mizuno M., Sano Y., Gondo N., Sugimoto K., Kusunoki M., Goto C., Matsuura N., Sakai T., Wakabayashi K.. The preventive effects of low-dose enteric-coated aspirin tablets on the development of colorectal tumours in Asian patients: a randomised trial. Gut, 2014, 63: 1755-1759 CrossRef PubMed Google Scholar

[73] Joo Jang H., Mi Hong E., Kim M., Hyun Kim J., Jang J., Woo Park S., Wu Byun H., Hee Koh D., Ho Choi M., Hyub Kae S., Lee J.. Simvastatin induces heme oxygenase-1 via NF-E2-related factor 2 (Nrf2) activation through ERK and PI3K/Akt pathway in colon cancer. Oncotarget, 2014, CrossRef PubMed Google Scholar

[74] Kanai, M. (2014). Therapeutic applications of curcumin for patients with pancreatic cancer. World J Gastroenterol 20, 9384–9391. Google Scholar

[75] Ke B., Zhao Z., Ye X., Gao Z., Manganiello V., Wu B., Ye J.. Inactivation of NF-κB p65 (RelA) in Liver Improves Insulin Sensitivity and Inhibits cAMP/PKA Pathway. Diabetes, 2015, 64: 3355-3362 CrossRef PubMed Google Scholar

[76] Kim B.H., Yi E.H., Ye S.K.. Signal transducer and activator of transcription 3 as a therapeutic target for cancer and the tumor microenvironment. Arch Pharm Res, 2016, 39: 1085-1099 CrossRef PubMed Google Scholar

[77] Kim S.R., Bae M.K., Kim J.Y., Wee H.J., Yoo M.A., Bae S.K.. Aspirin induces apoptosis through the blockade of IL-6-STAT3 signaling pathway in human glioblastoma A172 cells. Biochem Biophysical Res Commun, 2009, 387: 342-347 CrossRef PubMed Google Scholar

[78] King S.E.. Matrix metalloproteinases: new directions toward inhibition in the fight against cancers. Future Medicinal Chem, 2016, 8: 297-309 CrossRef PubMed Google Scholar

[79] Kmieć Z., Cyman M., Ślebioda T.J.. Cells of the innate and adaptive immunity and their interactions in inflammatory bowel disease. Adv Med Sci, 2017, 62: 1-16 CrossRef PubMed Google Scholar

[80] Koh S.J., Kim J.M., Kim I.K., Ko S.H., Kim J.S.. Anti-inflammatory mechanism of metformin and its effects in intestinal inflammation and colitis-associated colon cancer. J Gastroenterol Hepatol, 2014, 29: 502-510 CrossRef Google Scholar

[81] Kune, G.A., Kune, S., and Watson, L.F. (1988). Colorectal cancer risk, chronic illnesses, operations, and medications: case control results from the Melbourne Colorectal Cancer Study. Cancer Res 48, 4399–4404. Google Scholar

[82] Landman G.W.D., Kleefstra N., van Hateren K.J.J., Groenier K.H., Gans R.O.B., Bilo H.J.G.. Metformin Associated With Lower Cancer Mortality in Type 2 Diabetes: ZODIAC-16. Diabetes Care, 2010, 33: 322-326 CrossRef PubMed Google Scholar

[83] Lee J.H., Jeong Y.J., Lee S.W., Kim D., Oh S.J., Lim H.S., Oh H.K., Kim S.H., Kim W.J., Jung J.Y.. EGCG induces apoptosis in human laryngeal epidermoid carcinoma Hep2 cells via mitochondria with the release of apoptosis-inducing factor and endonuclease G. Cancer Lett, 2010, 290: 68-75 CrossRef PubMed Google Scholar

[84] Lee M.S., Hsu C.C., Wahlqvist M.L., Tsai H.N., Chang Y.H., Huang Y.C.. Type 2 diabetes increases and metformin reduces total, colorectal, liver and pancreatic cancer incidences in Taiwanese: a representative population prospective cohort study of 800,000 individuals. BMC Cancer, 2011, 11: 20 CrossRef PubMed Google Scholar

[85] Leone, A., Di Gennaro, E., Bruzzese, F., Avallone, A., and Budillon, A. (2014). New perspective for an old antidiabetic drug: metformin as anticancer agent. Cancer Treat Res 159, 355–376. Google Scholar

[86] Levin D., Bell S., Sund R., Hartikainen S.A., Tuomilehto J., Pukkala E., Keskimäki I., Badrick E., Renehan A.G., Buchan I.E., Bowker S.L., Minhas-Sandhu J.K., Zafari Z., Marra C., Johnson J.A., Stricker B.H., Uitterlinden A.G., Hofman A., Ruiter R., de Keyser C.E., MacDonald T.M., Wild S.H., McKeigue P.M., Colhoun H.M., Colhoun H.M., Colhoun H.M.. Pioglitazone and bladder cancer risk: a multipopulation pooled, cumulative exposure analysis. Diabetologia, 2015, 58: 493-504 CrossRef PubMed Google Scholar

[87] Li F., Zhang J., Arfuso F., Chinnathambi A., Zayed M.E., Alharbi S.A., Kumar A.P., Ahn K.S., Sethi G.. NF-κB in cancer therapy. Arch Toxicol, 2015a, 89: 711-731 CrossRef PubMed Google Scholar

[88] Li P., Wu H., Zhang H., Shi Y., Xu J., Ye Y., Xia D., Yang J., Cai J., Wu Y.. Aspirin use after diagnosis but not prediagnosis improves established colorectal cancer survival: a meta-analysis. Gut, 2015b, 64: 1419-1425 CrossRef PubMed Google Scholar

[89] Li W., Hua B., Saud S.M., Lin H., Hou W., Matter M.S., Jia L., Colburn N.H., Young M.R.. Berberine regulates AMP-activated protein kinase signaling pathways and inhibits colon tumorigenesis in mice. Mol Carcinog, 2015c, 54: 1096-1109 CrossRef PubMed Google Scholar

[90] Li Y., Chang S.C., Goldstein B.Y., Scheider W.L., Cai L., You N.C.Y., Tarleton H.P., Ding B., Zhao J., Wu M., Jiang Q., Yu S., Rao J., Lu Q.Y., Zhang Z.F., Mu L.. Green tea consumption, inflammation and the risk of primary hepatocellular carcinoma in a Chinese population. Cancer Epidemiology, 2011, 35: 362-368 CrossRef PubMed Google Scholar

[91] Li, Z., Geng, Y.N., Jiang, J.D., and Kong, W.J. (2014). Antioxidant and anti-inflammatory activities of berberine in the treatment of diabetes mellitus. Evid Based Complement Alternat Med 2014, 289264. Google Scholar

[92] Lim J.C.W., Chan T.K., Ng D.S.W., Sagineedu S.R., Stanslas J., Wong W.S.F.. Andrographolide and its analogues: versatile bioactive molecules for combating inflammation and cancer. Clinical Exp Pharmacology Physiol, 2012, 39: 300-310 CrossRef PubMed Google Scholar

[93] Lin H.H., Shi M.D., Tseng H.C., Chen J.H.. Andrographolide Sensitizes the Cytotoxicity of Human Colorectal Carcinoma Cells Toward Cisplatin via Enhancing Apoptosis Pathways In Vitro and In Vivo. Toxicol Sci, 2014, 139: 108-120 CrossRef PubMed Google Scholar

[94] Liu J., Liu S., Zhou H., Hanson T., Yang L., Chen Z., Zhou M.. Association of green tea consumption with mortality from all-cause, cardiovascular disease and cancer in a Chinese cohort of 165,000 adult men. Eur J Epidemiol, 2016, 31: 853-865 CrossRef PubMed Google Scholar

[95] Liu, J., Mu, Y.L., Jin, J., Li, J., and Cui, S.X. (2014). Effect of sulindac on miRNA-17 and miRNA-21 expressions in human colon cancer cells. Chin J Cancer Prev Treat 21, 485–489. Google Scholar

[96] Löffler D., Brocke-Heidrich K., Pfeifer G., Stocsits C., Hackermüller J., Kretzschmar A.K., Burger R., Gramatzki M., Blumert C., Bauer K., Cvijic H., Ullmann A.K., Stadler P.F., Horn F.. Interleukin-6 dependent survival of multiple myeloma cells involves the Stat3-mediated induction of microRNA-21 through a highly conserved enhancer. Blood, 2007, 110: 1330-1333 CrossRef PubMed Google Scholar

[97] Lytras T., Nikolopoulos G., Bonovas S.. Statins and the risk of colorectal cancer: An updated systematic review and meta-analysis of 40 studies. WJG, 2014, 20: 1858-1870 CrossRef PubMed Google Scholar

[98] Mahammedi H., Planchat E., Pouget M., Durando X., Curé H., Guy L., Van-Praagh I., Savareux L., Atger M., Bayet-Robert M., Gadea E., Abrial C., Thivat E., Chollet P., Eymard J.C.. The New Combination Docetaxel, Prednisone and Curcumin in Patients with Castration-Resistant Prostate Cancer: A Pilot Phase II Study. Oncology, 2016, 90: 69-78 CrossRef PubMed Google Scholar

[99] Mahran R.I., Hagras M.M., Sun D., Brenner D.E.. Bringing Curcumin to the Clinic in Cancer Prevention: a Review of Strategies to Enhance Bioavailability and Efficacy. AAPS J, 2017, 19: 54-81 CrossRef PubMed Google Scholar

[100] Malicki, S., Winiarski, M., Matlok, M., Kostarczyk, W., Guzdek, A., and Konturek, P.C. (2009). IL-6 and IL-8 responses of colorectal cancer in vivo and in vitro cancer cells subjected to simvastatin. J Physiol Pharmacol 60, 141–146. Google Scholar

[101] Manoharan S., Singh A.K., Suresh K., Vasudevan K., Subhasini R., Baskaran N.. Anti-tumor Initiating Potential of Andrographolide in 7,12-dimethylbenz[a]anthracene Induced Hamster Buccal Pouch Carcinogenesis. Asian Pac J Cancer Prevention, 2012, 13: 5701-5708 CrossRef Google Scholar

[102] Manthravadi S., Shrestha A., Madhusudhana S.. Impact of statin use on cancer recurrence and mortality in breast cancer: A systematic review and meta-analysis. Int J Cancer, 2016, 139: 1281-1288 CrossRef PubMed Google Scholar

[103] Marelli C., Gunnarsson C., Ross S., Haas S., Stroup D.F., Cload P., Clopton P., DeMaria A.N.. Statins and Risk of Cancer. J Am College Cardiology, 2011, 58: 530-537 CrossRef PubMed Google Scholar

[104] McFadden R.M.T., Larmonier C.B., Shehab K.W., Midura-Kiela M., Ramalingam R., Harrison C.A., Besselsen D.G., Chase J.H., Caporaso J.G., Jobin C., Ghishan F.K., Kiela P.R.. The Role of Curcumin in Modulating Colonic Microbiota During Colitis and Colon Cancer Prevention. Inflammatory Bowel Diseases, 2015, 21: 2483-2494 CrossRef PubMed Google Scholar

[105] Mima K., Nishihara R., Yang J., Dou R., Masugi Y., Shi Y., da Silva A., Cao Y., Song M., Nowak J., Gu M., Li W., Morikawa T., Zhang X., Wu K., Baba H., Giovannucci E.L., Meyerhardt J.A., Chan A.T., Fuchs C.S., Qian Z.R., Ogino S.. MicroRNA MIR21 (miR-21) and PTGS2 Expression in Colorectal Cancer and Patient Survival. Clinical Cancer Res, 2016, 22: 3841-3848 CrossRef PubMed Google Scholar

[106] Mishra, S.K., Tripathi, S., Shukla, A., Oh, S.H., and Kim, H.M. (2015). Andrographolide and analogues in cancer prevention. Front Biosci (Elite Ed) 7, 255–266. Google Scholar

[107] Mitrugno A., Sylman J.L., Ngo A.T.P., Pang J., Sears R.C., Williams C.D., McCarty O.J.T.. 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: C176-C189 CrossRef PubMed Google Scholar

[108] Momtazi, A.A., Shahabipour, F., Khatibi, S., Johnston, T.P., Pirro, M., and Sahebkar, A. (2016). Curcumin as a microRNA regulator in cancer: A review. Rev Physiol Biochem Pharmacol 171, 1–38. Google Scholar

[109] Morales D.R., Morris A.D.. Metformin in Cancer Treatment and Prevention. Annu Rev Med, 2015, 66: 17-29 CrossRef PubMed Google Scholar

[110] Mukherjee, S., Siddiqui, M.A., Dayal, S., Ayoub, Y.Z., and Malathi, K. (2014). Epigallocatechin-3-gallate suppresses proinflammatory cytokines and chemokines induced by Toll-like receptor 9 agonists in prostate cancer cells. J Inflamm Res 7, 89–101. Google Scholar

[111] Nan H., Hutter C.M., Lin Y., Jacobs E.J., Ulrich C.M., White E., Baron J.A., Berndt S.I., Brenner H., Butterbach K., Caan B.J., Campbell P.T., Carlson C.S., Casey G., Chang-Claude J., Chanock S.J., Cotterchio M., Duggan D., Figueiredo J.C., Fuchs C.S., Giovannucci E.L., Gong J., Haile R.W., Harrison T.A., Hayes R.B., Hoffmeister M., Hopper J.L., Hudson T.J., Jenkins M.A., Jiao S., Lindor N.M., Lemire M., Le Marchand L., Newcomb P.A., Ogino S., Pflugeisen B.M., Potter J.D., Qu C., Rosse S.A., Rudolph A., Schoen R.E., Schumacher F.R., Seminara D., Slattery M.L., Thibodeau S.N., Thomas F., Thornquist M., Warnick G.S., Zanke B.W., Gauderman W.J., Peters U., Hsu L., Chan A.T., Chan A.T., Chan A.T.. Association of Aspirin and NSAID Use With Risk of Colorectal Cancer According to Genetic Variants. JAMA, 2015, 313: 1133-1142 CrossRef PubMed Google Scholar

[112] Netea-Maier R.T., Plantinga T.S., van de Veerdonk F.L., Smit J.W., Netea M.G.. Modulation of inflammation by autophagy: Consequences for human disease. Autophagy, 2016, 12: 245-260 CrossRef PubMed Google Scholar

[113] Ng, K., Meyerhardt, J.A., Chan, A.T., Sato, K., Chan, J.A., Niedzwiecki, D., Saltz, L.B., Mayer, R.J., Benson, A.B. 3rd., Schaefer, P.L., Whittom, R., Hantel, A., Goldberg, R.M., Venook, A.P., Ogino, S., Giovannucci, E.L., and Fuchs, C.S. (2015). Aspirin and COX-2 inhibitor use in patients with stage III colon cancer. J Natl Cancer Inst 107, 345. Google Scholar

[114] Ning Y., Lenz H.J.. Targeting IL-8 in colorectal cancer. Expert Opin Therapeutic Targets, 2012, 16: 491-497 CrossRef PubMed Google Scholar

[115] Niraula S., Dowling R.J.O., Ennis M., Chang M.C., Done S.J., Hood N., Escallon J., Leong W.L., McCready D.R., Reedijk M., Stambolic V., Goodwin P.J.. Metformin in early breast cancer: a prospective window of opportunity neoadjuvant study. Breast Cancer Res Treat, 2012, 135: 821-830 CrossRef PubMed Google Scholar

[116] Oliveira M.R., Nabavi S.F., Daglia M., Rastrelli L., Nabavi S.M.. Epigallocatechin gallate and mitochondria—A story of life and death. Pharmacological Res, 2016, 104: 70-85 CrossRef PubMed Google Scholar

[117] O'Sullivan J., Sheridan J., Mulcahy H., Tenniswood M., Morrissey C.. The effect of green tea on oxidative damage and tumour formation in Lobund–Wistar rats. Eur J Cancer Prevention, 2008, 17: 489-501 CrossRef PubMed Google Scholar

[118] Pan M.R., Chang H.C., Hung W.C.. Non-steroidal anti-inflammatory drugs suppress the ERK signaling pathway via block of Ras/c-Raf interaction and activation of MAP kinase phosphatases. Cellular Signalling, 2008, 20: 1134-1141 CrossRef PubMed Google Scholar

[119] Pandey M.K., Sung B., Kunnumakkara A.B., Sethi G., Chaturvedi M.M., Aggarwal B.B.. Berberine Modifies Cysteine 179 of I B  Kinase, Suppresses Nuclear Factor- B-Regulated Antiapoptotic Gene Products, and Potentiates Apoptosis. Cancer Res, 2008, 68: 5370-5379 CrossRef PubMed Google Scholar

[120] Park W., Amin A.R.M.R., Chen Z.G., Shin D.M.. New Perspectives of Curcumin in Cancer Prevention. Cancer Prevention Res, 2013, 6: 387-400 CrossRef PubMed Google Scholar

[121] Patrignani P., Patrono C.. Aspirin and Cancer. J Am College Cardiology, 2016, 68: 967-976 CrossRef PubMed Google Scholar

[122] Peng S., Hang N., Liu W., Guo W., Jiang C., Yang X., Xu Q., Sun Y.. Andrographolide sulfonate ameliorates lipopolysaccharide-induced acute lung injury in mice by down-regulating MAPK and NF-κB pathways. Acta Pharmaceutica Sin B, 2016, 6: 205-211 CrossRef PubMed Google Scholar

[123] Pisanti S., Picardi P., Ciaglia E., D'Alessandro A., Bifulco M.. Novel prospects of statins as therapeutic agents in cancer. Pharmacological Res, 2014, 88: 84-98 CrossRef PubMed Google Scholar

[124] Qin L.H., Kong L., Shi G.J., Wang Z.T., Ge B.X.. Andrographolide Inhibits the Production of TNF-α and Interleukin-12 in Lipopolysaccharide-Stimulated Macrophages: Role of Mitogen-Activated Protein Kinases. Biol Pharm Bull, 2006, 29: 220-224 CrossRef Google Scholar

[125] Qu L.L., Yu B., Li Z., Jiang W.X., Jiang J.D., Kong W.J.. Gastrodin Ameliorates Oxidative Stress and Proinflammatory Response in Nonalcoholic Fatty Liver Disease through the AMPK/Nrf2 Pathway. Phytother Res, 2016, 30: 402-411 CrossRef PubMed Google Scholar

[126] Raza H., John A., Shafarin J.. Potentiation of LPS-Induced Apoptotic Cell Death in Human Hepatoma HepG2 Cells by Aspirin via ROS and Mitochondrial Dysfunction: Protection by N-Acetyl Cysteine. PLoS ONE, 2016, 11: e0159750 CrossRef PubMed ADS Google Scholar

[127] Rizos C.V., Elisaf M.S.. Metformin and cancer. Eur J Pharmacology, 2013, 705: 96-108 CrossRef PubMed Google Scholar

[128] Rogers, M.A., and Aronoff, D.M. (2016). The influence of non-steroidal anti-inflammatory drugs on the gut microbiome. Clin Microbiol Infect 22, 178.e1–178.e9. Google Scholar

[129] Rosato, V., Tavani, A., Gracia-Lavedan, E., Guinó, E., Castaño-Vinyals, G., Villanueva, C.M., Kogevinas, M., Polesel, J., Serraino, D., Pisa, F.E., Barbone, F., Moreno, V., La Vecchia, C., and Bosetti, C. (2016). Type 2 diabetes, antidiabetic medications, and colorectal cancer risk: Two case-control studies from Italy and Spain. Front Oncol 6, 210. Google Scholar

[130] Rothwell P.M., Fowkes F.G.R., Belch J.F., Ogawa H., Warlow C.P., Meade T.W.. Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials. Lancet, 2011, 377: 31-41 CrossRef Google Scholar

[131] Rothwell P.M., Price J.F., Fowkes F.G.R., Zanchetti A., Roncaglioni M.C., Tognoni G., Lee R., Belch J.F., Wilson M., Mehta Z., Meade T.W.. Short-term effects of daily aspirin on cancer incidence, mortality, and non-vascular death: analysis of the time course of risks and benefits in 51 randomised controlled trials. Lancet, 2012a, 379: 1602-1612 CrossRef Google Scholar

[132] Rothwell P.M., Wilson M., Price J.F., Belch J.F., Meade T.W., Mehta Z.. Effect of daily aspirin on risk of cancer metastasis: a study of incident cancers during randomised controlled trials. Lancet, 2012b, 379: 1591-1601 CrossRef Google Scholar

[133] Saber M.M., Galal M.A., Ain-Shoka A.A., Shouman S.A.. Combination of metformin and 5-aminosalicylic acid cooperates to decrease proliferation and induce apoptosis in colorectal cancer cell lines. BMC Cancer, 2016, 16: 126 CrossRef PubMed Google Scholar

[134] Saisho Y.. Metformin and Inflammation: Its Potential Beyond Glucose-lowering Effect. EMIDDT, 2015, 15: 196-205 CrossRef Google Scholar

[135] Samadder N.J., Mukherjee B., Huang S.C., Ahn J., Rennert H.S., Greenson J.K., Rennert G., Gruber S.B.. Risk of colorectal cancer in self-reported inflammatory bowel disease and modification of risk by statin and NSAID use. Cancer, 2011, 117: 1640-1648 CrossRef PubMed Google Scholar

[136] Schetter A.J., Heegaard N.H.H., Harris C.C.. Inflammation and cancer: interweaving microRNA, free radical, cytokine and p53 pathways. Carcinogenesis, 2010, 31: 37-49 CrossRef PubMed Google Scholar

[137] Schwitalla S., Fingerle A.A., Cammareri P., Nebelsiek T., Göktuna S.I., Ziegler P.K., Canli O., Heijmans J., Huels D.J., Moreaux G., Rupec R.A., Gerhard M., Schmid R., Barker N., Clevers H., Lang R., Neumann J., Kirchner T., Taketo M.M., van den Brink G.R., Sansom O.J., Arkan M.C., Greten F.R.. Intestinal Tumorigenesis Initiated by Dedifferentiation and Acquisition of Stem-Cell-like Properties. Cell, 2013, 152: 25-38 CrossRef PubMed Google Scholar

[138] Senggunprai L., Kukongviriyapan V., Prawan A., Kukongviriyapan U.. Quercetin and EGCG Exhibit Chemopreventive Effects in Cholangiocarcinoma Cells via Suppression of JAK/STAT Signaling Pathway. Phytother Res, 2014, 28: 841-848 CrossRef PubMed Google Scholar

[139] Shanmugam M.K., Rane G., Kanchi M.M., Arfuso F., Chinnathambi A., Zayed M.E., Alharbi S.A., Tan B.K.H., Kumar A.P., Sethi G.. The Multifaceted Role of Curcumin in Cancer Prevention and Treatment. Molecules, 2015, 20: 2728-2769 CrossRef PubMed Google Scholar

[140] Sharma R.A., Euden S.A., Platton S.L., Cooke D.N., Shafayat A., Hewitt H.R., Marczylo T.H., Morgan B., Hemingway D., Plummer S.M., Pirmohamed M., Gescher A.J., Steward W.P.. Phase I Clinical Trial of Oral Curcumin: Biomarkers of Systemic Activity and Compliance. Clinical Cancer Res, 2004, 10: 6847-6854 CrossRef PubMed Google Scholar

[141] Sheeja K., Guruvayoorappan C., Kuttan G.. Antiangiogenic activity of Andrographis paniculata extract and andrographolide. Int Immunopharmacology, 2007, 7: 211-221 CrossRef PubMed Google Scholar

[142] Shirakami, Y., Shimizu, M., Tsurumi, H., Hara, Y., Tanaka, T., and Moriwaki, H. (2008). EGCG and Polyphenon E attenuate inflammation-related mouse colon carcinogenesis induced by AOM plus DDS. Mol Med Rep 1, 355–361. Google Scholar

[143] Tolentino Silva M., Freire Galvao T., Ricardo Zimmerman I., Gomes Pereira M., Cruz Lopes L.. Non-aspirin Non-steroidal Anti-inflammatory Drugs for the Primary Chemoprevention of Non-gastrointestinal Cancer: Summary of Evidence. CPD, 2012, 18: 4047-4070 CrossRef Google Scholar

[144] Singh Ranger G.. The role of aspirin in colorectal cancer chemoprevention. Critical Rev Oncology/Hematology, 2016, 104: 87-90 CrossRef PubMed Google Scholar

[145] Singh S., Singh P.P.. Statin a day keeps cancer at bay. WJCO, 2013, 4: 43-46 CrossRef PubMed Google Scholar

[146] Stegeman, I., Bossuyt, P.M., Yu, T., Boyd, C., and Puhan, M.A. (2015). Aspirin for primary prevention of cardiovascular disease and cancer. A benefit and harm analysis. PLoS One 10, e0127194. Google Scholar

[147] Streicher S.A., Yu H., Lu L., Kidd M.S., Risch H.A.. Case-Control Study of Aspirin Use and Risk of Pancreatic Cancer. Cancer Epidemiology Biomarkers Prevention, 2014, 23: 1254-1263 CrossRef PubMed Google Scholar

[148] Sutcliffe S., Platz E.A.. Inflammation and prostate cancer: A focus on infections. Curr Urol Rep, 2008, 9: 243-249 CrossRef Google Scholar

[149] Takada, Y., Bhardwaj, A., Potdar, P., and Aggarwal, B.B. (2004). Nonsteroidal anti-inflammatory agents differ in their ability to suppress NF-κB activation, inhibition of expression of cyclooxygenase-2 and cyclin D1, and abrogation of tumor cell proliferation. Oncogene 23, 9247–9258. Google Scholar

[150] Tan P., Wei S., Tang Z., Gao L., Zhang C., Nie P., Yang L., Wei Q.. LDL-lowering therapy and the risk of prostate cancer: a meta-analysis of 6 randomized controlled trials and 36 observational studies. Sci Rep, 2016a, 6: 24521 CrossRef PubMed ADS Google Scholar

[151] Tan P., Wei S., Yang L., Tang Z., Cao D., Liu L., Lei J., Fan Y., Gao L., Wei Q.. The effect of statins on prostate cancer recurrence and mortality after definitive therapy: a systematic review and meta-analysis. Sci Rep, 2016b, 6: 29106 CrossRef PubMed ADS Google Scholar

[152] Tian Y., Ye Y., Gao W., Chen H., Song T., Wang D., Mao X., Ren C.. Aspirin promotes apoptosis in a murine model of colorectal cancer by mechanisms involving downregulation of IL-6–STAT3 signaling pathway. Int J Colorectal Dis, 2011, 26: 13-22 CrossRef PubMed Google Scholar

[153] Trudel D., Labbé D.P., Bairati I., Fradet V., Bazinet L., Têtu B.. Green tea for ovarian cancer prevention and treatment: A systematic review of the in vitro, in vivo and epidemiological studies. Gynecologic Oncology, 2012, 126: 491-498 CrossRef PubMed Google Scholar

[154] Tseng C.H.. Metformin and esophageal cancer risk in Taiwanese patients with type 2 diabetes mellitus. Oncotarget, 2017, CrossRef PubMed Google Scholar

[155] Tung, Y.T., Chen, H.L., Tsai, H.C., Yang, S.H., Chang, Y.C., and Chen, C.M. (2013). Therapeutic potential of andrographolide isolated from the leaves of Andrographis paniculata Nees for treating lung adenocarcinomas. Evid Based Complement Alternat Med 2013, 305898. Google Scholar

[156] Umar A., Steele V.E., Menter D.G., Hawk E.T.. Mechanisms of nonsteroidal anti-inflammatory drugs in cancer prevention. Seminars Oncology, 2016, 43: 65-77 CrossRef PubMed Google Scholar

[157] Unno T., Sakuma M., Mitsuhashi S.. Effect of Dietary Supplementation of (^|^minus;)-Epigallocatechin Gallate on Gut Microbiota and Biomarkers of Colonic Fermentation in Rats. J Nutr Sci Vitaminol, 2014, 60: 213-219 CrossRef Google Scholar

[158] Wang N., Tan H.Y., Li L., Yuen M.F., Feng Y.. Berberine and Coptidis Rhizoma as potential anticancer agents: Recent updates and future perspectives. J Ethnopharmacology, 2015, 176: 35-48 CrossRef PubMed Google Scholar

[159] Weber D.. Inflammation and cancer: tumor initiation, progression and metastasis, and Chinese botanical medicines. J Chin Integr Med, 2010, 8: 1006-1013 CrossRef Google Scholar

[160] Wood, W.G., Igbavboa, U., Muller, W.E., and Eckert, G.P. (2013). Statins, Bcl-2, and apoptosis: cell death or cell protection? Mol Neurobiol 48, 308–314. Google Scholar

[161] Wu L., Zhu J., Prokop L.J., Hassan Murad M.. Pharmacologic Therapy of Diabetes and Overall Cancer Risk and Mortality: A Meta-Analysis of 265 Studies. Sci Rep, 2015, 5: 10147 CrossRef PubMed ADS Google Scholar

[162] Xu, L.C., Chen, Z.L., Sun, Z.H., Wang, S.X., Xu, F., Gao, P., Zhou, C.K., and Wang, S,H. (2000). Clinical observation of the treatment of Lianbizhi injection on malignant tumor. J Jiangsu Clin Med 4, 277–279. Google Scholar

[163] Xu M., Xiao Y., Yin J., Hou W., Yu X., Shen L., Liu F., Wei L., Jia W.. Berberine Promotes Glucose Consumption Independently of AMP-Activated Protein Kinase Activation. PLoS ONE, 2014, 9: e103702 CrossRef PubMed ADS Google Scholar

[164] Yang S.S., Li R., Qu X., Fang W., Quan Z.. Atorvastatin decreases Toll-like receptor 4 expression and downstream signaling in human monocytic leukemia cells. Cellular Immunol, 2012, 279: 96-102 CrossRef PubMed Google Scholar

[165] Ye X., Fu J., Yang Y., Chen S.. Dose–Risk and Duration–Risk Relationships between Aspirin and Colorectal Cancer: A Meta-Analysis of Published Cohort Studies. PLoS ONE, 2013, 8: e57578 CrossRef PubMed ADS Google Scholar

[166] Yu L., Li L., Medeiros L.J., Young K.H.. NF-κB signaling pathway and its potential as a target for therapy in lymphoid neoplasms. Blood Rev, 2017, 31: 77-92 CrossRef PubMed Google Scholar

[167] Yu, O., Eberg, M., Benayoun, S., Aprikian, A., Batist, G., Suissa, S., and Azoulay, L. (2014). Use of statins and the risk of death in patients with prostate cancer. J Clin Oncol 32, 5–11. Google Scholar

[168] Yu T., Lao X., Zheng H.. Influencing COX-2 Activity by COX Related Pathways in Inflammation and Cancer. MRMC, 2016b, 16: 1230-1243 CrossRef Google Scholar

[169] Yue W., Yang C.S., DiPaola R.S., Tan X.L.. Repurposing of Metformin and Aspirin by Targeting AMPK-mTOR and Inflammation for Pancreatic Cancer Prevention and Treatment. Cancer Prevention Res, 2014, 7: 388-397 CrossRef PubMed Google Scholar

[170] Zhai, Z., Qu, X., Li, H., Ouyang, Z., Yan, W., Liu, G., Liu, X., Fan, Q., Tang, T., Dai, K., and Qin, A. (2015). Inhibition of MDA-MB-231 breast cancer cell migration and invasion activity by andrographolide via suppression of nuclear factor-κB-dependent matrix metalloproteinase-9 expression. Mol Med Rep 11, 1139–1145. Google Scholar

[171] Zhang C., Shu L., Kong A.N.T.. MicroRNAs: new Players in Cancer Prevention Targeting Nrf2, Oxidative Stress and Inflammatory Pathways. Curr Pharmacol Rep, 2015, 1: 21-30 CrossRef PubMed Google Scholar

[172] Zhang Y., Ye J.. Mitochondrial inhibitor as a new class of insulin sensitizer. Acta Pharmaceutica Sin B, 2012, 2: 341-349 CrossRef PubMed Google Scholar

[173] Zhong Z., Sanchez-Lopez E., Karin M.. Autophagy, Inflammation, and Immunity: A Troika Governing Cancer and Its Treatment. Cell, 2016, 166: 288-298 CrossRef PubMed Google Scholar

[174] Zhou, C.K., and Xu, L.C. (2001). Clinical observation of Lianbizhi injection for the treatment of cancer. Henan Med Inf 9, 22. Google Scholar

[175] Zhou J., Ong C.N., Hur G.M., Shen H.M.. Inhibition of the JAK-STAT3 pathway by andrographolide enhances chemosensitivity of cancer cells to doxorubicin. Biochem Pharmacology, 2010, 79: 1242-1250 CrossRef PubMed Google Scholar

  • Figure 1

    Inflammation- and cyclooxygenase (COX)-related mechanisms of aspirin in cancer prevention and treatment. (1) Chronic inflammation is able to promote tumorigenesis, cancer cell growth and spread through stimulation of the proinflammatory cytokines/nuclear factor-κB (NF-κB)/signal transducer and activator of transcription 3 (STAT3) pathways. On one hand, aspirin can down-regulate the expression of interleukin (IL)-6/tumor necrosis factor-α (TNF-α) through inhibiting the histone deacetylases (HDACs), and then block the activation NF-κB/STAT3; on the other hand, aspirin can suppress NF-κB through inhibiting the degradation of inhibitory κB-α (IκB-α). As a result, the expression levels of NF-κB/STAT3 target genes, like COX-2 and other oncogenic molecules, are down-regulated by aspirin, which will lead to the inhibition of tumorigenesis and growth. In addition, aspirin is able to down-regulate miRNA (miR)-21, which may also contribute to its anti-cancer activity. (2) Aspirin can inhibit the activity of COX-2 directly, which will lead to the decrease of prostaglandin E2 (PGE2) and subsequent tumor regression. (3) Aspirin can suppress the Wnt/βcatenin pathway through inhibiting protein phosphatase 2A (PP2A) or COX-2/PGE2, which will inhibit tumorigenesis. (4) Chronic inflammation can induce platelet activation, which will accelerate tumor progression. Through inhibiting COX-1, aspirin suppresses the activation of platelet, which may also contribute to its anti-cancer activity.

  • Table 1   Influences of different agents on inflammation-related molecules and pathways in cancer prevention and treatment




    IL-6/TNF-α↓, NF-κB/STAT3 activity↓, Wnt/βcatenin activity↓, miR-21↓, platelet activation↓

    Drew et al., 2016; Guo et al., 2016; Kim et al., 2009; Liu et al., 2014; Takada et al., 2004; Tian et al., 2011; Umar et al., 2016


    IL-1β/IL-6/TNF-α↓, AMPK activity↑, NF-κB/STAT3 activity↓

    Feng et al., 2014; Koh et al., 2014; Saber et al., 2016; Saisho, 2015


    Function of TAMs↓, IL-1β/IL-6/TNF-α↓, NF-κB activity↓, Nrf2/HO-1/NQO-1↑

    Coimbra et al., 2010; Jang et al., 2016; Malicki et al., 2009; Pisanti et al., 2014; Yang et al., 2012

    Green tea catechins

    IL-1β/IL-6/TNF-α↓, NLRP1↓, NF-κB/STAT3 activity↓

    Ellis et al., 2011; Henning et al., 2015; Hsu et al., 2011; Mukherjee et al., 2014; Senggunprai et al., 2014; Shirakami et al., 2008


    Function of macrophages↓, IL-1β/IL-6/TNF-α↓, autophagy↑, NLRP3↓, NF-κB/STAT3 activity↓, HO-1↑

    Chao et al., 2013; Gao and Wang, 2016; Guo et al., 2014; Qin et al., 2006; Sheeja et al., 2007; Zhai et al., 2015; Zhou et al., 2010


    Restoration of gut microbiota, IL-1β/IL-6/TNF-α↓, CRP↓, IL-10↑, NF-κB/STAT3 activity↓, miR-21↓

    Bimonte et al., 2016; Chen et al., 2015; Epstein et al., 2010; Gupta et al., 2013; Hanai et al., 2006; He et al., 2011b; Kanai, 2014; McFadden et al., 2015; Momtazi et al., 2016; Park et al., 2013; Shanmugam et al., 2015

    IL, interleukin; TNF-α, tumor necrosis factor-α; NF-κB, nuclear factor-κB; STAT3, signal transducer and activator of transcription 3; miR, miRNA; AMPK, AMP-activated protein kinase; TAMs, tumor-associated macrophages; Nrf2, nuclear factor erythroid-2-related factor-2; HO-1, heme oxygenase-1; NQO-1, NADPH quinine oxidoreductase-1; NLRP, NACHT, LRR and PYD domains-containing protein; CRP, C-reactive protein.

Copyright 2019 Science China Press Co., Ltd. 《中国科学》杂志社有限责任公司 版权所有