RESEARCH ARTICLE The Curcumin Analog C-150, Influencing NF- κB, UPR and Akt/Notch Pathways Has Potent Anticancer Activity In Vitro and In Vivo László Hackler, Jr. 1 , Béla Ózsvári 1 , Márió Gyuris 1 , Péter Sipos 2 , Gabriella Fábián 3 , Eszter Molnár 3 , Annamária Marton 4 , Nóra Faragó 1,5 , József Mihály 5 , Lajos István Nagy 1 , Tibor Szénási 5 , Andrea Diron 1 , Árpád Párducz 6 , Iván Kanizsai 1 , László G. Puskás 1,5 * 1 AVIDIN Ltd., Szeged, Hungary, 2 Department of Pharmaceutical Technology, University of Szeged, Szeged, Hungary, 3 AVICOR Ltd., Szeged, Hungary, 4 Institute of Biochemistry, Biological Research Center of the Hungarian Academy of Sciences, Szeged, Hungary, 5 Institute of Genetics, Biological Research Center of the Hungarian Academy of Sciences, Szeged, Hungary, 6 Institute of Biophysics, Biological Research Center of the Hungarian Academy of Sciences, Szeged, Hungary * laszlo@avidinbiotech.com Abstract C-150 a Mannich-type curcumin derivative, exhibited pronounced cytotoxic effects against eight glioma cell lines at micromolar concentrations. Inhibition of cell proliferation by C-150 was mediated by affecting multiple targets as confirmed at transcription and protein level. C-150 effectively reduced the transcription activation of NFkB, inhibited PKC-alpha which are constitutively over-expressed in glioblastoma. The effects of C-150 on the Akt/ Notch signaling were also demonstrated in a Drosophila tumorigenesis model. C-150 reduced the number of tumors in Drosophila with similar efficacy to mitoxantrone. In an in vivo orthotopic glioma model, C-150 significantly increased the median survival of treated nude rats com- pared to control animals. The multi-target action of C-150, and its preliminary in vivo efficacy would render this curcumin analogue as a potent clinical candidate against glioblastoma. Introduction Malignant glioma is the most common cancer of the central nervous system in adults with a median survival time of nine months following surgery, radiotherapy and chemotherapy. Despite advances in different therapies of glioblastoma, they are associated with significant side effects and only limited efficacy [1]. More effective therapeutic agents with fewer side effects are urgently needed. Since cancer arises via multiple pathological or signaling pathways, natural compounds or their derivatives have the potential to be developed into optimum pharmaceuticals for cancer because of their multi-function and multi-target characteristics. Many pieces of evidence point out the relevance of herbal medicines for cancer therapy and prevention, including polyunsatu- rated fatty acids [2–4], corosolic acid [5] and dietary phytochemicals among others [6–8]. Recent attention has focused on curcumin, also known as diferuloyl methane, a polyphenolic, yellow pigment found in the rhizome of turmeric (Curcuma longa). It has been attributed PLOS ONE | DOI:10.1371/journal.pone.0149832 March 4, 2016 1 / 16 OPEN ACCESS Citation: Hackler L, Jr., Ózsvári B, Gyuris M, Sipos P, Fábián G, Molnár E, et al. (2016) The Curcumin Analog C-150, Influencing NF-κB, UPR and Akt/ Notch Pathways Has Potent Anticancer Activity In Vitro and In Vivo. PLoS ONE 11(3): e0149832. doi:10.1371/journal.pone.0149832 Editor: Masaru Katoh, National Cancer Center, JAPAN Received: March 5, 2014 Accepted: February 5, 2016 Published: March 4, 2016 Copyright: © 2016 Hackler et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: All data are included within the paper and its Supporting Information files. Funding: This work was supported by the following grant: GOP-1.1.1-11-2011-0003 (Gazdaságfejlesztési Operatív Program, Development Operational Programme). Research in the laboratory of J. M. was supported by an EU FP7 grant HEALH-F2-2008- 20166, the Pfizer Hungary Award, OTKA grant K82039, TÁMOP -4.2.2.A-11/1/KONV-2012-0035 and the Hungarian Brain Research Program (KTIA- NAP_13-2014-0007). The funders had no role in study design, data collection and analysis, decision to