Please cite this article in press as: Bonaterra, G.A., et al., Mechanisms of the anti-proliferative and anti-inflammatory effects of the herbal fixed combination STW 5 (Iberogast ® ) on colon adenocarcinoma (HT29) cells in vitro. Phytomedicine (2013), http://dx.doi.org/10.1016/j.phymed.2013.02.011 ARTICLE IN PRESS G Model PHYMED-51393; No. of Pages 8 Phytomedicine xxx (2013) xxx–xxx Contents lists available at SciVerse ScienceDirect Phytomedicine j ourna l ho mepage: www.elsevier.de/phymed Mechanisms of the anti-proliferative and anti-inflammatory effects of the herbal fixed combination STW 5 (Iberogast ® ) on colon adenocarcinoma (HT29) cells in vitro G.A. Bonaterra a,∗ , O. Kelber b , D. Weiser b , R. Kinscherf a,1 a Anatomy and Cell Biology, Department of Medical Cell Biology, University of Marburg, Robert-Koch-Str. 8, 35032 Marburg, Germany b Scientific Department, Steigerwald Arzneimittelwerk GmbH, Havelstr. 5, 64295 Darmstadt, Germany a r t i c l e i n f o Keywords: Cancer Cyclooxygenase Inflammation NF-B NSAIDs STW 5 (Iberogast ® ) a b s t r a c t Introduction: Several conventional pharmaceuticals like non-steroidal anti-inflammatory drugs (NSAIDS) or selective cyclooxygenase-2 (COX-2) inhibitors have been demonstrated to exert anti-proliferative effects and to induce apoptosis in a variety of cell lines, e.g. colon, stomach, or prostate cancer cells. STW 5 (Iberogast ® ), a combination of nine plant extracts, is widely used in the treatment of gastrointestinal disorders, including functional dyspepsia and irritable bowel syndrome for which the involvement of an inflammatory etiology is discussed. To investigate the possible anti-proliferative effects, STW 5 and its components have been tested by using the colon-carcinoma cell line HT-29. The analyses have been performed in comparison to acetylsalicylic acid (ASA) and diclofenac (Diclo), which are well-known to reduce colon carcinoma risk. Results: STW 5 showed significant anti-proliferative and pro-apoptotic effects on HT-29 cancer cells, sim- ilar to NSAIDs under test. However, using the LDH assay, STW 5 revealed significantly lower cytotoxicity than Diclo at same concentrations. In contrast to NSAIDs, STW 5 induced COX-1/COX-2, caspase-3 and Bax mRNA expressions in HT-29 and blocked LPS mediated translocation of the NF-B p65 from the cyto- plasm into the nucleus in PMA-differentiated THP-1 macrophages. These effects might be relevant, e.g. for prevention of undesirable side effects like gastric erosions. Conclusion: Our data suggest that the pro-apoptotic effect of STW 5 on HT-29 cells is involving multiple targets and is possibly due to an activation of the caspase cascade via mitochondrial destabilization. Active concentrations of STW 5 are, in relation to therapeutic doses, comparable to those of ASA and Diclo, suggesting a similar favorable effect on colon carcinoma risk. © 2013 Elsevier GmbH. All rights reserved. Introduction Iberogast ® (STW 5) is a fixed combination of nine different herbal constituents (Wegener and Wagner 2006; Vinson 2009). Its components are an aqueous-ethanolic fresh plant extract from Iberis amara totalis and drug extracts from peppermint leaves (Menthae piperitae folium), chamomile flower (Matricariae flos), liquorice root (Liquiritiae radix), Angelica root (Angelicae radix), caraway fruit (Carvi fructus), milk thistle fruit (Silybi mar- iani fructus), lemon balm leaves (Melissae folium), and greater celandine herb (Chelidonii herba) (Kelber et al. 2006; Ammon et al. 2006; Michael et al. 2012) – each of which is reported to have multiple pharmacological properties relevant in gastrointestinal pathophysiology (Wegener and Wagner 2006). STW 5 is indicated ∗ Corresponding author. Tel.: +49 06421 2864097; fax: +49 06421 2868983. E-mail address: gabriel.bonaterra@staff.uni-marburg.de (G.A. Bonaterra). 1 Senior author. in the therapy of motility-related diseases of the gastrointesti- nal tract (Allescher and Wagner 2007; Raedsch et al. 2007; Rösch et al. 2006), and is widely used in Europe (Gundermann et al. 2003; Storra et al. 2004; Pilichiewicz et al. 2007; von Arnim et al. 2007). Inflammation is a mechanism significantly contributing to the etiology of functional gastrointestinal diseases like inflam- matory bowel disease, colitis or infections by Helicobacter pylori (Collins et al. 2001; Germann et al. 2006). In this context, STW 5 has been most recently shown to have anti-inflammatory properties, to influence intestinal motility and to be effective in randomized, double blind clinical studies in functional dyspepsia and inflam- matory bowel disease (Michael et al. 2012). Inflammatory bowel disease, Crohn’s disease, chronic ulcerative colitis have been asso- ciated with the development of colorectal carcinoma (Coussens and Werb 2002). Developing neoplasm containing tumor cells produce various cytokines and chemokines, which lead to attraction of dif- ferent leukocyte populations such as monocytes and macrophages producing several cytokines as tumor necrosis factor-alpha (TNF- ), interleukins and interferons (IFNs), cytotoxic factors as reactive 0944-7113/$ – see front matter © 2013 Elsevier GmbH. All rights reserved. http://dx.doi.org/10.1016/j.phymed.2013.02.011