title: A eudesmane-type sesquiterpene isolated from Pluchea odorata (L.) Cass. combats three hallmarks of cancer cells: Unrestricted proliferation, escape from apoptosis and early metastatic outgrowth in vitro.
abstract: Pluchea odorata is ethno pharmaceutically used to treat inflammation-associated disorders. The dichloromethane extract (DME) was tested in the carrageenan-induced rat paw oedema assay investigating its effect on inflammation that was inhibited by 37%. Also an in vitro anti-neoplastic potential was reported. However, rather limited information about the bio-activity of purified compounds and their cellular mechanisms are available. Therefore, two of the most abundant eudesmanes in P. odorata were isolated and their anti-neoplastic and anti-intravasative activities were studied. HL-60 cells were treated with P. odorata compounds and metabolic activity, cell number reduction, cell cycle progression and apoptosis induction were correlated with relevant protein expression. Tumour cell intravasation through lymph endothelial monolayers was measured and potential causal mechanisms were analyzed by Western blotting. Compound PO-1 decreased the metabolic activity of HL-60 cells (IC50 = 8.9 μM after 72 h) and 10 μM PO-1 induced apoptosis, while PO-2 showed just weak anti-neoplastic activities at concentrations beyond 100 μM. PO-1 arrested the cell cycle in G1 and this correlated with induction of JunB expression. Independent of this mechanism 25 μM PO-1 decreased MCF-7 spheroid intravasation through the lymph endothelial barrier. Hence, PO-1 inhibits an early step of metastasis, impairs unrestricted proliferation and induces apoptosis at low micromolar concentrations. These results warrant further testing in vivo to challenge the potential of PO-1 as novel lead compound.
authors.affiliation: Department of Pharmacognosy, University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria; Department of Clinical Pathology, Medical University of Vienna, Waehringer Guertel 18-20, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Blaschke
authors.affiliation: Department of Pharmacognosy, University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria.
authors.forename: Ruxandra
authors.initials: R
authors.lastname: McKinnon
authors.affiliation: Department of Clinical Pathology, Medical University of Vienna, Waehringer Guertel 18-20, Austria; Department of Clinical Pharmacy and Diagnostics, University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria.
authors.forename: Chi Huu
authors.initials: CH
authors.lastname: Nguyen
authors.affiliation: Department of Clinical Pathology, Medical University of Vienna, Waehringer Guertel 18-20, Austria.
authors.forename: Silvio
authors.initials: S
authors.lastname: Holzner
authors.affiliation: Department of Pharmacognosy, University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria; Department of Pharmaceutical Chemistry, University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria.
authors.forename: Martin
authors.initials: M
authors.lastname: Zehl
authors.affiliation: Department of Pharmacognosy, University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria.
authors.forename: Atanas Georgiev
authors.initials: AG
authors.lastname: Atanasov
authors.affiliation: Department of Medicine I, Institute of Cancer Research, Comprehensive Cancer Centre Vienna, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria.
authors.forename: Karin
authors.initials: K
authors.lastname: Schelch
authors.affiliation: Department of Clinical Pathology, Medical University of Vienna, Waehringer Guertel 18-20, Austria.
authors.forename: Sigurd
authors.initials: S
authors.lastname: Krieger
authors.affiliation: Institute for Ethnobiology, Playa Diana, San José/Petén, Guatemala.
authors.forename: Rene
authors.initials: R
authors.lastname: Diaz
authors.affiliation: Institute for Ethnobiology, Playa Diana, San José/Petén, Guatemala.
authors.forename: Richard
authors.initials: R
authors.lastname: Frisch
authors.affiliation: Finzelberg GmbH & Co. KG, Koblenzer Strasse 48-54, D-56626 Andernach, Germany.
authors.forename: Björn
authors.initials: B
authors.lastname: Feistel
authors.affiliation: Department of Clinical Pharmacy and Diagnostics, University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria.
authors.forename: Walter
authors.initials: W
authors.lastname: Jäger
authors.affiliation: Department of Pharmaceutical Chemistry, Division of Drug Design and Medicinal Chemistry, University of Vienna, Althanstraße 14, A-1090 Vienna, Austria.
authors.forename: Gerhard F
authors.initials: GF
authors.lastname: Ecker
authors.affiliation: Department of Pharmacognosy, University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria.
authors.forename: Verena M
authors.initials: VM
authors.lastname: Dirsch
authors.affiliation: Department of Medicine I, Institute of Cancer Research, Comprehensive Cancer Centre Vienna, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Grusch
authors.affiliation: Department of Pharmacodynamics and Biopharmacy, University of Szeged, Eötvös u. 6, H-6720 Szeged, Hungary.
authors.forename: Istvan
authors.initials: I
authors.lastname: Zupko
authors.affiliation: Department of Pharmaceutical Chemistry, University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria.
authors.forename: Ernst
authors.initials: E
authors.lastname: Urban
authors.affiliation: Department of Pharmacognosy, University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Kopp
authors.affiliation: Department of Clinical Pathology, Medical University of Vienna, Waehringer Guertel 18-20, Austria. Electronic address: georg.krupitza@meduniwien.ac.at.
authors.forename: Georg
authors.initials: G
authors.lastname: Krupitza
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D019659:Asteraceae / Q000737:chemistry*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D018922:HL-60 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D010936:Plant Extracts / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012503:Saponins / Q000494:pharmacology; D045787:Sesquiterpenes, Eudesmane / Q000494:pharmacology*; D013150:Spirostans / Q000494:pharmacology
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C093414:PO-1; C093415:PO-2; D010936:Plant Extracts; D012503:Saponins; D045787:Sesquiterpenes, Eudesmane; D013150:Spirostans; C015872:eudesmane
keywords: Anti-metastatic; Anti-neoplastic; CAS registry number: 210583-18-9; Lead compound