Anti-Cancer Agents in Medicinal ChemistryAnti-Cancer Agents in Medicinal ChemistryAnti-Cancer Agents in Medicinal Chemistry1871-52061875-5992Bentham Science64427510.2174/0118715206271583231206052403OncologyResearch ArticleA Contemporary Review on the Critical Role of Nonsteroidal Anti-inflammatory Agents in Colorectal Cancer TherapyZia SarabiParisainfo@benthamscience.netMoradiMohammadinfo@benthamscience.netBagheriMaliheinfo@benthamscience.netKhaliliMohammadinfo@benthamscience.netMoradifardShahrzadinfo@benthamscience.netJamialahmadiTannazinfo@benthamscience.netGhasemiFaezehinfo@benthamscience.netSahebkarAmirhosseininfo@benthamscience.netLaboratorio de Psicobiología, Campus Santiago Ramón y Cajal, University of SevillaDepartment of Biotechnology, Faculty of Biological Science and Technology, University of IsfahanDepartment of Biotechnology and Molecular Medicine, Arak University of Medical SciencesBlood Transfusion Research Center, High Institute for Research and Education in Transfusion MedicineApplied Biomedical Research Center, Mashhad University of Medical Sciences1504202424855957007012025Copyright ©; 2024, Bentham Science Publishers2024Bentham Science Publishershttps://journals.eco-vector.com/1871-5206/article/view/644275

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) are widely recognized as effective pain relievers and function by inhibiting the cyclooxygenase enzyme (COXs). Moreover, they have been found to participate in various cellular processes through different signaling pathways, such as WNT, MAPK, NF-KB, and PI3K/AKT/mTOR. This makes them potential candidates for chemoprevention of several malignancies, particularly colorectal cancer (CRC). However, the use of NSAIDs in cancer prevention and treatment is a complex issue due to their adverse effects and gastrointestinal toxicity. Therefore, it is crucial to explore combination therapies that can minimize side effects while maximizing synergistic effects with other agents and to evaluate the success rate of such approaches in both pre-clinical and clinical studies. In this review, we aim to provide an overview of the effects of NSAIDs in the prevention and treatment of CRC. We will focus on elucidating the possible mechanisms of action of these drugs, the signaling pathways involved in CRC, and the potential synergistic effects when combined with other therapeutic agents.

NSAIDscyclooxygenase enzymessignaling pathwaysmalignancycombination therapycolorectal cancer.Ewing, I.; Hurley, J.J.; Josephides, E.; Millar, A. The molecular genetics of colorectal cancer. Frontline Gastroenterol., 2014, 5(1), 26-30. doi: 10.1136/flgastro-2013-100329 PMID: 24416503Rawla, P.; Sunkara, T.; Barsouk, A. Epidemiology of colorectal cancer: Incidence, mortality, survival, and risk factors. Prz. Gastroenterol., 2019, 14(2), 89-103. doi: 10.5114/pg.2018.81072 PMID: 31616522Fotheringham, S.; Mozolowski, G.A.; Murray, E.M.A.; Kerr, D.J. Challenges and solutions in patient treatment strategies for stage II colon cancer. Gastroenterol. Rep., 2019, 7(3), 151-161. doi: 10.1093/gastro/goz006 PMID: 31217978Tomić, T.; Domínguez-López, S.; Barrios-Rodríguez, R. Non-aspirin non-steroidal anti-inflammatory drugs in prevention of colorectal cancer in people aged 40 or older: A systematic review and meta-analysis. Cancer Epidemiol., 2019, 58, 52-62. doi: 10.1016/j.canep.2018.11.002 PMID: 30472477Favoriti, P.; Carbone, G.; Greco, M.; Pirozzi, F.; Pirozzi, R.E.M.; Corcione, F. Worldwide burden of colorectal cancer: A review. Updates Surg., 2016, 68(1), 7-11. doi: 10.1007/s13304-016-0359-y PMID: 27067591Wu, J.; Xia, C.; Liu, C.; Zhang, Q.; Xia, C. The role of gut microbiota and drug interactions in the development of colorectal cancer. Front. Pharmacol., 2023, 14, 1265136. doi: 10.3389/fphar.2023.1265136 PMID: 37680706Werner, J.; Heinemann, V. Standards and challenges of care for colorectal cancer today. Visc. Med., 2016, 32(3), 156-157. doi: 10.1159/000447070 PMID: 27493941Zhang, Y.; Chen, Z.; Li, J. The current status of treatment for colorectal cancer in China. Medicine, 2017, 96(40), e8242. doi: 10.1097/MD.0000000000008242 PMID: 28984783Messersmith, W.A. NCCN guidelines updates: management of metastatic colorectal cancer. J. Natl. Compr. Canc. Netw., 2019, 17(5), 599-603.Labianca, R.; Nordlinger, B.; Beretta, G.D.; Mosconi, S.; Mandalà, M.; Cervantes, A.; Arnold, D. Early colon cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann. Oncol., 2013, 24(Suppl. 6), vi64-vi72. doi: 10.1093/annonc/mdt354 PMID: 24078664Fakih, M.G. Metastatic colorectal cancer: Current state and future directions. J. Clin. Oncol., 2015, 33(16), 1809-1824. doi: 10.1200/JCO.2014.59.7633 PMID: 25918280Seymour, M.T.; Maughan, T.S.; Ledermann, J.A.; Topham, C.; James, R.; Gwyther, S.J.; Smith, D.B.; Shepherd, S.; Maraveyas, A.; Ferry, D.R.; Meade, A.M.; Thompson, L.; Griffiths, G.O.; Parmar, M.K.B.; Stephens, R.J. Different strategies of sequential and combination chemotherapy for patients with poor prognosis advanced colorectal cancer (MRC FOCUS): A randomised controlled trial. Lancet, 2007, 370(9582), 143-152. doi: 10.1016/S0140-6736(07)61087-3 PMID: 17630037Xie, Y.H.; Chen, Y.X.; Fang, J.Y. Comprehensive review of targeted therapy for colorectal cancer. Signal Transduct. Target. Ther., 2020, 5(1), 22. doi: 10.1038/s41392-020-0116-z PMID: 32296018Yau, T.O. Precision treatment in colorectal cancer: Now and the future. JGH Open, 2019, 3(5), 361-369. doi: 10.1002/jgh3.12153 PMID: 31633039Wong, R.S. Role of nonsteroidal anti-inflammatory drugs (NSAIDs) in cancer prevention and cancer promotion. Adv. Pharmacol. Sci., 2019, 2019, 3418975.Ruder, E.H.; Laiyemo, A.O.; Graubard, B.I.; Hollenbeck, A.R.; Schatzkin, A.; Cross, A.J. Non-steroidal anti-inflammatory drugs and colorectal cancer risk in a large, prospective cohort. Am. J. Gastroenterol., 2011, 106(7), 1340-1350. doi: 10.1038/ajg.2011.38 PMID: 21407185Trabert, B.; Ness, R.B.; Lo-Ciganic, W.H.; Murphy, M.A.; Goode, E.L.; Poole, E.M.; Brinton, L.A.; Webb, P.M.; Nagle, C.M.; Jordan, S.J.; Risch, H.A.; Rossing, M.A.; Doherty, J.A.; Goodman, M.T.; Lurie, G.; Kjaer, S.K.; Hogdall, E.; Jensen, A.; Cramer, D.W.; Terry, K.L.; Vitonis, A.; Bandera, E.V.; Olson, S.; King, M.G.; Chandran, U.; Anton-Culver, H.; Ziogas, A.; Menon, U.; Gayther, S.A.; Ramus, S.J.; Gentry-Maharaj, A.; Wu, A.H.; Pearce, C.L.; Pike, M.C.; Berchuck, A.; Schildkraut, J.M.; Wentzensen, N. Aspirin, nonaspirin nonsteroidal anti-inflammatory drug, and acetaminophen use and risk of invasive epithelial ovarian cancer: A pooled analysis in the Ovarian Cancer Association Consortium. J. Natl. Cancer Inst., 2014, 106(2), djt431. doi: 10.1093/jnci/djt431 PMID: 24503200Dierssen-Sotos, T.; Gómez-Acebo, I.; de Pedro, M.; Pérez-Gómez, B.; Servitja, S.; Moreno, V.; Amiano, P.; Fernandez-Villa, T.; Barricarte, A.; Tardon, A.; Diaz-Santos, M.; Peiro-Perez, R.; Marcos-Gragera, R.; Lope, V.; Gracia-Lavedan, E.; Alonso, M.H.; Michelena-Echeveste, M.J.; Garcia-Palomo, A.; Guevara, M.; Castaño-Vinyals, G.; Aragonés, N.; Kogevinas, M.; Pollán, M.; Llorca, J. Use of non-steroidal anti-inflammatory drugs and risk of breast cancer: The spanish multi-case-control (mcc) study. BMC Cancer, 2016, 16(1), 660. doi: 10.1186/s12885-016-2692-4 PMID: 27542890Doat, S.; Cénée, S.; Trétarre, B.; Rebillard, X.; Lamy, P.J.; Bringer, J.P.; Iborra, F.; Murez, T.; Sanchez, M.; Menegaux, F. Nonsteroidal anti‐inflammatory drugs (NSAIDs) and prostate cancer risk: Results from the EPICAP study. Cancer Med., 2017, 6(10), 2461-2470. doi: 10.1002/cam4.1186 PMID: 28941222Reddy, B.S.; Hirose, Y.; Lubet, R.; Steele, V.; Kelloff, G.; Paulson, S.; Seibert, K.; Rao, C.V. Chemoprevention of colon cancer by specific cyclooxygenase-2 inhibitor, celecoxib, administered during different stages of carcinogenesis. Cancer Res., 2000, 60(2), 293-297. PMID: 10667579Rao, C.V.; Rivenson, A.; Simi, B.; Zang, E.; Kelloff, G.; Steele, V.; Reddy, B.S. Chemoprevention of colon carcinogenesis by sulindac, a nonsteroidal anti-inflammatory agent. Cancer Res., 1995, 55(7), 1464-1472. PMID: 7882354Amitay, E.L.; Carr, P.R.; Jansen, L.; Walter, V.; Roth, W.; Herpel, E.; Kloor, M.; Bläker, H.; Chang-Claude, J.; Brenner, H.; Hoffmeister, M. Association of aspirin and nonsteroidal anti-inflammatory drugs with colorectal cancer risk by molecular subtypes. J. Natl. Cancer Inst., 2019, 111(5), 475-483. doi: 10.1093/jnci/djy170 PMID: 30388256Rao, C.; Reddy, B. NSAIDs and chemoprevention. Curr. Cancer Drug Targets, 2004, 4(1), 29-42. doi: 10.2174/1568009043481632 PMID: 14965265Jana, N.R. NSAIDs and apoptosis. Cell. Mol. Life Sci., 2008, 65(9), 1295-1301. doi: 10.1007/s00018-008-7511-x PMID: 18292966Tsioulias, G.J.; Go, M.F.; Rigas, B. NSAIDs and colorectal cancer control: Promise and challenges. Curr. Pharmacol. Rep., 2015, 1(5), 295-301. doi: 10.1007/s40495-015-0042-x PMID: 26688785Lai, H.; Liu, Y.; Wu, J.; Cai, J.; Jie, H.; Xu, Y.; Deng, S. Targeting cancer-related inflammation with non-steroidal anti-inflammatory drugs: Perspectives in pharmacogenomics. Front. Pharmacol., 2022, 13, 1078766. doi: 10.3389/fphar.2022.1078766 PMID: 36545311Sheng, J.; Sun, H.; Yu, F.B.; Li, B.; Zhang, Y.; Zhu, Y.T. The role of cyclooxygenase-2 in colorectal cancer. Int. J. Med. Sci., 2020, 17(8), 1095-1101. doi: 10.7150/ijms.44439 PMID: 32410839Adnan, M.; Mohammad, K.I.; Hossain Manik, M.E. Anticancer agents in combination with statins. J. Bioequivalence Bioavailab., 2017, 9(4), 463-466. doi: 10.4172/jbb.1000345Zhang, Z.; Chen, F.; Shang, L. Advances in antitumor effects of NSAIDs. Cancer Manag. Res., 2018, 10, 4631-4640. doi: 10.2147/CMAR.S175212 PMID: 30410398Tougeron, D.; Sha, D.; Manthravadi, S.; Sinicrope, F.A. Aspirin and colorectal cancer: Back to the future. Clin. Cancer Res., 2014, 20(5), 1087-1094. doi: 10.1158/1078-0432.CCR-13-2563 PMID: 24327271Willoughby, D.A.; Moore, A.R.; Colville-Nash, P.R. COX-1, COX-2, and COX-3 and the future treatment of chronic inflammatory disease. Lancet, 2000, 355(9204), 646-648. doi: 10.1016/S0140-6736(99)12031-2 PMID: 10696997Ogino, S.; Kirkner, G.J.; Nosho, K.; Irahara, N.; Kure, S.; Shima, K.; Hazra, A.; Chan, A.T.; Dehari, R.; Giovannucci, E.L.; Fuchs, C.S. Cyclooxygenase-2 expression is an independent predictor of poor prognosis in colon cancer. Clin. Cancer Res., 2008, 14(24), 8221-8227. doi: 10.1158/1078-0432.CCR-08-1841 PMID: 19088039Herbert, K.; Kerr, R.; Kerr, D.J.; Church, D.N. Are NSAIDs coming back to colorectal cancer therapy or not? Curr. Colorectal Cancer Rep., 2014, 10(4), 363-371. doi: 10.1007/s11888-014-0247-0Kurumbail, R.; Kiefer, J.R.; Marnett, L.J. Cyclooxygenase enzymes: Catalysis and inhibition. Curr. Opin. Struct. Biol., 2001, 11(6), 752-760. doi: 10.1016/S0959-440X(01)00277-9 PMID: 11751058Gurpinar, E.; Grizzle, W.E.; Piazza, G.A. NSAIDs inhibit tumorigenesis, but how? Clin. Cancer Res., 2014, 20(5), 1104-1113. doi: 10.1158/1078-0432.CCR-13-1573 PMID: 24311630Berg, J.; Christoph, T.; Widerna, M.; Bodenteich, A. Isoenzyme-specific cyclooxygenase inhibitors: A whole cell assay system using the human erythroleukemic cell line HEL and the human monocytic cell line Mono Mac 6. J. Pharmacol. Toxicol. Methods, 1997, 37(4), 179-186. doi: 10.1016/S1056-8719(97)00016-6 PMID: 9279772Blobaum, A.L.; Marnett, L.J. Structural and functional basis of cyclooxygenase inhibition. J. Med. Chem., 2007, 50(7), 1425-1441. doi: 10.1021/jm0613166 PMID: 17341061Fosslien, E. Biochemistry of cyclooxygenase (COX)-2 inhibitors and molecular pathology of COX-2 in neoplasia. Crit. Rev. Clin. Lab. Sci., 2000, 37(5), 431-502. doi: 10.1080/10408360091174286 PMID: 11078056Gonzalez-Angulo, A.M.; Fuloria, J.; Prakash, O. Cyclooxygenase 2 inhibitors and colon cancer. Ochsner J., 2002, 4(3), 176-179. PMID: 22822342Fearon, E.R. Molecular genetics of colorectal cancer. Annu. Rev. Pathol., 2011, 6(1), 479-507. doi: 10.1146/annurev-pathol-011110-130235 PMID: 21090969Maier, T.J.; Janssen, A.; Schmidt, R.; Geisslinger, G.; Grösch, S. Targeting the beta‐catenin/APC pathway: a novel mechanism to explain the cyclooxygenase‐2‐independent anticarcinogenic effects of celecoxib in human colon carcinoma cells. FASEB J., 2005, 19(10), 1353-1355. doi: 10.1096/fj.04-3274fje PMID: 15946992Deng, L.; Hu, S.; Baydoun, A.R.; Chen, J.; Chen, X.; Cong, X. Aspirin induces apoptosis in mesenchymal stem cells requiring Wnt/β‐catenin pathway. Cell Prolif., 2009, 42(6), 721-730. doi: 10.1111/j.1365-2184.2009.00639.x PMID: 19706045Qiu, W.; Wang, X.; Leibowitz, B.; Liu, H.; Barker, N.; Okada, H.; Oue, N.; Yasui, W.; Clevers, H.; Schoen, R.E.; Yu, J.; Zhang, L. Chemoprevention by nonsteroidal anti-inflammatory drugs eliminates oncogenic intestinal stem cells via SMAC-dependent apoptosis. Proc. Natl. Acad. Sci. USA, 2010, 107(46), 20027-20032. doi: 10.1073/pnas.1010430107 PMID: 21041628Tinsley, H.N.; Gary, B.D.; Thaiparambil, J.; Li, N.; Lu, W.; Li, Y.; Maxuitenko, Y.Y.; Keeton, A.B.; Piazza, G.A. Colon tumor cell growth-inhibitory activity of sulindac sulfide and other nonsteroidal anti-inflammatory drugs is associated with phosphodiesterase 5 inhibition. Cancer Prev. Res., 2010, 3(10), 1303-1313. doi: 10.1158/1940-6207.CAPR-10-0030 PMID: 20876730Rice, P.L.; Kelloff, J.; Sullivan, H.; Driggers, L.J.; Beard, K.S.; Kuwada, S.; Piazza, G.; Ahnen, D.J. Sulindac metabolites induce caspase- and proteasome-dependent degradation of β-catenin protein in human colon cancer cells. Mol. Cancer Ther., 2003, 2(9), 885-892. PMID: 14555707Thompson, W.J.; Piazza, G.A.; Li, H.; Liu, L.; Fetter, J.; Zhu, B.; Sperl, G.; Ahnen, D.; Pamukcu, R. Exisulind induction of apoptosis involves guanosine 3′,5′-cyclic monophosphate phosphodiesterase inhibition, protein kinase G activation, and attenuated β-catenin. Cancer Res., 2000, 60(13), 3338-3342. PMID: 10910034He, T.C.; Chan, T.A.; Vogelstein, B.; Kinzler, K.W. PPAR delta is an APC-regulated target of nonsteroidal anti-inflammatory drugs. Cell, 1999, 99(3), 335-345. doi: 10.1016/S0092-8674(00)81664-5 PMID: 10555149Greenspan, E.J.; Madigan, J.P.; Boardman, L.A.; Rosenberg, D.W. Ibuprofen inhibits activation of nuclear β-catenin in human colon adenomas and induces the phosphorylation of GSK-3β. Cancer Prev. Res., 2011, 4(1), 161-171. doi: 10.1158/1940-6207.CAPR-10-0021 PMID: 21205744Hoskin, A.J.; Holt, A.K.; Legge, D.N.; Collard, T.J.; Williams, A.C.; Vincent, E.E. Aspirin and the metabolic hallmark of cancer: Novel therapeutic opportunities for colorectal cancer. Explor. Target. Antitumor Ther., 2023, 4(4), 600-615. doi: 10.37349/etat.2023.00155 PMID: 37720350Hawcroft, G.; D’Amico, M.; Albanese, C.; Markham, A.F.; Pestell, R.G.; Hull, M.A. Indomethacin induces differential expression of β-catenin, γ-catenin and T-cell factor target genes in human colorectal cancer cells. Carcinogenesis, 2002, 23(1), 107-114. doi: 10.1093/carcin/23.1.107 PMID: 11756231Holmes-McNary, M. Nuclear factor kappa B signaling in catabolic disorders. Curr. Opin. Clin. Nutr. Metab. Care, 2002, 5(3), 255-263. doi: 10.1097/00075197-200205000-00004 PMID: 11953650Sakamoto, K.; Maeda, S.; Hikiba, Y.; Nakagawa, H.; Hayakawa, Y.; Shibata, W.; Yanai, A.; Ogura, K.; Omata, M. Constitutive NF-kappaB activation in colorectal carcinoma plays a key role in angiogenesis, promoting tumor growth. Clin. Cancer Res., 2009, 15(7), 2248-2258. doi: 10.1158/1078-0432.CCR-08-1383 PMID: 19276252Kopp, E.; Ghosh, S. Inhibition of NF-kappa B by sodium salicylate and aspirin. Science, 1994, 265(5174), 956-959. doi: 10.1126/science.8052854 PMID: 8052854Din, F.V.N.; Stark, L.A.; Dunlop, M.G. Aspirin-induced nuclear translocation of NFκB and apoptosis in colorectal cancer is independent of p53 status and DNA mismatch repair proficiency. Br. J. Cancer, 2005, 92(6), 1137-1143. doi: 10.1038/sj.bjc.6602455 PMID: 15770215Ouyang, N.; Ji, P.; Williams, J.L. A novel NSAID derivative, phospho-ibuprofen, prevents AOM-induced colon cancer in rats. Int. J. Oncol., 2013, 42(2), 643-650. doi: 10.3892/ijo.2012.1756 PMID: 23291777Schrör, K. Pharmacology and cellular/molecular mechanisms of action of aspirin and Non-aspirin NSAIDs in colorectal cancer. Best Pract. Res. Clin. Gastroenterol., 2011, 25(4-5), 473-484. doi: 10.1016/j.bpg.2011.10.016 PMID: 22122764Stark, L.A.; Din, F.V.N.; Zwacka, R.M.; Dunlop, M.G. Aspirin‐induced activation of the NF‐κB signaling pathway: A novel mechanism for aspirin‐mediated apoptosis in colon cancer cells. FASEB J., 2001, 15(7), 1273-1275. doi: 10.1096/fj.00-0529fje PMID: 11344111Brady, R.R.W.; Loveridge, C.J.; Dunlop, M.G.; Stark, L.A. c-Src dependency of NSAID-induced effects on NF- B-mediated apoptosis in colorectal cancer cells. Carcinogenesis, 2011, 32(7), 1069-1077. doi: 10.1093/carcin/bgr077 PMID: 21551129Cho, M.; Gwak, J.; Park, S.; Won, J.; Kim, D.E.; Yea, S.S.; Cha, I.J.; Kim, T.K.; Shin, J.G.; Oh, S. Diclofenac attenuates Wnt/β‐catenin signaling in colon cancer cells by activation of NF‐κB. FEBS Lett., 2005, 579(20), 4213-4218. doi: 10.1016/j.febslet.2005.06.049 PMID: 16051228Chen, J.; Stark, L. Aspirin prevention of colorectal cancer: focus on NF-κB signalling and the nucleolus. Biomedicines, 2017, 5(3), 43. doi: 10.3390/biomedicines5030043 PMID: 28718829Qi, M.; Elion, E.A. MAP kinase pathways. J. Cell Sci., 2005, 118(16), 3569-3572. doi: 10.1242/jcs.02470 PMID: 16105880Slattery, M.L.; Lundgreen, A.; Wolff, R.K. MAP kinase genes and colon and rectal cancer. Carcinogenesis, 2012, 33(12), 2398-2408. doi: 10.1093/carcin/bgs305 PMID: 23027623Saletti, P.; Molinari, F.; De Dosso, S.; Frattini, M. EGFR signaling in colorectal cancer: A clinical perspective. Gastrointest. Cancer, 2015, 5, 21-38.Arisan, E.D.; Ergül, Z.; Bozdağ, G.; Rencüzoğulları, Ö.; Çoker-Gürkan, A.; Obakan-Yerlikaya, P.; Coşkun, D.; Palavan-Ünsal, N. Diclofenac induced apoptosis via altering PI3K/Akt/MAPK signaling axis in HCT 116 more efficiently compared to SW480 colon cancer cells. Mol. Biol. Rep., 2018, 45(6), 2175-2184. doi: 10.1007/s11033-018-4378-2 PMID: 30406888Pan, 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. Cell. Signal., 2008, 20(6), 1134-1141. doi: 10.1016/j.cellsig.2008.02.004 PMID: 18374541Bagheri, M.; Tabatabae, F.M.A.; Mirzaei, H.; Ghasemi, F. Evaluation of antitumor effects of aspirin and LGK974 drugs on cellular signaling pathways, cell cycle and apoptosis in colorectal cancer cell lines compared to oxaliplatin drug. Fundam. Clin. Pharmacol., 2020, 34(1), 51-64. doi: 10.1111/fcp.12492 PMID: 31233627Elder, D.J.E.; Halton, D.E.; Playle, L.C.; Paraskeva, C. The MEK/ERK pathway mediates COX‐2‐selective NSAID‐induced apoptosis and induced COX‐2 protein expression in colorectal carcinoma cells. Int. J. Cancer, 2002, 99(3), 323-327. doi: 10.1002/ijc.10330 PMID: 11992399Kim, T.; Jin, S.; Kim, W.; Kang, E.; Choi, K.; Kim, H.; Shin, S.; Kang, J. Prolonged activation of mitogen-activated protein kinases during NSAID-induced apoptosis in HT-29 colon cancer cells. Int. J. Colorectal Dis., 2001, 16(3), 167-173. doi: 10.1007/s003840100301 PMID: 11459290Lee, E.; Park, H.; Kang, H. Sodium salicylate induces apoptosis in HCT116 colorectal cancer cells through activation of p38MAPK. Int. J. Oncol., 2003, 23(2), 503-508. doi: 10.3892/ijo.23.2.503 PMID: 12851702Lennon, A.M.; Ramauge, M.; Pierre, M. Role of redox status on the activation of mitogen-activated protein kinase cascades by NSAIDs. Biochem. Pharmacol., 2002, 63(2), 163-170. doi: 10.1016/S0006-2952(01)00826-7 PMID: 11841790Danielsen, S.A.; Eide, P.W.; Nesbakken, A.; Guren, T.; Leithe, E.; Lothe, R.A. Portrait of the PI3K/AKT pathway in colorectal cancer. Biochimica et biophysica acta (BBA)-. Rev. Can., 2015, 1855(1), 104-121.Yu, L.; Chen, Y.; Tooze, S.A. Autophagy pathway: Cellular and molecular mechanisms. Autophagy, 2018, 14(2), 207-215. doi: 10.1080/15548627.2017.1378838 PMID: 28933638Din, FV; Valanciute, A; Houde, VP; Zibrova, D; Green, KA Sakamoto, K Aspirin inhibits mTOR signaling, activates AMPactivated protein kinase, and induces autophagy in colorectal cancer cells. Gastroenterology, 2012, 142(7), 1504-1515. e3.Wang, X.W.; Zhang, Y-J. Targeting mTOR network in colorectal cancer therapy. World J. Gastroenterol., 2014, 20(15), 4178-4188. doi: 10.3748/wjg.v20.i15.4178 PMID: 24764656Chen, Z.; Wang, C.; Dong, H.; Wang, X.; Gao, F.; Zhang, S.; Zhang, X. Aspirin has a better effect on PIK3CA mutant colorectal cancer cells by PI3K/Akt/Raptor pathway. Mol. Med., 2020, 26(1), 14. doi: 10.1186/s10020-020-0139-5 PMID: 32000660Grancher, A.; Michel, P.; Di Fiore, F.; Sefrioui, D. Colorectal cancer chemoprevention: Is aspirin still in the game? Cancer Biol. Ther., 2022, 23(1), 446-461. doi: 10.1080/15384047.2022.2104561 PMID: 35905195Hall, D.C.N.; Benndorf, R.A. Aspirin sensitivity of PIK3CA-mutated colorectal cancer: Potential mechanisms revisited. Cell. Mol. Life Sci., 2022, 79(7), 393. doi: 10.1007/s00018-022-04430-y PMID: 35780223Zumwalt, T.J.; Wodarz, D.; Komarova, N.L.; Toden, S.; Turner, J.; Cardenas, J.; Burn, J.; Chan, A.T.; Boland, C.R.; Goel, A. Aspirin-induced chemoprevention and response kinetics are enhanced by PIK3CA mutations in colorectal cancer cells. Cancer Prev. Res., 2017, 10(3), 208-218. doi: 10.1158/1940-6207.CAPR-16-0175 PMID: 28154202Coyle, C.; Cafferty, F.H.; Langley, R.E. Aspirin and colorectal cancer prevention and treatment: is it for everyone? Curr. Colorectal Cancer Rep., 2016, 12(1), 27-34. doi: 10.1007/s11888-016-0306-9 PMID: 27069437Ogino, S.; Lochhead, P.; Giovannucci, E.; Meyerhardt, J.A.; Fuchs, C.S.; Chan, A.T. Discovery of colorectal cancer PIK3CA mutation as potential predictive biomarker: Power and promise of molecular pathological epidemiology. Oncogene, 2014, 33(23), 2949-2955. doi: 10.1038/onc.2013.244 PMID: 23792451Domingo, E.; Church, D.N.; Sieber, O.; Ramamoorthy, R.; Yanagisawa, Y.; Johnstone, E.; Davidson, B.; Kerr, D.J.; Tomlinson, I.P.M.; Midgley, R. Evaluation of PIK3CA mutation as a predictor of benefit from nonsteroidal anti-inflammatory drug therapy in colorectal cancer. J. Clin. Oncol., 2013, 31(34), 4297-4305. doi: 10.1200/JCO.2013.50.0322 PMID: 24062397Fujishita, T.; Aoki, K.; Lane, H.A.; Aoki, M.; Taketo, M.M. Inhibition of the mTORC1 pathway suppresses intestinal polyp formation and reduces mortality in ApcΔ716 mice. Proc. Natl. Acad. Sci. USA, 2008, 105(36), 13544-13549. doi: 10.1073/pnas.0800041105 PMID: 18768809Zhou, H.; Liu, W.; Su, Y.; Wei, Z.; Liu, J.; Kolluri, S.K.; Wu, H.; Cao, Y.; Chen, J.; Wu, Y.; Yan, T.; Cao, X.; Gao, W.; Molotkov, A.; Jiang, F.; Li, W.G.; Lin, B.; Zhang, H.P.; Yu, J.; Luo, S.P.; Zeng, J.Z.; Duester, G.; Huang, P.Q.; Zhang, X.K. NSAID sulindac and its analog bind RXRalpha and inhibit RXRalpha-dependent AKT signaling. Cancer Cell, 2010, 17(6), 560-573. doi: 10.1016/j.ccr.2010.04.023 PMID: 20541701Ricchi, P.; Zarrilli, R.; di Palma, A.; Acquaviva, A.M. Nonsteroidal anti-inflammatory drugs in colorectal cancer: from prevention to therapy. Br. J. Cancer, 2003, 88(6), 803-807. doi: 10.1038/sj.bjc.6600829 PMID: 12644813Mohammed, A.; Yarla, N.S.; Madka, V.; Rao, C.V. Clinically relevant anti-inflammatory agents for chemoprevention of colorectal cancer: New perspectives. Int. J. Mol. Sci., 2018, 19(8), 2332. doi: 10.3390/ijms19082332 PMID: 30096840Zhou, P.; Cheng, S.W.; Yang, R.; Wang, B.; Liu, J. Combination chemoprevention. Eur. J. Cancer Prev., 2012, 21(3), 231-240. doi: 10.1097/CEJ.0b013e32834dbbfd PMID: 22456425Bahrami, A.; Parsamanesh, N.; Atkin, S.L.; Banach, M.; Sahebkar, A. Effect of statins on toll-like receptors: A new insight to pleiotropic effects. Pharmacol. Res., 2018, 135, 230-238. doi: 10.1016/j.phrs.2018.08.014 PMID: 30120976Bland, A.R.; Payne, F.M.; Ashton, J.C.; Jamialahmadi, T.; Sahebkar, A. The cardioprotective actions of statins in targeting mitochondrial dysfunction associated with myocardial ischaemia-reperfusion injury. Pharmacol. Res., 2022, 175, 105986. doi: 10.1016/j.phrs.2021.105986 PMID: 34800627Bytyçi, I.; Penson, P.E.; Mikhailidis, D.P.; Wong, N.D.; Hernandez, A.V.; Sahebkar, A.; Thompson, P.D.; Mazidi, M.; Rysz, J.; Pella, D.; Reiner, Ž.; Toth, P.P.; Banach, M. Prevalence of statin intolerance: A meta-analysis. Eur. Heart J., 2022, 43(34), 3213-3223. doi: 10.1093/eurheartj/ehac015 PMID: 35169843Chruściel, P.; Sahebkar, A.; Rembek-Wieliczko, M.; Serban, M.C.; Ursoniu, S.; Mikhailidis, D.P.; Jones, S.R.; Mosteoru, S.; Blaha, M.J.; Martin, S.S.; Rysz, J.; Toth, P.P.; Lip, G.Y.H.; Pencina, M.J.; Ray, K.K.; Banach, M. Impact of statin therapy on plasma adiponectin concentrations: A systematic review and meta-analysis of 43 randomized controlled trial arms. Atherosclerosis, 2016, 253, 194-208. doi: 10.1016/j.atherosclerosis.2016.07.897 PMID: 27498397Ferretti, G.; Bacchetti, T.; Sahebkar, A. Effect of statin therapy on paraoxonase-1 status: A systematic review and meta-analysis of 25 clinical trials. Prog. Lipid Res., 2015, 60, 50-73. doi: 10.1016/j.plipres.2015.08.003 PMID: 26416579Kandelouei, T.; Abbasifard, M.; Imani, D.; Aslani, S.; Razi, B.; Fasihi, M. Effect of statins on serum level of hs-CRP and CRP in patients with cardiovascular diseases: A systematic review and meta-analysis of randomized controlled trials. Mediators Inflamm., 2022, 2022, 8732360. doi: 10.1155/2022/8732360Koushki, K.; Shahbaz, S.K.; Mashayekhi, K.; Sadeghi, M.; Zayeri, Z.D.; Taba, M.Y.; Banach, M.; Al-Rasadi, K.; Johnston, T.P.; Sahebkar, A. Anti-inflammatory action of statins in cardiovascular disease: The role of inflammasome and toll-like receptor pathways. Clin. Rev. Allergy Immunol., 2021, 60(2), 175-199. doi: 10.1007/s12016-020-08791-9 PMID: 32378144Mollazadeh, H.; Tavana, E.; Fanni, G.; Bo, S.; Banach, M.; Pirro, M.; von Haehling, S.; Jamialahmadi, T.; Sahebkar, A. Effects of statins on mitochondrial pathways. J. Cachexia Sarcopenia Muscle, 2021, 12(2), 237-251. doi: 10.1002/jcsm.12654 PMID: 33511728Sahebkar, A.; Chew, G.T.; Watts, G.F. Recent advances in pharmacotherapy for hypertriglyceridemia. Prog. Lipid Res., 2014, 56(1), 47-66. doi: 10.1016/j.plipres.2014.07.002 PMID: 25083925Serban, C.; Sahebkar, A.; Ursoniu, S.; Mikhailidis, D.P.; Rizzo, M.; Lip, G.Y.H.; Kees Hovingh, G.; Kastelein, J.J.P.; Kalinowski, L.; Rysz, J.; Banach, M. A systematic review and meta-analysis of the effect of statins on plasma asymmetric dimethylarginine concentrations. Sci. Rep., 2015, 5(1), 9902. doi: 10.1038/srep09902 PMID: 25970700Sohrevardi, S.; Nasab, F.; Mirjalili, M.; Bagherniya, M.; Tafti, A.; Jarrahzadeh, M.; Azarpazhooh, M.; Saeidmanesh, M.; Banach, M.; Jamialahmadi, T.; Sahebkar, A. Effect of atorvastatin on delirium status of patients in the intensive care unit: A randomized controlled trial. Arch. Med. Sci., 2019, 17(5), 1423-1428. doi: 10.5114/aoms.2019.89330 PMID: 34522273Vahedian-Azimi, A.; Mohammadi, S.M.; Banach, M.; Beni, F.H.; Guest, P.C.; Al-Rasadi, K. Improved COVID-19 outcomes following statin therapy: An updated systematic review and meta-analysis. BioMed Res. Int., 2021, 2021, 1901772.Seliger, C.; Schaertl, J.; Gerken, M.; Luber, C.; Proescholdt, M.; Riemenschneider, M.J.; Leitzmann, M.F.; Hau, P.; Klinkhammer-Schalke, M. Use of statins or NSAIDs and survival of patients with high-grade glioma. PLoS One, 2018, 13(12), e0207858. doi: 10.1371/journal.pone.0207858 PMID: 30507932Suh, N.; Reddy, B.S.; DeCastro, A.; Paul, S.; Lee, H.J.; Smolarek, A.K.; So, J.Y.; Simi, B.; Wang, C.X.; Janakiram, N.B.; Steele, V.; Rao, C.V. Combination of atorvastatin with sulindac or naproxen profoundly inhibits colonic adenocarcinomas by suppressing the p65/β-catenin/cyclin D1 signaling pathway in rats. Cancer Prev. Res., 2011, 4(11), 1895-1902. doi: 10.1158/1940-6207.CAPR-11-0222 PMID: 21764859Reddy, B.S.; Wang, C.X.; Kong, A.N.; Khor, T.O.; Zheng, X.; Steele, V.E.; Kopelovich, L.; Rao, C.V. Prevention of azoxymethane-induced colon cancer by combination of low doses of atorvastatin, aspirin, and celecoxib in F 344 rats. Cancer Res., 2006, 66(8), 4542-4546. doi: 10.1158/0008-5472.CAN-05-4428 PMID: 16618783Chang, W.C.L.; Jackson, C.; Riel, S.; Cooper, H.S.; Devarajan, K.; Hensley, H.H.; Zhou, Y.; Vanderveer, L.A.; Nguyen, M.T.; Clapper, M.L. Differential preventive activity of sulindac and atorvastatin in Apc +/Min-FCCC mice with or without colorectal adenomas. Gut, 2018, 67(7), 1290-1298. doi: 10.1136/gutjnl-2017-313942 PMID: 29122850Xiao, H.; Zhang, Q.; Lin, Y.; Reddy, B.S.; Yang, C.S. Combination of atorvastatin and celecoxib synergistically induces cell cycle arrest and apoptosis in colon cancer cells. Int. J. Cancer, 2008, 122(9), 2115-2124. doi: 10.1002/ijc.23315 PMID: 18172863Swamy, M.; Cooma, I.; Reddy, B.; Rao, C. Lamin B, caspase-3 activity, and apoptosis induction by a combination of HMG-CoA reductase inhibitor and COX-2 inhibitors: A novel approach in developing effective chemopreventive regimens. Int. J. Oncol., 2002, 20(4), 753-759. doi: 10.3892/ijo.20.4.753 PMID: 11894121Agarwal, B.; Halmos, B.; Feoktistov, A.S.; Protiva, P.; Ramey, W.G.; Chen, M.; Pothoulakis, C.; Lamont, J.T.; Holt, P.R. Mechanism of lovastatin-induced apoptosis in intestinal epithelial cells. Carcinogenesis, 2002, 23(3), 521-528. doi: 10.1093/carcin/23.3.521 PMID: 11895868Hoffmeister, M.; Chang-Claude, J.; Brenner, H. Individual and joint use of statins and low‐dose aspirin and risk of colorectal cancer: A population‐based case–control study. Int. J. Cancer, 2007, 121(6), 1325-1330. doi: 10.1002/ijc.22796 PMID: 17487832Alexiou, G.A.; Lianos, G.D.; Ragos, V.; Galani, V.; Kyritsis, A.P. Difluoromethylornithine in cancer: New advances. Future Oncol., 2017, 13(9), 809-819. doi: 10.2217/fon-2016-0266 PMID: 28125906Raj, K.P.; Zell, J.A.; Rock, C.L.; McLaren, C.E.; Zoumas-Morse, C.; Gerner, E.W.; Meyskens, F.L. Role of dietary polyamines in a phase III clinical trial of difluoromethylornithine (DFMO) and sulindac for prevention of sporadic colorectal adenomas. Br. J. Cancer, 2013, 108(3), 512-518. doi: 10.1038/bjc.2013.15 PMID: 23340449Meyskens, F.L., Jr; McLaren, C.E.; Pelot, D.; Fujikawa-Brooks, S.; Carpenter, P.M.; Hawk, E.; Kelloff, G.; Lawson, M.J.; Kidao, J.; McCracken, J.; Albers, C.G.; Ahnen, D.J.; Turgeon, D.K.; Goldschmid, S.; Lance, P.; Hagedorn, C.H.; Gillen, D.L.; Gerner, E.W. Difluoromethylornithine plus sulindac for the prevention of sporadic colorectal adenomas: A randomized placebo-controlled, double-blind trial. Cancer Prev. Res., 2008, 1(1), 32-38. doi: 10.1158/1940-6207.CAPR-08-0042 PMID: 18841250Thompson, PA; Wertheim, BC; Zell, JA; Chen, W-P; McLaren, CE; LaFleur, BJ Levels of rectal mucosal polyamines and prostaglandin E2 predict ability of DFMO and sulindac to prevent colorectal adenoma Gastroenterology, 2010, 139(3), 797-805. e1. doi: 10.1053/j.gastro.2010.06.005Ignatenko, N.A.; Besselsen, D.G.; Stringer, D.E.; Blohm-Mangone, K.A.; Cui, H.; Gerner, E.W. Combination chemoprevention of intestinal carcinogenesis in a murine model of familial adenomatous polyposis. Nutr. Cancer, 2008, 60(Suppl. 1), 30-35. doi: 10.1080/01635580802401317 PMID: 19003578Mackenzie, G.G.; Ouyang, N.; Xie, G.; Vrankova, K.; Huang, L.; Sun, Y.; Komninou, D.; Kopelovich, L.; Rigas, B. Phospho-sulindac (OXT-328) combined with difluoromethylornithine prevents colon cancer in mice. Cancer Prev. Res., 2011, 4(7), 1052-1060. doi: 10.1158/1940-6207.CAPR-11-0067 PMID: 21464038Jacoby, R.F.; Cole, C.E.; Tutsch, K.; Newton, M.A.; Kelloff, G.; Hawk, E.T.; Lubet, R.A. Chemopreventive efficacy of combined piroxicam and difluoromethylornithine treatment of Apc mutant Min mouse adenomas, and selective toxicity against Apc mutant embryos. Cancer Res., 2000, 60(7), 1864-1870. PMID: 10766173Kemp Bohan, P.M.; Mankaney, G.; Vreeland, T.J.; Chick, R.C.; Hale, D.F.; Cindass, J.L.; Hickerson, A.T.; Ensley, D.C.; Sohn, V.; Clifton, G.T.; Peoples, G.E.; Burke, C.A. Chemoprevention in familial adenomatous polyposis: Past, present and future. Fam. Cancer, 2021, 20(1), 23-33. doi: 10.1007/s10689-020-00189-y PMID: 32507936Burke, C.A.; Dekker, E.; Samadder, N.J.; Stoffel, E.; Cohen, A. Efficacy and safety of eflornithine (CPP-1X)/sulindac combination therapy versus each as monotherapy in patients with familial adenomatous polyposis (FAP): Design and rationale of a randomized, double-blind, Phase III trial. BMC Gastroenterol., 2016, 16(1), 87. doi: 10.1186/s12876-016-0494-4 PMID: 27480131Petrera, M.; Paleari, L.; Puntoni, M.; Caviglia, S.; Clavarezza, M.; Romagnolli, P. ASAMET: A randomized, 2x2 biomarker prevention trial of low-dose aspirin and metformin in colorectal cancer. J. Clin. Oncol., 2017, 35(15)Palazzolo, G.; Mollica, H.; Lusi, V.; Rutigliani, M.; Di Francesco, M.; Pereira, R.C.; Filauro, M.; Paleari, L.; DeCensi, A.; Decuzzi, P. Modulating the distant spreading of patient-derived colorectal cancer cells via aspirin and metformin. Transl. Oncol., 2020, 13(4), 100760. doi: 10.1016/j.tranon.2020.100760 PMID: 32247264De Monte, A.; Brunetti, D.; Cattin, L.; Lavanda, F.; Naibo, E.; Malagoli, M.; Stanta, G.; Bonin, S. Metformin and aspirin treatment could lead to an improved survival rate for Type 2 diabetic patients with stage II and III colorectal adenocarcinoma relative to non-diabetic patients. Mol. Clin. Oncol., 2018, 8(3), 504-512. doi: 10.3892/mco.2018.1554 PMID: 29456855Xu, K.; Shu, H.K.G. Transcription factor interactions mediate EGF-dependent COX-2 expression. Mol. Cancer Res., 2013, 11(8), 875-886. doi: 10.1158/1541-7786.MCR-12-0706 PMID: 23635401Torrance, C.J.; Jackson, P.E.; Montgomery, E.; Kinzler, K.W.; Vogelstein, B.; Wissner, A.; Nunes, M.; Frost, P.; Discafani, C.M. Combinatorial chemoprevention of intestinal neoplasia. Nat. Med., 2000, 6(9), 1024-1028. doi: 10.1038/79534 PMID: 10973323Buchanan, F.G.; Holla, V.; Katkuri, S.; Matta, P.; DuBois, R.N. Targeting cyclooxygenase-2 and the epidermal growth factor receptor for the prevention and treatment of intestinal cancer. Cancer Res., 2007, 67(19), 9380-9388. doi: 10.1158/0008-5472.CAN-07-0710 PMID: 17909047Samadder, N.J.; Kuwada, S.K.; Boucher, K.M.; Byrne, K.; Kanth, P.; Samowitz, W.; Jones, D.; Tavtigian, S.V.; Westover, M.; Berry, T.; Jasperson, K.; Pappas, L.; Smith, L.; Sample, D.; Burt, R.W.; Neklason, D.W. Association of sulindac and erlotinib vs placebo with colorectal neoplasia in familial adenomatous polyposis: Secondary analysis of a randomized clinical trial. JAMA Oncol., 2018, 4(5), 671-677. doi: 10.1001/jamaoncol.2017.5431 PMID: 29423501Tortora, G.; Caputo, R.; Damiano, V.; Melisi, D.; Bianco, R.; Fontanini, G.; Veneziani, B.M.; De Placido, S.; Bianco, A.R.; Ciardiello, F. Combination of a selective cyclooxygenase-2 inhibitor with epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 and protein kinase A antisense causes cooperative antitumor and antiangiogenic effect. Clin. Cancer Res., 2003, 9(4), 1566-1572. PMID: 12684433Tuccillo, C.; Romano, M.; Troiani, T.; Martinelli, E.; Morgillo, F.; De Vita, F.; Bianco, R.; Fontanini, G.; Bianco, R.A.; Tortora, G.; Ciardiello, F. Antitumor activity of ZD6474, a vascular endothelial growth factor-2 and epidermal growth factor receptor small molecule tyrosine kinase inhibitor, in combination with SC-236, a cyclooxygenase-2 inhibitor. Clin. Cancer Res., 2005, 11(3), 1268-1276. doi: 10.1158/1078-0432.1268.11.3 PMID: 15709198Valverde, A.; Peñarando, J.; Cañas, A.; López-Sánchez, L.M.; Conde, F.; Guil-Luna, S.; Hernández, V.; Villar, C.; Morales-Estévez, C.; de la Haba-Rodríguez, J.; Aranda, E.; Rodríguez-Ariza, A. The addition of celecoxib improves the antitumor effect of cetuximab in colorectal cancer: Role of EGFR-RAS-FOXM1-β-catenin signaling axis. Oncotarget, 2017, 8(13), 21754-21769. doi: 10.18632/oncotarget.15567 PMID: 28423516Davis, J.S.; Kanikarla-Marie, P.; Gagea, M.; Yu, P.L.; Fang, D.; Sebastian, M.; Yang, P.; Hawk, E.; Dashwood, R.; Lichtenberger, L.M.; Menter, D.; Kopetz, S. Sulindac plus a phospholipid is effective for polyp reduction and safer than sulindac alone in a mouse model of colorectal cancer development. BMC Cancer, 2020, 20(1), 871. doi: 10.1186/s12885-020-07311-4 PMID: 32912193Al-Obaidi, Z.M.J.; Mousa, T.H. I; Ali, A.A., II Synthesis of novel ibuprofen-tranexamic acid codrug: Estimation of the clinical activity against hct116 colorectal carcinoma cell line and the determination of toxicity profile against mdck normal kidney cell line. Int. J. Drug Deliv. Techn., 2019, 9(2), 226-2350. doi: 10.25258/ijddt.9.2.18El‐Mahdy, N.A.; El‐Sayad, M.E.S.; El‐Kadem, A.H.; Abu‐Risha, S.E.S. Targeting IL‐10, ZO‐1 gene expression and IL‐6/STAT‐3 trans‐signaling by a combination of atorvastatin and mesalazine to enhance anti‐inflammatory effects and attenuates progression of oxazolone‐induced colitis. Fundam. Clin. Pharmacol., 2021, 35(1), 143-155. PMID: 32383169Ishikawa, H.; Mutoh, M.; Sato, Y.; Doyama, H.; Tajika, M.; Tanaka, S.; Horimatsu, T.; Takeuchi, Y.; Kashida, H.; Tashiro, J.; Ezoe, Y.; Nakajima, T.; Ikematsu, H.; Hori, S.; Suzuki, S.; Otani, T.; Takayama, T.; Ohda, Y.; Mure, K.; Wakabayashi, K.; Sakai, T. Chemoprevention with low-dose aspirin, mesalazine, or both in patients with familial adenomatous polyposis without previous colectomy (J-FAPP Study IV): A multicentre, double-blind, randomised, two-by-two factorial design trial. Lancet Gastroenterol. Hepatol., 2021, 6(6), 474-481. doi: 10.1016/S2468-1253(21)00018-2 PMID: 33812492Pennarun, B.; Kleibeuker, J.H.; Boersma-van Ek, W.; Hollema, H.; de Vries, E.G.; de Jong, S. Sorafenib plus aspirin promotes TRAIL-induced apoptosis by targeting FLIP and Mcl-1 and potentiates growth inhibition in colon cancer cells. In: Improving the response to molecular targeting of the TRAIL death receptors in colon cancer cells; , 2010; p. 153.Shpitz, B.; Giladi, N.; Sagiv, E.; Lev-Ari, S.; Liberman, E.; Kazanov, D.; Arber, N. Celecoxib and curcumin additively inhibit the growth of colorectal cancer in a rat model. Digestion, 2006, 74(3-4), 140-144. doi: 10.1159/000098655 PMID: 17228149Lerdwanangkun, P.; Wonganan, P.; Storer, R.J.; Limpanasithikul, W. Combined effects of celecoxib and cepharanthine on human colorectal cancer cells in vitro. J. Appl. Pharm. Sci., 2019, 9(4), 117-125. doi: 10.7324/JAPS.2019.90415Pence, B.C.; Belasco, E.J.; Lyford, C.P. Combination aspirin and/or calcium chemoprevention with colonoscopy in colorectal cancer prevention: cost-effectiveness analyses. Cancer Epidemiol. Biomarkers Prev., 2013, 22(3), 399-405. doi: 10.1158/1055-9965.EPI-12-0658 PMID: 23250933Pommergaard, H-C; Burcharth, J; Rosenberg, J; Raskov, H Aspirin, calcitriol, and calcium do not prevent adenoma recurrence in a randomized controlled trial. Gastroenterology, 2016, 150(1), 114-122. e4. doi: 10.1053/j.gastro.2015.09.010Ma, S.C.; Zhang, J.Q.; Yan, T.H.; Miao, M.X.; Cao, Y.M.; Cao, Y.B.; Zhang, L.C.; Li, L. Novel strategies to reverse chemoresistance in colorectal cancer. Cancer Med., 2023, 12(10), 11073-11096. doi: 10.1002/cam4.5594 PMID: 36645225Okda, T.; Abd-Elghaffar, S.; Katary, M.; Abd-αlhaseeb, M. Chemopreventive and anticancer activities of indomethacin and vitamin D combination on colorectal cancer induced by 1,2-dimethylhydrazine in rats. Biomed. Rep., 2020, 14(2), 27. doi: 10.3892/br.2020.1403 PMID: 33408861Gong, E.Y.; Shin, Y.J.; Hwang, I.Y.; Kim, J.H.; Kim, S.M.; Moon, J.H.; Shin, J.S.; Lee, D.H.; Hur, D.Y.; Jin, D.H.; Hong, S.W.; Lee, W.K.; Lee, W.J. Combined treatment with vitamin C and sulindac synergistically induces p53- and ROS-dependent apoptosis in human colon cancer cells. Toxicol. Lett., 2016, 258, 126-133. doi: 10.1016/j.toxlet.2016.06.019 PMID: 27339904Yang, Z.; Xiao, H.; Jin, H.; Koo, P.T.; Tsang, D.J.; Yang, C.S. Synergistic actions of atorvastatin with γ‐tocotrienol and celecoxib against human colon cancer HT29 and HCT116 cells. Int. J. Cancer, 2010, 126(4), 852-863. doi: 10.1002/ijc.24766 PMID: 19626588Swamy, M.V.; Patlolla, J.M.R.; Steele, V.E.; Kopelovich, L.; Reddy, B.S.; Rao, C.V. Chemoprevention of familial adenomatous polyposis by low doses of atorvastatin and celecoxib given individually and in combination to APCMin mice. Cancer Res., 2006, 66(14), 7370-7377. doi: 10.1158/0008-5472.CAN-05-4619 PMID: 16849589Guruswamy, S.; Rao, C.V. Synergistic effects of lovastatin and celecoxib on caveolin-1 and its down-stream signaling molecules: Implications for colon cancer prevention. Int. J. Oncol., 2009, 35(5), 1037-1043. PMID: 19787257Ulusan, A.M.; Rajendran, P.; Dashwood, W.M.; Yavuz, O.F.; Kapoor, S.; Gustafson, T.A.; Savage, M.I.; Brown, P.H.; Sei, S.; Mohammed, A.; Vilar, E.; Dashwood, R.H. Optimization of erlotinib plus sulindac dosing regimens for intestinal cancer prevention in an APC-mutant model of familial adenomatous polyposis (FAP). Cancer Prev. Res., 2021, 14(3), 325-336. doi: 10.1158/1940-6207.CAPR-20-0262 PMID: 33277315Rajendran, P.; Ulusan, A.; Dashwood, W.M.; Kapoor, S.; Mohammed, A.; Sei, S.; Rashid, A.; Brown, P.H.; Vilar-Sanchez, E.; Dashwood, R.H. Abstract 21: Optimization of dosing regimens of sulindac in combination with erlotinib for small intestine and colorectal cancer prevention. Cancer Res., 2020, 80(16), 21. doi: 10.1158/1538-7445.AM2020-21Sinicrope, F.A.; Penington, R.C. Sulindac sulfide–induced apoptosis is enhanced by a small-molecule Bcl-2 inhibitor and by TRAIL in human colon cancer cells overexpressing Bcl-2. Mol. Cancer Ther., 2005, 4(10), 1475-1483. doi: 10.1158/1535-7163.MCT-05-0137 PMID: 16227396Fu, J.; Xu, Y.; Yang, Y.; Liu, Y.; Ma, L.; Zhang, Y. Aspirin suppresses chemoresistance and enhances antitumor activity of 5-Fu in 5-Fu-resistant colorectal cancer by abolishing 5-Fu-induced NF-κB activation. Sci. Rep., 2019, 9(1), 16937. doi: 10.1038/s41598-019-53276-1 PMID: 31729451Holt, A.K.; Najumudeen, A.K.; Hoskin, A.J.; Legge, D.N.; Mortensson, E.M.; Flanagan, D.J. Aspirin reprogrammes colorectal cancer cell metabolism and sensitises to glutaminase inhibition. bioRxiv, 2022, 11(1), 18. doi: 10.1101/2022.08.24.505115Chudy-Onwugaje, K.; Huang, W.Y.; Su, L.J.; Purdue, M.P.; Johnson, C.C.; Wang, L.; Katki, H.A.; Barry, K.H.; Berndt, S.I. Aspirin, ibuprofen, and reduced risk of advanced colorectal adenoma incidence and recurrence and colorectal cancer in the PLCO cancer screening trial. Cancer, 2021, 127(17), 3145-3155. doi: 10.1002/cncr.33623 PMID: 33974712Shebl, F.M.; Hsing, A.W.; Park, Y.; Hollenbeck, A.R.; Chu, L.W.; Meyer, T.E.; Koshiol, J. Non-steroidal anti-inflammatory drugs use is associated with reduced risk of inflammation-associated cancers: NIH-AARP study. PLoS One, 2014, 9(12), e114633. doi: 10.1371/journal.pone.0114633 PMID: 25551641Murff, H.J.; Shrubsole, M.J.; Chen, Z.; Smalley, W.E.; Chen, H.; Shyr, Y.; Ness, R.M.; Zheng, W. Nonsteroidal anti-inflammatory drug use and risk of adenomatous and hyperplastic polyps. Cancer Prev. Res., 2011, 4(11), 1799-1807. doi: 10.1158/1940-6207.CAPR-11-0107 PMID: 21764857Lynch, P.M.; Burke, C.A.; Phillips, R.; Morris, J.S.; Slack, R.; Wang, X.; Liu, J.; Patterson, S.; Sinicrope, F.A.; Rodriguez-Bigas, M.A.; Half, E.; Bulow, S.; Latchford, A.; Clark, S.; Ross, W.A.; Malone, B.; Hasson, H.; Richmond, E.; Hawk, E. An international randomised trial of celecoxib versus celecoxib plus difluoromethylornithine in patients with familial adenomatous polyposis. Gut, 2016, 65(2), 286-295. doi: 10.1136/gutjnl-2014-307235 PMID: 25792707Bertagnolli, M.M.; Eagle, C.J.; Zauber, A.G.; Redston, M.; Breazna, A.; Kim, K.; Tang, J.; Rosenstein, R.B.; Umar, A.; Bagheri, D.; Collins, N.T.; Burn, J.; Chung, D.C.; Dewar, T.; Foley, T.R.; Hoffman, N.; Macrae, F.; Pruitt, R.E.; Saltzman, J.R.; Salzberg, B.; Sylwestrowicz, T.; Hawk, E.T. Five-year efficacy and safety analysis of the adenoma prevention with celecoxib trial. Cancer Prev. Res., 2009, 2(4), 310-321. doi: 10.1158/1940-6207.CAPR-08-0206 PMID: 19336730He, P.; Yang, C.; Ye, G.; Xie, H.; Zhong, W. Risks of colorectal neoplasms and cardiovascular thromboembolic events after the combined use of selective COX‐2 inhibitors and aspirin with 5‐year follow‐up: A meta‐analysis. Colorectal Dis., 2019, 21(4), 417-426. doi: 10.1111/codi.14556 PMID: 30656820