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Activity of Aspirin Analogues and Vanillin in a Human Colorectal Cancer Cell Line

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Activity of Aspirin Analogues and Vanillin in a Human Colorectal Cancer Cell Line ONCOLOGY REPORTS 26: 557-565, 2011 Activity of aspirin analogues and vanillin in a human colorectal cancer cell line JOLLy DeB, HARPReeT DIBRA, SONg SHAN, SuJITH RAJAN, JAINABA MANNeH, CHANDRA S. Kankipati, CHRIS J. PeRRy and IAIN D. NICHOLL School of Applied Sciences, university of Wolverhampton, Wolverhampton WV1 1Ly, uK Received February 22, 2011; Accepted April 19, 2011 DOI: 10.3892/or.2011.1320 Abstract. Colorectal cancer is the third most common cancer greater toxicity than ASA against the SW480 cell line. A and is associated with significant morbidity and mortality. novel method for synthesis of BCS, a compound that has Epidemiological and animal studies indicate that regular erratic commercial availability, is described. We propose that acetylsalicylic acid (aspirin) intake is associated with a the anti-inflammatory and anticancer capacity of BCS and the reduction in the incidence of colorectal cancer. Acetylsalicylic other analogues described herein is worthy of investigation. acid (ASA) has also been shown to inhibit colorectal cancer cell proliferation in vitro. The molecular basis for this specific Introduction cytotoxicity is an area of considerable debate. To investigate the toxicity of salicylates, the sensitivity of the DNA mismatch There is abundant epidemiological and experimental evidence repair proficient SW480 human colorectal cancer cell line to that regular ingestion of non-steroidal anti-inflammatory four categories of compounds with varying degrees of structural drugs (NSAIDs) including aspirin (ASA) promotes colorectal similarity to acetylsalicylic acid was tested. These compounds tumour regression and reduces the relative risk of developing were: i) salicylic acid analogues with substituents at the colorectal cancer (1-6). There is also substantial evidence that 5-position; ii) ASA analogues with extended chain lengths in ASA is specifically cytotoxic against colorectal cancer (CRC) the acyl group; iii) vanillin (4-hydroxy-3-methoxybenzalde- cells cultured in vitro (7). However, gastrointestinal and renal hyde; and iv) bis(2-carboxyphenyl) succinate (BCS) and disturbances preclude the universality of ASA as a chemo- structurally similar derivatives thereof. It was found that preventative agent, and so much effort has gone into the compounds with amino and acetamido substituents at the synthesis of novel NSAID derivatives which retain anti- salicylate 5-position were less toxic than ASA itself. Modifi- neoplastic activities with minimal side effects (8). cations to the length of the hydrocarbon chain in the acyl Rather surprisingly, the molecular basis for the anti- groups of ASA analogues also marginally reduced toxicity. proliferative effect of NSAIDs, including ASA, in colorectal Vanillin exhibited relatively limited toxicity against the cancer cells is deeply controversial, with a range of theories in SW480 colorectal cancer cell line. Commercially available circulation (reviewed in ref. 9). Mechanistically NSAIDs can, and in-house synthesised BCS (diaspirin) were notably more for example, i) inhibit cyclooxygenases (COX) (7,10), ii) inhibitory to cell growth than ASA itself, yet retained inhibit NF-κB (11,12), iii) activate NF-κB (13), iv) select for substantial specificity against colorectal cancer cell lines vs. microsatellite stability (14), v) down-regulate BCL-2 expression non-colorectal cancer cell lines. BCS and ASA were toxic to (15), vi) up-regulate BAX (16) or XRCC3 expression (17), vii) SW480 cells through initiation of necrotic and apoptotic inhibit protein phosphatase 2A (18) and viii) induce expression pathways. Fumaroyldiaspirin and benzoylaspirin exhibited of the DNA mismatch repair proteins hMLH1, hMSH2, hMSH6 and hPMS2 in DNA MMR proficient cells, which ultimately facilitates apoptosis (programmed cell death) (19). To gain insight into ASA-based cytoxicity we sought to investigate the capacity of several modified salicylates and Correspondence to: Dr Iain D. Nicholl, Research Institute in vanillin to inhibit the growth of SW480 CRC cells, as a prelude Healthcare Science, School of Applied Sciences, university of to investigation of any possible structure/activity relationships. Wolverhampton, Wulfruna Street, Wolverhampton WV1 1Ly, uK The SW480 adenocarcinoma cell line is DNA mismatch e-mail: [email protected] repair competent with a mutant p53 status [and is COX-2- in vitro Abbreviations: ASA, acetylsalicylic acid; BCS, bis(2-carboxyphenyl) negative (20)] and is thus a good model for this purpose. succinate, diaspirin; CRC, colorectal cancer; MTT, 3-(4,5-dimethyl- Salicylic acid derivatives modified at the 5-position or with thiazol-2-yl)-2,5-diphenyltetrazolium bromide; NSAIDs, non-steroidal altered acyl group chain lengths were somewhat less toxic than anti-inflammatory drugs ASA; however, we found that bis(2-carboxyphenyl) succinate and derivatives were significantly more toxic than ASA, and Key words: aspirin, aspirin analogues, diaspirin, colorectal cancer this toxicity was noticeably greater in cell lines with CRC origin. 558 DeB et al: Diaspirin and Cytotoxicity in colorectal canceR Cells Table I. Properties of the alkanoyl salicylates prepared. a X (Fig. 1B) mp [lit. value (Ref.)] (˚C) νC=O/cm (acid; ester) Yield (%) Mr expected/found CH3CO-acetyl 134-136 [135 (25)] 1679; 1749 82 180.2/179.3 CH3CH2CO-propanoyl 88-91 [90-93 (26)] 1680; 1759 79 194.2/196.9 CH3(CH2)2CO-butanoyl 78-81 [78-79 (26)] 1680; 1754 75 208.2/208.4 CH3(CH2)4CO-hexanoyl 72-75 [73-75 (26)] 1689; 1768 72 236.3/233.4 a Molar masses (Mr) were determined by dissolving ~0.5 g of compound (weighed to 4 dp) in ethanol/water and titrating with standardised 0.1 M NaOH using phenolphthalein indicator. The primary standard was potassium hydrogen phthalate. Values shown are the means of at least two separate determinations. mp, melting point; lit., literature. Materials and methods aqueous methanol or ethanol/toluene to produce colourless solids in every case. In this way samples of the analogues Chemicals and reagents. Aspirin, salicylic acid (2-hydroxy- [(Fig. 1B) X = i-v] were prepared. yields, melting points, benzoic acid), MTT reagent [3-(4,5-dimethylthiazol-2-yl)-2,5- purity criteria (Mr by acid-base titration) and IR carbonyl diphenyltetrazolium bromide], bis(2-carboxyphenyl) succinate stretching frequencies are provided in Table I. (BCS), 5-aminosalicylic acid (5-amino-2-hydroxybenzoic acid), vanillin (4-hydroxy-3-methoxybenzaldehyde) and Bis(2-carboxyphenyl) succinate (BCS) (Fig. 1D). Salicylic acid DMSO (dimethyl sulfoxide) were purchased from Sigma- (27.6 g; 0.2 mol) was added to a 2-neck 250-ml Quickfit round Aldrich (Dorset, uK). Dulbecco's modified eagle's medium bottom flask fitted with a condenser, dropping funnel, silica (DMeM) was from PAA Laboratories, and Leibovitz L-15 gel guard tubes and magnetic stirrer. Pyridine (16.1 ml; 0.2 mol) medium was from Sigma. All other reagents were obtained was added through the dropping funnel, followed by dry THF from Sigma-Aldrich unless otherwise stated. Other chemicals (75 ml; dried over anhydrous magnesium sulphate for 24 h). were synthesised in our laboratories using the methods The mixture was then stirred magnetically until the salicylic described. As BCS availability is intermittent we offer a acid had completely dissolved. A solution of succinyl chloride method for its synthesis. (11.0 ml; 0.1 mol) in dry THF (25 ml) was then added dropwise (over 20-30 min) with vigorous stirring. A mildly exothermic Synthesis of materials. All infrared data provided were obtained reaction ensued and a precipitate was soon apparent. Additional on the pure solids using a genesis II ATR FTIR spectrometer. dry THF (up to 30 ml) was added when the slurry became too High resolution mass spectra were obtained from the ePSRC thick to stir efficiently. The mixture was then stirred vigorously National Mass Spectrometry Service Centre, Swansea, uK. for a further 1 h. The resulting mixture was then poured slowly into ice-cold water (300-500 ml) which was rapidly stirred in N,O-diacetyl-5-aminosalicylic acid (DASA) (Fig. 1Aii). a 1-liter conical flask. Stirring was continued (up to 1 h) until 5-Aminosalicylic acid (Fig. 1Ai) (15.3 g; 0.1 mol) was mixed the precipitated product was sufficiently crystalline to be filtered with glacial acetic acid (60 ml) and acetic anhydride (60 ml) with a Buchner apparatus. More cold water was added at this and refluxed for 4 h. The hot solution was then poured onto stage when solidification of the product was slow. The crude ice/water (400 ml) and stirred thoroughly until the precipitate yield was 29.5 g (82%). The product was re-crystallised from was properly solidified. The mixture was then stored at 5˚C ethanol to produce a white solid. IR: νC=O acid 1680/cm, νC=O for 12-18 h. The resulting crude product was filtered under ester 1749/cm; mp: 169-171˚C [lit. 160-165˚C (21), 183-184˚C + vacuum and re-crystallised from aqueous ethanol. The yield (22), 178-180˚C (23)], m/z (CI) 376.1030 (M + NH4 , C18H14O8NH4 of white solid was 15.3 g (65%); mp 192-196˚C [lit. 196-198˚C requires 376.1027). Our material, after re-crystallisation, gave + (24)], m/z (CI) 255.0976 (M + NH4 , C11H11NO5NH4 requires a negative phenol test with ferric chloride solution, and the 255.0975). IR spectrum was essentially identical to the commercial compound. General method for synthesis of alkanoylsalicylate analogues (Fig. 1B). Salicylic acid (6 g; 0.0435 mol) in a 100-ml conical Benozylaspirin (Fig. 1E). Benzoylaspirin was prepared using flask was mixed with dry THF (35 ml) and pyridine (4 ml; the method described for the alkanoylsalicylate analogues 0.05 mol), and the solution was then stirred until the salicylic (Fig. 1B) above, using benzoyl chloride as the appropriate acid acid had completely dissolved. The appropriate acid chloride chloride. A longer reaction time (20-24 h) was allowed before (0.0435 mol dissolved in 10 ml THF) was then added dropwise the addition of cold water.
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