Generic placeholder image

Current Clinical Pharmacology

Author(s): Rajagopal S. Kilari, Asma’u I.J. Bashir, Andreue Devitt, Christopher J. Perry, Stephen T. Safrany and Iain D. Nicholl*

DOI: 10.2174/1574884713666181112141151

Cite As
The Cytotoxicity and Synergistic Potential of Aspirin and Aspirin Analogues Towards Oesophageal and Colorectal Cancer

Page: [141 - 151] Pages: 11

  • * (Excluding Mailing and Handling)

Abstract

Background: Oesophageal cancer (OC) is a deadly cancer because of its aggressive nature with survival rates that have barely improved in decades. Epidemiologic studies have shown that low-dose daily intake of aspirin can decrease the incidence of OC.

Methods: The toxicity of aspirin and aspirin derivatives to OC and a CRC cell line were investigated in the presence and absence of platins.

Results: The data in this study show the effects of a number of aspirin analogues and aspirin on OC cell lines that originally presented as squamous cell carcinoma (SSC) and adenocarcinoma (ADC). The aspirin analogues fumaryldiaspirin (PN517) and the benzoylsalicylates (PN524, PN528 and PN529), were observed to be more toxic against the OC cell lines than aspirin. Both quantitative and qualitative apoptosis experiments reveal that these compounds largely induce apoptosis, although some necrosis was evident with PN528 and PN529. Failure to recover following the treatment with these analogues emphasized that these drugs are largely cytotoxic in nature. The OE21 (SSC) and OE33 (ADC) cell lines were more sensitive to the aspirin analogues compared to the Flo-1 cell line (ADC). A non-cancerous oesophageal primary cells NOK2101, was used to determine the specificity of the aspirin analogues and cytotoxicity assays revealed that analogues PN528 and PN529 were selectively toxic to cancer cell lines, whereas PN508, PN517 and PN524 also induced cell death in NOK2101. In combination index testing synergistic interactions of the most promising compounds, including aspirin, with cisplatin, oxaliplatin and carboplatin against the OE33 cell line and the SW480 colorectal cancer (CRC) cell line were investigated. Compounds PN517 and PN524, and to a lesser extent PN528, synergised with cisplatin against OE33 cells. Cisplatin and oxaliplatin synergised with aspirin and PN517 when tested against the SW480 cell line.

Conclusion: These findings indicate the potential and limitations of aspirin and aspirin analogues as chemotherapeutic agents against OC and CRC when combined with platins.

Keywords: Oesophageal cancer, platins, aspirin, aspirin analogues, apoptosis, morbidity.

Graphical Abstract

[1]
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018; 68(6): 394-424.
[http://dx.doi.org/10.3322/caac.21492] [PMID: 30207593]
[2]
Layke JC, Lopez PP. Esophageal cancer: a review and update. Am Fam Physician 2006; 73(12): 2187-94.
[PMID: 16836035]
[3]
Reid BJ, Li X, Galipeau PC, Vaughan TL. Barrett’s oesophagus and oesophageal adenocarcinoma: time for a new synthesis. Nat Rev Cancer 2010; 10(2): 87-101.
[http://dx.doi.org/10.1038/nrc2773] [PMID: 20094044]
[4]
Siewert JR, Ott K. Are squamous and adenocarcinomas of the esophagus the same disease? Semin Radiat Oncol 2007; 17(1): 38-44.
[http://dx.doi.org/10.1016/j.semradonc.2006.09.007] [PMID: 17185196]
[5]
Edgren G, Adami HO, Weiderpass E, Nyrén O. A global assessment of the oesophageal adenocarcinoma epidemic. Gut 2013; 62(10): 1406-14.
[http://dx.doi.org/10.1136/gutjnl-2012-302412] [PMID: 22917659]
[6]
Thun MJ, Namboodiri MM, Calle EE, Flanders WD, Heath CW Jr. Aspirin use and risk of fatal cancer. Cancer Res 1993; 53(6): 1322-7.
[PMID: 8443812]
[7]
Farrow DC, Vaughan TL, Hansten PD, et al. Use of aspirin and other nonsteroidal anti-inflammatory drugs and risk of esophageal and gastric cancer. Cancer Epidemiol Biomarkers Prev 1998; 7(2): 97-102.
[PMID: 9488582]
[8]
Funkhouser EM, Sharp GB. Aspirin and reduced risk of esophageal carcinoma. Cancer 1995; 76(7): 1116-9.
[http://dx.doi.org/10.1002/1097-0142(19951001)76:7<1116:AID-CNCR2820760703>3.0.CO;2-I] [PMID: 8630885]
[9]
Corley DA, Kerlikowske K, Verma R, Buffler P. Protective association of aspirin/NSAIDs and esophageal cancer: a systematic review and meta-analysis. Gastroenterology 2003; 124(1): 47-56.
[http://dx.doi.org/10.1053/gast.2003.50008] [PMID: 12512029]
[10]
Bosetti C, Rosato V, Gallus S, Cuzick J, La Vecchia C. Aspirin and cancer risk: a quantitative review to 2011. Ann Oncol 2012; 23(6): 1403-15.
[http://dx.doi.org/10.1093/annonc/mds113] [PMID: 22517822]
[11]
Cuzick J, Thorat MA, Bosetti C, et al. Estimates of benefits and harms of prophylactic use of aspirin in the general population. Ann Oncol 2015; 26(1): 47-57.
[http://dx.doi.org/10.1093/annonc/mdu225] [PMID: 25096604]
[12]
Vaughan TL, Dong LM, Blount PL, et al. Non-steroidal anti-inflammatory drugs and risk of neoplastic progression in Barrett’s oesophagus: a prospective study. Lancet Oncol 2005; 6(12): 945-52.
[http://dx.doi.org/10.1016/S1470-2045(05)70431-9] [PMID: 16321762]
[13]
Kostadinov RL, Kuhner MK, Li X, et al. NSAIDs modulate clonal evolution in Barrett’s esophagus. PLoS Genet 2013; 9(6)e1003553
[http://dx.doi.org/10.1371/journal.pgen.1003553] [PMID: 23785299]
[14]
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(7): 1073-81.
[http://dx.doi.org/10.1093/carcin/bgp127] [PMID: 19468060]
[15]
Rubio CA. Antitumoral activity of indomethacin on experimental esophageal tumors. J Natl Cancer Inst 1984; 72(3): 705-7.
[PMID: 6583454]
[16]
Rizvi S, Demars CJ, Comba A, et al. Combinatorial chemoprevention reveals a novel smoothened-independent role of GLI1 in esophageal carcinogenesis. Cancer Res 2010; 70(17): 6787-96.
[http://dx.doi.org/10.1158/0008-5472.CAN-10-0197] [PMID: 20647328]
[17]
Levy GN. Prostaglandin H synthases, nonsteroidal anti-inflammatory drugs, and colon cancer. FASEB J 1997; 11(4): 234-47.
[http://dx.doi.org/10.1096/fasebj.11.4.9068612] [PMID: 9068612]
[18]
Tegeder I, Pfeilschifter J, Geisslinger G. Cyclooxygenase-independent actions of cyclooxygenase inhibitors. FASEB J 2001; 15(12): 2057-72.
[http://dx.doi.org/10.1096/fj.01-0390rev] [PMID: 11641233]
[19]
Elwood PC, Gallagher AM, Duthie GG, Mur LA, Morgan G. Aspirin, salicylates, and cancer. Lancet 2009; 373(9671): 1301-9.
[http://dx.doi.org/10.1016/S0140-6736(09)60243-9] [PMID: 19328542]
[20]
Gurpinar E, Grizzle WE, Piazza GA. COX-Independent Mechanisms of Cancer Chemoprevention by Anti-Inflammatory Drugs. Front Oncol 2013; 3: 181.
[http://dx.doi.org/10.3389/fonc.2013.00181] [PMID: 23875171]
[21]
Vane JR, Botting RM. The mechanism of action of aspirin. Thromb Res 2003; 110(5-6): 255-8.
[http://dx.doi.org/10.1016/S0049-3848(03)00379-7] [PMID: 14592543]
[22]
Williams CS, Mann M, DuBois RN. The role of cyclooxygenases in inflammation, cancer, and development. Oncogene 1999; 18(55): 7908-16.
[http://dx.doi.org/10.1038/sj.onc.1203286] [PMID: 10630643]
[23]
Greenhough A, Smartt HJ, Moore AE, et al. The COX-2/PGE2 pathway: key roles in the hallmarks of cancer and adaptation to the tumour microenvironment. Carcinogenesis 2009; 30(3): 377-86.
[http://dx.doi.org/10.1093/carcin/bgp014] [PMID: 19136477]
[24]
Shirvani VN, Ouatu-Lascar R, Kaur BS, Omary MB, Triadafilopoulos G. Cyclooxygenase 2 expression in Barrett’s esophagus and adenocarcinoma: Ex vivo induction by bile salts and acid exposure. Gastroenterology 2000; 118(3): 487-96.
[http://dx.doi.org/10.1016/S0016-5085(00)70254-X] [PMID: 10702199]
[25]
Wilson KT, Fu S, Ramanujam KS, Meltzer SJ. Increased expression of inducible nitric oxide synthase and cyclooxygenase-2 in Barrett’s esophagus and associated adenocarcinomas. Cancer Res 1998; 58(14): 2929-34.
[PMID: 9679948]
[26]
Yu HP, Shi LY, Lu WH, Su YH, Li YY, Xu SQ. Expression of cyclooxygenase-2 (COX-2) in human esophageal cancer and in vitro inhibition by a specific COX-2 inhibitor, NS-398. J Gastroenterol Hepatol 2004; 19(6): 638-42.
[http://dx.doi.org/10.1111/j.1440-1746.2004.03345.x] [PMID: 15151617]
[27]
Zimmermann KC, Sarbia M, Weber AA, Borchard F, Gabbert HE, Schrör K. Cyclooxygenase-2 expression in human esophageal carcinoma. Cancer Res 1999; 59(1): 198-204.
[PMID: 9892207]
[28]
Gupta RA, Tejada LV, Tong BJ, et al. Cyclooxygenase-1 is overexpressed and promotes angiogenic growth factor production in ovarian cancer. Cancer Res 2003; 63(5): 906-11.
[PMID: 12615701]
[29]
Daikoku T, Wang D, Tranguch S, et al. Cyclooxygenase-1 is a potential target for prevention and treatment of ovarian epithelial cancer. Cancer Res 2005; 65(9): 3735-44.
[http://dx.doi.org/10.1158/0008-5472.CAN-04-3814] [PMID: 15867369]
[30]
Kopp E, Ghosh S. Inhibition of NF-kappa B by sodium salicylate and aspirin. Science 1994; 265(5174): 956-9.
[http://dx.doi.org/10.1126/science.8052854] [PMID: 8052854]
[31]
Yin MJ, Yamamoto Y, Gaynor RB. The anti-inflammatory agents aspirin and salicylate inhibit the activity of I(kappa)B kinase-beta. Nature 1998; 396(6706): 77-80.
[http://dx.doi.org/10.1038/23948] [PMID: 9817203]
[32]
Thoms HC, Dunlop MG, Stark LA. p38-mediated inactivation of cyclin D1/cyclin-dependent kinase 4 stimulates nucleolar translocation of RelA and apoptosis in colorectal cancer cells. Cancer Res 2007; 67(4): 1660-9.
[http://dx.doi.org/10.1158/0008-5472.CAN-06-1038] [PMID: 17308107]
[33]
Yu HG, Huang JA, Yang YN, et al. The effects of acetylsalicylic acid on proliferation, apoptosis, and invasion of cyclooxygenase-2 negative colon cancer cells. Eur J Clin Invest 2002; 32(11): 838-46.
[http://dx.doi.org/10.1046/j.1365-2362.2002.01080.x] [PMID: 12423325]
[34]
Din FV, Valanciute A, Houde VP, Zibrova D, Green KA, Sakamoto K, et al. Aspirin inhibits mTOR signaling, activates AMP-activated protein kinase, and induces autophagy in colorectal cancer cells. Gastroenterology 2012; 142(7): 1504.
[35]
Hawley SA, Fullerton MD, Ross FA, et al. The ancient drug salicylate directly activates AMP-activated protein kinase. Science 2012; 336(6083): 918-22.
[http://dx.doi.org/10.1126/science.1215327] [PMID: 22517326]
[36]
Liao X, Lochhead P, Nishihara R, et al. Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival. N Engl J Med 2012; 367(17): 1596-606.
[http://dx.doi.org/10.1056/NEJMoa1207756] [PMID: 23094721]
[37]
Deb J, Dibra H, Shan S, et al. Activity of aspirin analogues and vanillin in a human colorectal cancer cell line. Oncol Rep 2011; 26(3): 557-65.
[PMID: 21617874]
[38]
Claudius AK, Kankipati CS, Kilari RS, et al. Identification of aspirin analogues that repress NF-κB signalling and demonstrate anti-proliferative activity towards colorectal cancer in vitro and in vivo. Oncol Rep 2014; 32(4): 1670-80.
[http://dx.doi.org/10.3892/or.2014.3373] [PMID: 25109257]
[39]
Zaugg RH, Walder JA, Walder RY, Steele JM, Klotz IM. Modification of hemoglobin with analogs of aspirin. J Biol Chem 1980; 255(7): 2816-21.
[PMID: 7358711]
[40]
Rockett JC, Larkin K, Darnton SJ, Morris AG, Matthews HR. Five newly established oesophageal carcinoma cell lines: phenotypic and immunological characterization. Br J Cancer 1997; 75(2): 258-63.
[http://dx.doi.org/10.1038/bjc.1997.42] [PMID: 9010035]
[41]
Hughes SJ, Nambu Y, Soldes OS, et al. Fas/APO-1 (CD95) is not translocated to the cell membrane in esophageal adenocarcinoma. Cancer Res 1997; 57(24): 5571-8.
[PMID: 9407969]
[42]
Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 1983; 65(1-2): 55-63.
[http://dx.doi.org/10.1016/0022-1759(83)90303-4] [PMID: 6606682]
[43]
Chan M, Gravel M, Bramoullé A, et al. Synergy between the NAMPT inhibitor GMX1777(8) and pemetrexed in non-small cell lung cancer cells is mediated by PARP activation and enhanced NAD consumption. Cancer Res 2014; 74(21): 5948-54.
[http://dx.doi.org/10.1158/0008-5472.CAN-14-0809] [PMID: 25145669]
[44]
Luo HY, Wei W, Shi YX, et al. Cetuximab enhances the effect of oxaliplatin on hypoxic gastric cancer cell lines. Oncol Rep 2010; 23(6): 1735-45.
[PMID: 20428833]
[45]
Toscano F, Parmentier B, Fajoui ZE, et al. p53 dependent and independent sensitivity to oxaliplatin of colon cancer cells. Biochem Pharmacol 2007; 74(3): 392-406.
[http://dx.doi.org/10.1016/j.bcp.2007.05.001] [PMID: 17559811]
[46]
Yan KH, Yao CJ, Chang HY, Lai GM, Cheng AL, Chuang SE. The synergistic anticancer effect of troglitazone combined with aspirin causes cell cycle arrest and apoptosis in human lung cancer cells. Mol Carcinog 2010; 49(3): 235-46.
[PMID: 19908241]
[47]
Zhou J, Zhou Y, Yin B, et al. 5-Fluorouracil and oxaliplatin modify the expression profiles of microRNAs in human colon cancer cells in vitro. Oncol Rep 2010; 23(1): 121-8.
[PMID: 19956872]
[48]
Chou TC, Talalay P. Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul 1984; 22: 27-55.
[http://dx.doi.org/10.1016/0065-2571(84)90007-4] [PMID: 6382953]
[49]
Bijnsdorp IV, Giovannetti E, Peters GJ. Analysis of drug interactions. Methods Mol Biol 2011; 731: 421-34.
[http://dx.doi.org/10.1007/978-1-61779-080-5_34] [PMID: 21516426]
[50]
Chou TC. Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol Rev 2006; 58(3): 621-81.
[http://dx.doi.org/10.1124/pr.58.3.10] [PMID: 16968952]
[51]
Vermes I, Haanen C, Steffens-Nakken H, Reutelingsperger C. A novel assay for apoptosis. Flow cytometric detection of phosphatidylserine expression on early apoptotic cells using fluorescein labelled Annexin V. J Immunol Methods 1995; 184(1): 39-51.
[http://dx.doi.org/10.1016/0022-1759(95)00072-I] [PMID: 7622868]
[52]
Alcindor T, Beauger N. Oxaliplatin: a review in the era of molecularly targeted therapy. Curr Oncol 2011; 18(1): 18-25.
[http://dx.doi.org/10.3747/co.v18i1.708] [PMID: 21331278]
[53]
Chou TC. Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res 2010; 70(2): 440-6.
[http://dx.doi.org/10.1158/0008-5472.CAN-09-1947] [PMID: 20068163]
[54]
Din FV, Dunlop MG, Stark LA. Evidence for colorectal cancer cell specificity of aspirin effects on NF kappa B signalling and apoptosis. Br J Cancer 2004; 91(2): 381-8.
[http://dx.doi.org/10.1038/sj.bjc.6601913] [PMID: 15188000]
[55]
Sundström J, Hedberg J, Thuresson M, Aarskog P, Johannesen KM, Oldgren J. Low-dose aspirin discontinuation and risk of cardiovascular events: A swedish nationwide, population-based cohort study. Circulation 2017; 136(13): 1183-92.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.117.028321] [PMID: 28947478]
[56]
Dong H, Liu G, Jiang B, et al. The effects of aspirin plus cisplatin on SGC7901/CDDP cells in vitro. Biomed Rep 2014; 2(3): 344-8.
[http://dx.doi.org/10.3892/br.2014.241] [PMID: 24748972]
[57]
Shirakawa K, Wang L, Man N, et al. Salicylate, diflunisal and their metabolites inhibit CBP/p300 and exhibit anticancer activity. eLife 2016; 5: 5.
[http://dx.doi.org/10.7554/eLife.11156] [PMID: 27244239]
[58]
Schwenger P, Bellosta P, Vietor I, Basilico C, Skolnik EY, Vilcek J. Sodium salicylate induces apoptosis via p38 mitogen-activated protein kinase but inhibits tumor necrosis factor-induced c-Jun N-terminal kinase/stress-activated protein kinase activation. Proc Natl Acad Sci USA 1997; 94(7): 2869-73.
[http://dx.doi.org/10.1073/pnas.94.7.2869] [PMID: 9096313]