Practical uses for ecdysteroids in mammals including humans: an update

Abstract

Ecdysteroids are widely used as inducers for gene-switch systems based on insect ecdysteroid receptors and genes of interest placed under the control of ecdysteroid-response elements. We review here these systems, which are currently mainly used in vitro with cultured cells in order to analyse the role of a wide array of genes, but which are expected to represent the basis for future gene therapy strategies. Such developments raise several questions, which are addressed in detail.

First, the metabolic fate of ecdysteroids in mammals, including humans, is only poorly known, and the rapid catabolism of ecdysteroids may impede their use as in vivo inducers.

A second set of questions arose in fact much earlier with the pioneering “heterophylic” studies of Burdette in the early sixties on the pharmacological effects of ecdysteroids on mammals. These and subsequent studies showed a wide range of effects, most of them being beneficial for the organism (e.g. hypoglycaemic, hypocholesterolaemic, anabolic). These effects are reviewed and critically analysed, and some hypotheses are proposed to explain the putative mechanisms involved.

All of these pharmacological effects have led to the development of a wide array of ecdysteroid-containing preparations, which are primarily used for their anabolic and/or “adaptogenic” properties on humans (or horses or dogs). In the same way, increasing numbers of patents have been deposited concerning various beneficial effects of ecdysteroids in many medical or cosmetic domains, which make ecdysteroids very attractive candidates for several practical uses.

It may be questioned whether all these pharmacological actions are compatible with the development of ecdysteroid-inducible gene switches for gene therapy, and also if ecdysteroids should be classified among doping substances.

Abbreviation:
20E	20-hydroxyecdysone
2d20E	2-deoxy-20-hydroxyecdysone
2dE	2-deoxyecdysone
BAH	bisacylhydrazine
BmEcR	Bombyx mori EcR
CfEcR	Choristoneura fumiferana EcR
CfUSP	Choristoneura fumiferana USP
CHO	Chinese hamster ovary
CMV	cytomegalovirus
DBD	DNA-binding domain
DmEcR	Drosophila melanogaster EcR
AbbE	ecdysone
EcR	ecdysteroid receptor
EcRE	ecdysteroid response element
EHT	effective half-time
ERE	oestrogen response element
GR	glucocorticoid receptor
GRE	glucocorticoid response element
HEK	human embryonic kidney
HvEcR	Heliothis virescens EcR
LBD	ligand binding domain
murA	muristerone A
PKA	protein kinase A
polB	polypodine B
ponA	ponasterone A
PPAR	peroxisome proliferator-activated receptor
RAR	retinoic acid receptor
RXR	retinoid X receptor
TR	thyroid receptor
USP	ultraspiracle
VDR	vitamin D receptor
VEGF	vascular endothelial growth factor