Research Article Multiple Effects of Berberine Derivatives on Colon Cancer Cells Luis Miguel Guamán Ortiz, 1,2 Micol Tillhon, 1 Michael Parks, 1 Ilaria Dutto, 1 Ennio Prosperi, 1 Monica Savio, 3 Andrea G. Arcamone, 4 Franco Buzzetti, 4 Paolo Lombardi, 4 and Anna Ivana Scovassi 1 1 Istituto di Genetica Molecolare CNR, 27100 Pavia, Italy 2 Departamento de Ciencias de la Salud, Universidad T´ ecnica Particular de Loja, San Cayetano Alto, Calle Par´ ıs, 1101608 Loja, Ecuador 3 Department of Molecular Medicine, Immunology and General Pathology Unit, University of Pavia, Via Ferrata 9, 27100 Pavia, Italy 4 Naxospharma srl, Via Giuseppe Di Vittorio 70, 20026 Novate Milanese, Italy Correspondence should be addressed to Anna Ivana Scovassi; scovassi@igm.cnr.it Received 28 February 2014; Revised 24 April 2014; Accepted 24 April 2014; Published 18 June 2014 Academic Editor: Steve Winder Copyright © 2014 Luis Miguel Guam´ an Ortiz et al. his is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. he pharmacological use of the plant alkaloid berberine is based on its antibacterial and anti-inlammatory properties; recently, anticancer activity has been attributed to this compound. To exploit this interesting feature, we synthesized three berberine derivatives, namely, NAX012, NAX014, and NAX018, and we tested their efects on two human colon carcinoma cell lines, that is, HCT116 and SW613-B3, which are characterized by wt and mutated p53, respectively. We observed that cell proliferation is more afected by cell treatment with the derivatives than with the lead compound; moreover, the derivatives proved to induce cell cycle arrest and cell death through apoptosis, thus suggesting that they could be promising anticancer drugs. Finally, we detected typical signs of autophagy in cells treated with berberine derivatives. 1. Introduction Berberine (BBR) is an isoquinoline quaternary alkaloid present in many medicinal plants such as Hydrastis canaden- sis, Berberis aristata, Coptis chinensis, C. rhizome, C. japonica, Phellodendron amurense, P. chinense Schneid., and other plant species used around the world in traditional medicine. Plants containing BBR have been used for the prevention and treatment of many diseases, including gastrointestinal infections, abdominal pain and diarrhea, hyperglycemia, hyperlipidemia, metabolic syndrome, polycystic ovary syn- drome, obesity, fatty liver, and coronary artery disorders [1– 4]. It is well known that some alkaloids, such as the topoi- somerase I inhibitors camptothecin and vinblastine (both isolated from plants), which interact with tubulin, have already been successfully used as chemotherapeutic drugs. Accordingly, also BBR proved to have anticancer efects [3– 12] on diferent tumor cell lines. he nitrogen atom present at the 7-position of the alkaloid skeleton of the BBR molecule (Figure 1(a)) has a positive charge possibly responsible for its ability to form strong complexes with either DNA or RNA [6, 13, 14], thus inducing DNA damage and promoting telomerase inhibition and topoisomerase poisoning [15, 16]. Moreover, BBR can suppress gene transcription by afecting the association between the TATA-binding protein and the TATA box in the gene promoters [17], and regulating the expression of Bcl-2-family members, such as Bax, Bcl-2, and Bcl-xL, which play crucial roles in apoptosis [18, 19]. Additionally, the general antioxidant and anti-inlammatory properties of BBR has been correlated to the inhibition of cyclooxygenase-2 (COX-2) [20, 21]. hese events may lead to cell cycle arrest, induce cell death via apoptosis, and also activate autophagy [22]. he structure of BBR represents a biologically inter- esting skeleton and also an attractive natural lead com- pound for the introduction of various chemical modiica- tions in appropriate positions, in search for more selec- tive, discriminated, and narrowed medical applications [13]. herefore, aiming at ameliorating the anticancer properties Hindawi Publishing Corporation BioMed Research International Volume 2014, Article ID 924585, 12 pages http://dx.doi.org/10.1155/2014/924585