Amelioration of an undesired action of deguelin.
The pharmaceutical world has greatly benefited from the well-characterized structure-function relationships of toxins with endogenous biomolecules, such as ion-channels, receptors, and signaling molecules. Thus, therapeutics derived from toxins have been aggressively pursued. However, the multifunctional role of various toxins may lead to undesirable off-target effects, hindering their use as therapeutic agents. In this paper, we suggest that previously unsuccessful toxins (due to off-target effects) may be revisited with mixtures by utilizing the pharmacodynamic response to the potential primary therapeutic as a starting point for finding new targets to ameliorate the unintended responses. In this proof of principle study, the pharmacodynamic response of HepG2 cells to a potential primary therapeutic (deguelin, a plant-derived chemopreventive agent) was monitored, and a possible secondary target (p38MAPK) was identified. As a single agent, deguelin decreased cellular viability at higher doses (>10 μM), but inhibited oxygen consumption over a wide dosing range (1.0-100 μM). Our results demonstrate that inhibition of oxygen consumption is related to an increase in p38MAPK phosphorylation, and may only be an undesired side effect of deguelin (i.e., one that does not contribute to the decrease in HepG2 viability). We further show that deguelin's negative effect on oxygen consumption can be diminished while maintaining efficacy when used as a therapeutic mixture with the judiciously selected secondary inhibitor (SB202190, p38MAPK inhibitor). These preliminary findings suggest that an endogenous response-directed mixtures approach, which uses a pharmacodynamic response to a primary therapeutic to determine a secondary target, allows previously unsuccessful toxins to be revisited as therapeutic mixtures.
C. Eugene Bennett Department of Chemistry, West Virginia University, 217 Clark Hall, Prospect Street, P.O. Box 6045, Morgantown, WV 26506, United States.
Julie A
JA
Vrana
Nathan
N
Boggs
Holly N
HN
Currie
Jonathan
J
Boyd
D017209:Apoptosis / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D056945:Hep G2 Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D010100:Oxygen / Q000378:metabolism; D010766:Phosphorylation; D010936:Plant Extracts / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D012402:Rotenone / Q000031:analogs & derivatives* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D004791:Enzyme Inhibitors; D007093:Imidazoles; D010936:Plant Extracts; D011725:Pyridines; D012402:Rotenone; D048051:p38 Mitogen-Activated Protein Kinases; C107676:deguelin; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole; D010100:Oxygen
Deguelin; Pharmacodynamics; Plant-derived therapeutics; Therapeutic mixtures