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: Marina Bury, Esther Novo-Uzal, Anna Andolfi, Sara Cimini, Nathalie Wauthoz, Petra Heffeter, Benjamin Lallemand, Fabiana Avolio, Cédric Delporte, Alessio Cimmino, Jacques Dubois, Pierre Van Antwerpen, Maria Chiara Zonno, Maurizio Vurro, Yves Poumay, Walter Berger, Antonio Evidente, Laura De Gara, Robert Kiss, Vittoria Locato
• Journal: International journal of oncology (Int J Oncol) Vol. 43 Issue 2 Pg. 575-85 (Aug 2013) ISSN: 1791-2423 [Electronic] Greece
• PMID: 23754298 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Sesterterpenes
• ophiobolin A
• Hydrogen Peroxide

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Drug Resistance, Neoplasm
• Female
• Humans
• Hydrogen Peroxide (metabolism)
• Keratinocytes (drug effects, metabolism)
• Mice
• Neoplasms (drug therapy)
• Plant Cells (drug effects)
• Sesterterpenes (pharmacology)
• Tobacco (cytology)