title: The Limonoids TS3 and Rubescin E Induce Apoptosis in Human Hepatoma Cell Lines and Interfere with NF-κB Signaling.
abstract: Hepatocellular carcinoma (HCC) is extremely resistant towards pharmacological therapy. To date, the multi-kinase inhibitor Sorafenib is the only available therapeutic agent with the potential to prolong patient survival. Using the human hepatoma cell lines HepG2 and Huh7, we analyzed anti-cancer activities of 6 purified havanensin type limonoids isolated from the traditional African medicinal plant Trichilia rubescens Oliv. Our results show that two of the compounds, TR4 (TS3) and TR9 (Rubescin E) reduced hepatoma cell viability, but not primary hepatocyte viability, at TC50s of 5 to 10 μM. These were significantly lower than the TC50s for Sorafenib, the histone deacetylase inhibitor SAHA or 5-Fluoruracil. In comparison, TR3 (Rubescin D), a limonoid isolated in parallel and structurally highly similar to TR4 and TR9, did not interfere with hepatoma cell viability. Both, TR4 and TR9, but not TR3, induced apoptosis in hepatoma cells and interfered with NF-κB activation. TR4 as well as TR9 significantly supported anti-cancer activities of Sorafenib. In summary, the limonoids TR4 and TR9 exhibit anti-cancer activities and support Sorafenib effects in vitro, having the potential to support future HCC therapy.
authors: Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg Eppendorf, Hamburg, Germany.
authors: Nicole
authors: N
authors: Lange
authors: University of Yaoundé I, Department of Organic Chemistry, P.O BOX: 812, Yaoundé, Cameroon.
authors: Armelle Tsamo
authors: AT
authors: Tontsa
authors: Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg Eppendorf, Hamburg, Germany.
authors: Claudia
authors: C
authors: Wegscheid
authors: University of Yaoundé I, Department of Organic Chemistry, P.O BOX: 812, Yaoundé, Cameroon.
authors: Pierre
authors: P
authors: Mkounga
authors: University of Yaoundé I, Department of Organic Chemistry, P.O BOX: 812, Yaoundé, Cameroon.
authors: Augustin Ephrem
authors: AE
authors: Nkengfack
authors: Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg Eppendorf, Hamburg, Germany.
authors: Christine
authors: http://orcid.org/0000-0001-7633-5702
authors: C
authors: Loscher
authors: Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg Eppendorf, Hamburg, Germany.|California Institute for Medical Research, San Jose, CA, United States of America.
authors: Gabriele
authors: G
authors: Sass
authors: Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg Eppendorf, Hamburg, Germany.
authors: Gisa
authors: G
authors: Tiegs
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D006801:Humans; D036701:Limonins / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000473:pathology*; D016328:NF-kappa B / Q000378:metabolism*; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D000077157:Sorafenib
chemical_list: D000970:Antineoplastic Agents; D036701:Limonins; D016328:NF-kappa B; D010671:Phenylurea Compounds; C000621660:rubescin E; D009536:Niacinamide; D000077157:Sorafenib