title: Ophiobolin A, a sesterterpenoid fungal phytotoxin, displays higher in vitro growth-inhibitory effects in mammalian than in plant cells and displays in vivo antitumor activity.
abstract: Ophiobolin A, a sesterterpenoid produced by plant pathogenic fungi, was purified from the culture extract of Drechslera gigantea and tested for its growth-inhibitory activity in both plant and mammalian cells. Ophiobolin A induced cell death in Nicotiana tabacum L. cv. Bright Yellow 2 (TBY-2) cells at concentrations ≥10 µM, with the TBY-2 cells showing typical features of apoptosis-like cell death. At a concentration of 5 µM, ophiobolin A did not affect plant cell viability but prevented cell proliferation. When tested on eight cancer cell lines, concentrations <1 µM of ophiobolin A inhibited growth by 50% after 3 days of culture irrespective of their multidrug resistance (MDR) phenotypes and their resistance levels to pro-apoptotic stimuli. It is, thus, unlikely that ophiobolin A exerts these in vitro growth-inhibitory effects in cancer cells by activating pro-apoptotic processes. Highly proliferative human keratinocytes appeared more sensitive to the growth-inhibitory effects of ophiobolin A than slowly proliferating ones. Ophiobolin A also displayed significant antitumor activity at the level of mouse survival when assayed at 10 mg/kg in the B16F10 mouse melanoma model with lung pseudometastases. Ophiobolin A could, thus, represent a novel scaffold to combat cancer types that display various levels of resistance to pro-apoptotic stimuli and/or various MDR phenotypes.
authors.affiliation: Laboratoire de Toxicologie, Faculté de Pharmacie, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Marina
authors.initials: M
authors.lastname: Bury
authors.forename: Esther
authors.initials: E
authors.lastname: Novo-Uzal
authors.forename: Anna
authors.initials: A
authors.lastname: Andolfi
authors.forename: Sara
authors.initials: S
authors.lastname: Cimini
authors.forename: Nathalie
authors.initials: N
authors.lastname: Wauthoz
authors.forename: Petra
authors.initials: P
authors.lastname: Heffeter
authors.forename: Benjamin
authors.initials: B
authors.lastname: Lallemand
authors.forename: Fabiana
authors.initials: F
authors.lastname: Avolio
authors.forename: Cédric
authors.initials: C
authors.lastname: Delporte
authors.forename: Alessio
authors.initials: A
authors.lastname: Cimmino
authors.forename: Jacques
authors.initials: J
authors.lastname: Dubois
authors.forename: Pierre
authors.initials: P
authors.lastname: Van Antwerpen
authors.forename: Maria Chiara
authors.initials: MC
authors.lastname: Zonno
authors.forename: Maurizio
authors.initials: M
authors.lastname: Vurro
authors.forename: Yves
authors.initials: Y
authors.lastname: Poumay
authors.forename: Walter
authors.initials: W
authors.lastname: Berger
authors.forename: Antonio
authors.initials: A
authors.lastname: Evidente
authors.forename: Laura
authors.initials: L
authors.lastname: De Gara
authors.forename: Robert
authors.initials: R
authors.lastname: Kiss
authors.forename: Vittoria
authors.initials: V
authors.lastname: Locato
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy*; D059828:Plant Cells / Q000187:drug effects; D054830:Sesterterpenes / Q000494:pharmacology*; D014026:Nicotiana / Q000166:cytology
chemical_list: D000970:Antineoplastic Agents; D054830:Sesterterpenes; C040764:ophiobolin A; D006861:Hydrogen Peroxide