PMID- 28254663 OWN - NLM STAT- MEDLINE DCOM- 20180220 LR - 20180220 IS - 1950-6007 (Electronic) IS - 0753-3322 (Linking) VI - 89 DP - 2017 May TI - Anti-tumorigenic and anti-angiogenic effects of natural conifer Abies sibirica terpenoids in vivo and in vitro. PG - 386-395 LID - S0753-3322(16)31989-8 [pii] LID - 10.1016/j.biopha.2017.02.035 [doi] AB - AIM: The natural terpenoid compound was explored in vitro and in vivo to investigate the anti-HCC properties. METHODS: For our study we used Abisilin((R))- a novel natural pharmacological terpenoid compound extracted and purified from coniferous Pinaceae trees. Anti-tumorigenic properties of different concentrations of Abisilin((R)) were tested on murine hepatoma Hepa 1-6 cell lines. The analysis of proliferation and apoptosis was performed using immunofluorescence microscopy, FACS and qPCR. As an in vivo approach, we tested Abisilin((R)) (400mg/kg/day, 14 days, orally) in xenograft mouse models of liver cancer and investigated tumor growth, proliferation, apoptosis and angiogenesis by means of Western blotting, immunofluorescence microscopy and qPCR. RESULTS: Application of Abisilin((R)) for 24h at a dosage ranging from 0.03 to 0.045mg significantly reduced the number of viable Hepa 1-6 cells and induced apoptotic cell death with microscopic evidence of changes in cell morphology, and positive TUNEL, cleaved caspase 3 and Annexin V/Propidium Iodide (PI) stainings. Furthermore, treatment with Abisilin((R)) strongly inhibited proliferation, impaired mitosis and prompted cell cycle arrest by down-regulation of the Cyclin D1, E1 and A2 expression levels. In Hepa 1-6 xenograft in vivo model, Abisilin((R)) considerably decreased the xenograft tumor size and tumor volume. Consistently with in vitro Abisilin((R)) administration elicited apoptosis and inhibit proliferation in the xenograft tumor. We also found that Abisilin((R)) remarkably decrease microvessel density, diminished tumor angiogenesis and reduced expression of ICAM-1. Moreover, the expression of pAMPK, a cellular energy sensor, was up-regulated after Abisilin((R)) application. CONCLUSIONS: Anti-proliferative, pro-apoptotic activity and anti-angiogenic potential of natural conifer terpenoids might turn these compounds into an attractive drug candidate for combination therapy against liver cancer. CI - Copyright (c) 2017 Elsevier Masson SAS. All rights reserved. FAU - Nevzorova, Yulia A AU - Nevzorova YA AD - Department of Internal Medicine III, University Hospital RWTH Aachen, Pauwelsstrasse 30, D-52074, Aachen, Germany. Electronic address: ynevzorova@ukaachen.de. FAU - Grossmann, Johannes AU - Grossmann J AD - Department of Internal Medicine I, Evangelical Hospital Bethesda, Ludwig-Weber-Strasse 15, 41061, Monchengladbach, Germany. FAU - Trautwein, Christian AU - Trautwein C AD - Department of Internal Medicine III, University Hospital RWTH Aachen, Pauwelsstrasse 30, D-52074, Aachen, Germany. LA - eng PT - Journal Article DEP - 20170228 PL - France TA - Biomed Pharmacother JT - Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie JID - 8213295 RN - 0 (Antineoplastic Agents, Phytogenic) RN - 0 (Plant Extracts) RN - 0 (Terpenes) SB - IM MH - Abies/*chemistry MH - Animals MH - Antineoplastic Agents, Phytogenic/chemistry/*pharmacology MH - Apoptosis/drug effects MH - Cell Line, Tumor MH - Dose-Response Relationship, Drug MH - Male MH - Mice MH - Neoplasms, Experimental/drug therapy MH - Neovascularization, Physiologic/*drug effects MH - Plant Extracts/chemistry/pharmacology MH - Terpenes/*chemistry OTO - NOTNLM OT - Conifer terpenoids OT - Hepa 1-6 cells OT - Hepatocellular carcinoma OT - Xenograft model EDAT- 2017/03/04 06:00 MHDA- 2018/02/21 06:00 CRDT- 2017/03/04 06:00 PHST- 2016/10/18 00:00 [received] PHST- 2017/02/09 00:00 [revised] PHST- 2017/02/10 00:00 [accepted] PHST- 2017/03/04 06:00 [pubmed] PHST- 2018/02/21 06:00 [medline] PHST- 2017/03/04 06:00 [entrez] AID - S0753-3322(16)31989-8 [pii] AID - 10.1016/j.biopha.2017.02.035 [doi] PST - ppublish SO - Biomed Pharmacother. 2017 May;89:386-395. doi: 10.1016/j.biopha.2017.02.035. Epub 2017 Feb 28.