Molecular and cellular pharmacology Quinaldic acid inhibits proliferation of colon cancer HT-29 cells in vitro: Effects on signaling pathways Ewa Langner a,b,n , Katarzyna Walczak a , Witold Jeleniewicz c , Waldemar A. Turski d , Grażyna Rajtar a a Department of Pharmacology, Medical University in Lublin, Chodźki 4a, 20-093 Lublin, Poland b Department of Medical Biology, Institute of Agricultural Medicine, Jaczewskiego 2, 20-090 Lublin, Poland c Department of Biochemistry and Molecular Biology, Medical University in Lublin, Chodźki 1, 20-093 Lublin, Poland d Department of Experimental and Clinical Pharmacology, Medical University in Lublin, Jaczewskiego 8, 20-090 Lublin, Poland article info Article history: Received 9 January 2015 Received in revised form 20 February 2015 Accepted 23 February 2015 Available online 20 March 2015 Keywords: Quinaldic acid Kynurenic acid Colon cancer Cancer cells proliferation Chemical compounds studied in this article: Quinaldic acid (PubChem CID: 7124) abstract Quinaldic acid is presumed to be a derivative of kynurenic acid, a tryptophan metabolite with proven antiproliferative activity towards cancer cells in vitro. The aim of present study was to evaluate the activity of quinaldic acid in colon cancer cells. The antiproliferative potential of quinaldic acid was assessed in HT-29, LS180 and Caco-2 cells. Suppression of metabolic activity (IC 50 of 0.5 mM for HT-29 and LS180 cells, 0.9 mM for Caco-2 cells) and DNA synthesis (IC 50 of 2.7, 4.3, 2mM for HT-29, LS180 and Caco-2 cells, respectively) were observed in all tested cell lines. It is noteworthy that quinaldic acid in antiproliferative concentrations was non-toxic to normal colon epithelium CCD 841 CoTr cells. Concomitantly, alterations in several signaling pathways in HT-29 cells were observed. Quinaldic acid led to changes in the phosphorylation level of extracellular-signal-regulated kinase (ERK) 1/2, p38, cAMP response element-binding protein (CREB) and Akt (protein kinase B) kinases. Moreover, changes in the CREB transcription factor were also found at the gene expression level. Antiproliferative activity and signaling pathways modulatory potential of quinaldic acid in colon cancer cells in vitro has been stated. & 2015 Elsevier B.V. All rights reserved. 1. Introduction Quinaldic acid origin, synthesis pathway and metabolism have not been clearly established so far. Brown and Price (1956) observed that quinaldic acid may be a tryptophan metabolite arising from the kynurenine pathway. It is proposed that quinaldic acid constitutes a dehydroxylation product of kynurenic acid (Kaihara and Price, 1962), the endogenous tryptophan metabolite, which antiproliferative activ- ity in colon cancer (Walczak et al., 2011), renal cancer (Walczak et al., 2012b) and glioblastoma cells in vitro (Walczak et al., 2014a) has been already stated. Quinaldic acid has been found in animal urea, although at a significantly lower level compared to kynurenic acid. It is suggested that intestinal microflora may be involved in the produc- tion of quinaldic acid (Gal and Sherman, 1978; Yokoi et al., 1998). Despite diverse biological activities, i.e. affecting gluconeogenesis (Veneziale et al., 1967; Hanson et al., 1969), proinsulin synthesis and insulin release (Noto and Okamoto, 1978), chelating metal ions or removing oxygen species (Allen, 2002; Bowden et al., 1976; Bartram and Kent, 1946) as well as suppressing the growth of pathogenic microflora within the colon (Lee and Lee, 2009), the role of quinaldic acid in the human organism is still poorly elucidated. Considering the high level of structural similarity between the tested compound and kynurenic acid, the antiproliferative activity of which has already been revealed, and its presence in the human organism, evaluation of chemopreventive potential of quinaldic acid seems to be well-founded. The present study aims at describing previously unknown effects of quinaldic acid, and for the first time examines the effect of quinaldic acid on colon cancer cells proliferation in vitro, and potential molecular mechanism (s) of its activity. 2. Materials and methods 2.1. Drugs Quinaldic acid was purchased from Sigma Aldrich (St. Louis, MO, USA) and dissolved in 1 N NaOH followed by phosphate buffered saline (PBS) addition (final concentration of NaOH in stock solution did not exceed 25%). Working solutions were prepared each time in fresh medium with the amount of NaOH not exceeding 0.125%. Contents lists available at ScienceDirect journal homepage: www.elsevier.com/locate/ejphar European Journal of Pharmacology http://dx.doi.org/10.1016/j.ejphar.2015.02.053 0014-2999/& 2015 Elsevier B.V. All rights reserved. n Corresponding author at: Department of Pharmacology, Medical University in Lublin, Chodźki 4a, 20-093 Lublin, Poland. Tel.: þ48 814486774. E-mail address: ewa.langner@gmail.com (E. Langner). European Journal of Pharmacology 757 (2015) 21–27