The Curcumin Analog C-150, Influencing NF-κB, UPR and Akt/Notch Pathways Has Potent Anticancer Activity In Vitro and In Vivo

• Published in: PloS one 2016-03, Vol.11 (3), p.e0149832-e0149832
• Main Authors: Hackler, Jr, László, Ózsvári, Béla, Gyuris, Márió, Sipos, Péter, Fábián, Gabriella, Molnár, Eszter, Marton, Annamária, Faragó, Nóra, Mihály, József, Nagy, Lajos István, Szénási, Tibor, Diron, Andrea, Párducz, Árpád, Kanizsai, Iván, Puskás, László G
• Format: Article
• Language: English
• Subjects: Acrylamides - chemistry; AKT protein; Animals; Anticancer properties; Antineoplastic Agents - chemistry; Antitumor activity; Apoptosis; Biology and Life Sciences; Brain cancer; Brain Neoplasms - drug therapy; Brain Neoplasms - metabolism; Brain tumors; Cancer therapies; Cell cycle; Cell Line, Tumor; Cell Proliferation; Curcumin; Curcumin - analogs & derivatives; Curcumin - chemistry; Cytotoxicity; Drosophila melanogaster; Drug Screening Assays, Antitumor; Endoplasmic reticulum; Female; Fruit flies; Gene expression; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Glioblastoma; Glioblastoma - drug therapy; Glioblastoma - metabolism; Glioma; Glioma cells; Humans; Inhibitory Concentration 50; Kinases; Medicine and Health Sciences; Melanoma, Experimental; Mice; Mitoxantrone; Neoplasm Transplantation; NF-kappa B - antagonists & inhibitors; NF-κB protein; Notch protein; Protein kinase C; Proteins; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Rats; Rats, Nude; Receptors, Notch - antagonists & inhibitors; Receptors, Notch - metabolism; Research and Analysis Methods; Signal Transduction; Signaling; Stress response; Transcription activation; Transcription, Genetic; Tumorigenesis; Tumors; Unfolded Protein Response - drug effects
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0149832

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 compared 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.